2021/12/28 更新

写真a

タザワ ヒロシ
田澤 大
TAZAWA Hiroshi
所属
岡山大学病院 准教授
職名
准教授
外部リンク

学位

  • 医学博士 ( 秋田大学 )

研究キーワード

  • 消化器外科学

  • 遺伝子治療学

研究分野

  • ライフサイエンス / 消化器外科学

  • ライフサイエンス / 腫瘍診断、治療学

学歴

  • 秋田大学    

    1996年4月 - 2000年3月

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  • 秋田大学   School of Medicine   School of Medicine

    1989年4月 - 1995年3月

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  • 富山県立高岡高等学校     普通科

    1986年4月 - 1989年3月

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経歴

  • 岡山大学   新医療研究開発センター 探索的医薬品開発室   准教授

    2016年7月 - 現在

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  • 岡山大学   新医療研究開発センター 探索的医薬品開発室   助教

    2011年10月 - 2016年6月

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  • 岡山大学   遺伝子・細胞治療センター   助教

    2010年4月 - 2011年9月

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  • 岡山大学   Graduate School of Medicine , Dentistry and Pharmaceutical Sciences   特任助教

    2007年12月 - 2010年3月

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  • 国立がんセンター研究所   生化学部   研究員

    2005年2月 - 2007年11月

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  • WHO国際癌研究機関(IARC、フランス)   内因性発癌リスク因子部門   客員研究員

    2002年4月 - 2005年1月

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  • 山形県鶴岡協立病院   外科   医員

    2000年4月 - 2002年3月

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  • 北海道大学   病理部門

    1998年4月 - 2000年3月

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  • 秋田大学   第ニ外科

    1997年4月 - 1998年3月

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  • 秋田県厚生連雄勝中央病院   外科   研修医

    1995年4月 - 1997年3月

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▼全件表示

所属学協会

▼全件表示

委員歴

  • 日本癌学会   評議員  

    2019年1月 - 現在   

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    団体区分:学協会

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  • 日本遺伝子細胞治療学会   評議員  

    2017年7月 - 現在   

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    団体区分:学協会

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論文

  • Oncolytic virotherapy reverses chemoresistance in osteosarcoma by suppressing MDR1 expression. 査読 国際誌

    Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Yusuke Mochizuki, Hiroya Kondo, Shuhei Osaki, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Koji Ueda, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancer chemotherapy and pharmacology   88 ( 3 )   513 - 524   2021年9月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Osteosarcoma (OS) is a malignant bone tumor primarily affecting children and adolescents. The prognosis of chemotherapy-refractory OS patients is poor. We developed a tumor suppressor p53-expressing oncolytic adenovirus (OBP-702) that exhibits antitumor effects against human OS cells. Here, we demonstrate the chemosensitizing effect of OBP-702 in human OS cells. MATERIALS AND METHODS: The in vitro and in vivo antitumor activities of doxorubicin (DOX) and OBP-702 were assessed using parental and DOX-resistant OS cells (U2OS, MNNG/HOS) and a DOX-resistant MNNG/HOS xenograft tumor model. RESULTS: DOX-resistant OS cells exhibited high multidrug resistant 1 (MDR1) expression, which was suppressed by OBP-702 or MDR1 siRNA, resulting in enhanced DOX-induced apoptosis. Compared to monotherapy, OBP-702 and DOX combination therapy significantly suppressed tumor growth in the DOX-resistant MNNG/HOS xenograft tumor model. CONCLUSION: Our results suggest that MDR1 is an attractive therapeutic target for chemoresistant OS. Tumor-specific virotherapy is thus a promising strategy for reversing chemoresistance in OS patients via suppression of MDR1 expression.

    DOI: 10.1007/s00280-021-04310-5

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  • CSF1/CSF1R Signaling Inhibitor Pexidartinib (PLX3397) Reprograms Tumor-Associated Macrophages and Stimulates T-cell Infiltration in the Sarcoma Microenvironment. 査読 国際共著 国際誌

    Tomohiro Fujiwara, Mohamed A Yakoub, Andrew Chandler, Alexander B Christ, Guangli Yang, Ouathek Ouerfelli, Vinagolu K Rajasekhar, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Hiroshi Tazawa, Yildirim Dogan, Malcolm A S Moore, Toshiyoshi Fujiwara, Toshifumi Ozaki, Ed Purdue, John H Healey

    Molecular cancer therapeutics   20 ( 8 )   1388 - 1399   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Colony-stimulating factor 1 (CSF1) is a primary regulator of the survival, proliferation, and differentiation of monocyte/macrophage that sustains the protumorigenic functions of tumor-associated macrophages (TAMs). Considering current advances in understanding the role of the inflammatory tumor microenvironment, targeting the components of the sarcoma microenvironment, such as TAMs, is a viable strategy. Here, we investigated the effect of PLX3397 (pexidartinib) as a potent inhibitor of the CSF1 receptor (CSF1R). PLX3397 was recently approved by the Food and Drug Administration (FDA) to treat tenosynovial giant cell tumor and reprogram TAMs whose infiltration correlates with unfavorable prognosis of sarcomas. First, we confirmed by cytokine arrays of tumor-conditioned media (TCM) that cytokines including CSF1 are secreted from LM8 osteosarcoma cells and NFSa fibrosarcoma cells. The TCM, like CSF1, stimulated ERK1/2 phosphorylation in bone marrow-derived macrophages (BMDMs), polarized BMDMs toward an M2 (TAM-like) phenotype, and strikingly promoted BMDM chemotaxis. In vitro administration of PLX3397 suppressed pERK1/2 stimulation by CSF1 or TCM, and reduced M2 polarization, survival, and chemotaxis in BMDMs. Systemic administration of PLX3397 to the osteosarcoma orthotopic xenograft model significantly suppressed the primary tumor growth and lung metastasis, and thus improved metastasis-free survival. PLX3397 treatment concurrently depleted TAMs and FOXP3+ regulatory T cells and, surprisingly, enhanced infiltration of CD8+ T cells into the microenvironments of both primary and metastatic osteosarcoma sites. Our preclinical results show that PLX3397 has strong macrophage- and T-cell-modulating effects that may translate into cancer immunotherapy for bone and soft-tissue sarcomas.

    DOI: 10.1158/1535-7163.MCT-20-0591

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  • Phase I dose-escalation study of endoscopic intratumoral injection of OBP-301 (Telomelysin) with radiotherapy in oesophageal cancer patients unfit for standard treatments. 査読 国際誌

    Yasuhiro Shirakawa, Hiroshi Tazawa, Shunsuke Tanabe, Nobuhiko Kanaya, Kazuhiro Noma, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Shunsuke Kagawa, Kuniaki Katsui, Susumu Kanazawa, Yasuo Urata, Toshiyoshi Fujiwara

    European journal of cancer (Oxford, England : 1990)   153   98 - 108   2021年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    PURPOSE: OBP-301 (Telomelysin) is an attenuated type-5 adenovirus that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 sensitises human cancer cells to ionising radiation by inhibiting DNA repair, and radiation enhances coxsackievirus and adenovirus receptor-mediated OBP-301 infection on the contrary. We assessed OBP-301 with radiotherapy in oesophageal cancer patients unfit for standard chemoradiation treatments. METHODS: A phase I dose-escalation study of OBP-301 with radiotherapy was conducted in 13 histologically confirmed oesophageal cancer patients deemed unfit to undergo surgery or chemotherapy. Study treatment consisted of OBP-301 administration by intratumoural needle injection using a flexible endoscope on days 1, 18 and 32. Radiotherapy was administered concurrently over 6 weeks, beginning on day 4, to a total of 60 Gy. RESULTS: Of the 13 patients, 7, 3 and 3 patients were treated with 1010, 1011 and 1012 virus particles, respectively. Study group comprised 10 males and 3 females, with a median age of 82 years (range, 53-91 years). All patients developed a transient, self-limited lymphopenia. Distribution studies revealed transient virus shedding in the plasma. Eight patients had local complete response (CR); all of them exhibited no pathologically viable malignant cells in biopsy specimens, and 3 patients had a partial response. The objective response rate was 91.7%. The clinical CR rate was 83.3% in stage I and 60.0% in stage II/III. Histopathological examination revealed massive infiltration of CD8+ cells and increased PD-L1 expression. CONCLUSION: Multiple courses of endoscopic intratumoural OBP-301 injection with radiotherapy are feasible and provide clinical benefits in patients with oesophageal cancer unfit for standard treatments.

    DOI: 10.1016/j.ejca.2021.04.043

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  • Immuno-hyperthermia effected by antibody-conjugated nanoparticles selectively targets and eradicates individual cancer cells. 査読 国際共著 国際誌

    Tetsuya Kagawa, Yuki Matsumi, Hiromichi Aono, Toshiaki Ohara, Hiroshi Tazawa, Kunitoshi Shigeyasu, Shuya Yano, Sho Takeda, Yasuhiro Komatsu, Robert M Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

    Cell cycle (Georgetown, Tex.)   1 - 11   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Hyperthermia has been used for cancer therapy for along period of time, but has shown limited clinical efficacy. Induction-heating hyperthermia using the combination of magnetic nanoparticles (MNPs) and an alternating magnetic field (AMF), termed magnetic hyperthermia (MHT), has previously shown efficacy in an orthotopic mouse model of disseminated gastric cancer. In the present study, superparamagnetic iron oxide nanoparticles (SPIONs), atype of MNP, were conjugated with an anti-HER2 antibody, trastuzumab and termed anti-HER2-antibody-linked SPION nanoparticles (anti-HER2 SPIONs). Anti-HER2 SPIONs selectively targeted HER2-expressing cancer cells co-cultured along with normal fibroblasts and HER2-negative cancer cells and caused apoptosis only in the HER2-expressing individual cancer cells. The results of the present study show proof-of-concept of anovel hyperthermia technology, immuno-MHT for selective cancer therapy, that targets individual cancer cells.AbbreviationsAMF:alternating magnetic fieldDDW:double distilled waterDMEM:Dulbecco's Modified Eagle's Mediumf:frequencyFBS:fetal bovine serumFITC:Fluorescein isothiocyanateGFP:green fluorescent proteinH:amplitudeHsp:heat shock proteinMHT:magnetic hyperthermiaMNPs:magnetic nanoparticlesPI:propidium iodideRFP:red fluorescent proteinSPION:superparamagnetic iron oxide (Fe3O4) nanoparticle.

    DOI: 10.1080/15384101.2021.1915604

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  • Hyperthermia generated by magnetic nanoparticles for effective treatment of disseminated peritoneal cancer in an orthotopic nude-mouse model. 査読 国際共著 国際誌

    Yuki Matsumi, Tetsuya Kagawa, Shuya Yano, Hiroshi Tazawa, Kunitoshi Shigeyasu, Sho Takeda, Toshiaki Ohara, Hiromichi Aono, Robert M Hoffman, Toshiyoshi Fujiwara, Hiroyuki Kishimoto

    Cell cycle (Georgetown, Tex.)   1 - 12   2021年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Magnetic hyperthermia (MHT), which combines magnetic nanoparticles (MNPs) with an alternating magnetic field (AMF), holds promise as a cancer therapy. There have been many studies about hyperthermia, most of which have been performed by direct injection of MNPs into tumor tissues. However, there have been no reports of treating peritoneal disseminated disease with MHT to date. In the present study, we treated peritoneal metastasis of gastric cancer with MHT using superparamagnetic iron oxide (Fe3O4) nanoparticle (SPION) coated with carboxydextran as an MNP, in an orthotopic mouse model mimicking early peritoneal disseminated disease of gastric cancer. SPIONs of an optimal size were intraperitoneally administered, and an AMF (390 kHz, 28 kAm-1) was applied for 10 minutes, four times every three days. Three weeks after the first MHT treatment, the peritoneal metastases were significantly inhibited compared with the AMF-alone group or the untreated-control group. The results of the present study show that MHT can be applied as a new treatment option for disseminated peritoneal gastric cancer.Abbreviations: AMF: alternating magnetic field; Cy1: cytology-positive; DMEM: Dulbecco's Modified Eagle's Medium; FBS: fetal bovine serum; H&E: hematoxylin and eosin; HIPEC: hyperthermic intraperitoneal chemotherapy; MEM: Minimum Essential Medium; MHT: magnetic hyperthermia; MNPs: magnetic nanoparticles; P0: macroscopic peritoneal dissemination; RFP: red fluorescent protein; SPION: superparamagnetic iron oxide (Fe3O4) nanoparticle.

    DOI: 10.1080/15384101.2021.1919441

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  • Local oncolytic adenovirotherapy produces an abscopal effect via tumor-derived extracellular vesicles. 査読 国際誌

    Yoshihiko Kakiuchi, Shinji Kuroda, Nobuhiko Kanaya, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Chiaki Yagi, Ryoma Sugimoto, Yuki Hamada, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

    Molecular therapy   29 ( 10 )   2920 - 2930   2021年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Extracellular vesicles (EVs) play important roles in various intercellular communication processes. The abscopal effect is an interesting phenomenon in cancer treatment, in which immune activation is generally considered a main factor. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), and occasionally observed therapeutic effects on distal tumors after local treatment in immunodeficient mice. Here, we hypothesized that EVs may be involved in the abscopal effect of OBP-301. EVs isolated from the supernatant of HCT116 human colon carcinoma cells treated with OBP-301 were confirmed to contain OBP-301, and showed cytotoxic activity (apoptosis and autophagy) similar to OBP-301. In bilateral subcutaneous HCT116 and CT26 tumor models, intratumoral administration of OBP-301 produced potent antitumor effects on tumors that were not directly treated with OBP-301, involving direct mediation by tumor-derived EVs containing OBP-301. This indicates that immune activation is not the main factor in this abscopal effect. Moreover, tumor-derived EVs exhibited high tumor tropism in orthotopic HCT116 rectal tumors, in which adenovirus E1A and adenovirus type 5 proteins were observed in metastatic liver tumors after localized rectal tumor treatment. In conclusion, local treatment with OBP-301 has the potential to produce abscopal effects via tumor-derived EVs.

    DOI: 10.1016/j.ymthe.2021.05.015

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  • Oncolytic virotherapy promotes radiosensitivity in soft tissue sarcoma by suppressing anti-apoptotic MCL1 expression. 査読 国際誌

    Toshinori Omori, Hiroshi Tazawa, Yasuaki Yamakawa, Shuhei Osaki, Joe Hasei, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    PloS one   16 ( 4 )   e0250643   2021年4月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Soft tissue sarcoma (STS) is a rare cancer that develops from soft tissues in any part of the body. Despite major advances in the treatment of STS, patients are often refractory to conventional radiotherapy, leading to poor prognosis. Enhancement of sensitivity to radiotherapy would therefore improve the clinical outcome of STS patients. We previously revealed that the tumor-specific, replication-competent oncolytic adenovirus OBP-301 kills human sarcoma cells. In this study, we investigated the radiosensitizing effect of OBP-301 in human STS cells. The in vitro antitumor effect of OBP-301 and ionizing radiation in monotherapy or combination therapy was assessed using highly radiosensitive (RD-ES and SK-ES-1) and moderately radiosensitive (HT1080 and NMS-2) STS cell lines. The expression of markers for apoptosis and DNA damage were evaluated in STS cells after treatment. The therapeutic potential of combination therapy was further analyzed using SK-ES-1 and HT1080 cells in subcutaneous xenograft tumor models. The combination of OBP-301 and ionizing radiation showed a synergistic antitumor effect in all human STS cell lines tested, including those that show different radiosensitivity. OBP-301 was found to enhance irradiation-induced apoptosis and DNA damage via suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1), which was expressed at higher levels in moderately radiosensitive cell lines. The combination of OBP-301 and ionizing radiation showed a more profound antitumor effect compared to monotherapy in SK-ES-1 (highly radiosensitive) and HT1080 (moderately radiosensitive) subcutaneous xenograft tumors. OBP-301 is a promising antitumor reagent to improve the therapeutic potential of radiotherapy by increasing radiation-induced apoptosis in STS.

    DOI: 10.1371/journal.pone.0250643

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  • Nanog is a promising chemo-resistant stemness marker and therapeutic target by iron chelators for esophageal cancer. 査読 国際誌

    Toru Narusaka, Toshiaki Ohara, Kazuhiro Noma, Noriyuki Nishiwaki, Yuki Katsura, Takuya Kato, Hiroaki Sato, Yasuko Tomono, Satoru Kikuchi, Hiroshi Tazawa, Yasuhiro Shirakawa, Akihiro Matsukawa, Toshiyoshi Fujiwara

    International journal of cancer   149 ( 2 )   347 - 357   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Esophageal cancer is a disease showing poor prognosis. Although combination chemotherapy using cisplatin and 5-fluorouracil is standard for unresectable esophageal cancer, the response rate is 35%. Cancer stem cells (CSCs) and inflammation are reportedly responsible for the poor prognosis of esophageal cancer. However, comprehensive analyses have not been conducted and proposals for progress remain lacking. Iron is known to be a key factor in the stemness of CSCs. This study focused on the therapeutic potential of iron control using iron chelators for CSCs in esophageal cancer. Among 134 immunohistochemically analyzed cases, Nanog expression was high in 98 cases and low in 36 cases. High Nanog expression correlated with low overall and disease-free survivals. The iron chelators deferasirox (DFX) and SP10 suppressed the proliferation and expression of stemness markers in TE8 and OE33 cells. DFX and SP10 did not induce compensatory interleukin (IL)-6 secretion, although cisplatin did result in high induction. Moreover, BBI608 and SSZ, as other CSC-targeting drugs, could not suppress the expression of stemness markers. Together, Nanog expression appears related to poor prognosis in esophageal cancer patients, and inhibition of stemness and compensatory IL-6 secretion by iron chelators may offer a novel therapeutic strategy for esophageal cancer.

    DOI: 10.1002/ijc.33544

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  • Role of Tumor-Associated Macrophages in Sarcomas. 招待 査読 国際共著 国際誌

    Tomohiro Fujiwara, John Healey, Koichi Ogura, Aki Yoshida, Hiroya Kondo, Toshiaki Hata, Miho Kure, Hiroshi Tazawa, Eiji Nakata, Toshiyuki Kunisada, Toshiyoshi Fujiwara, Toshifumi Ozaki

    Cancers   13 ( 5 )   1086   2021年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Sarcomas are complex tissues in which sarcoma cells maintain intricate interactions with their tumor microenvironment. Tumor-associated macrophages (TAMs) are a major component of tumor-infiltrating immune cells in the tumor microenvironment and have a dominant role as orchestrators of tumor-related inflammation. TAMs promote tumor growth and metastasis, stimulate angiogenesis, mediate immune suppression, and limit the antitumor activity of conventional chemotherapy and radiotherapy. Evidence suggests that the increased infiltration of TAMs and elevated expression of macrophage-related genes are associated with poor prognoses in most solid tumors, whereas evidence of this in sarcomas is limited. Based on these findings, TAM-targeted therapeutic strategies, such as inhibition of CSF-1/CSF-1R, CCL2/CCR2, and CD47/SIRPα, have been developed and are currently being evaluated in clinical trials. While most of the therapeutic challenges that target sarcoma cells have been unsuccessful and the prognosis of sarcomas has plateaued since the 1990s, several clinical trials of these strategies have yielded promising results and warrant further investigation to determine their translational benefit in sarcoma patients. This review summarizes the roles of TAMs in sarcomas and provides a rationale and update of TAM-targeted therapy as a novel treatment approach for sarcomas.

    DOI: 10.3390/cancers13051086

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  • Targeting neutrophil extracellular traps with thrombomodulin prevents pancreatic cancer metastasis. 査読 国際誌

    Hiroki Kajioka, Shunsuke Kagawa, Atene Ito, Masashi Yoshimoto, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Yuzo Umeda, Kazuhiro Noma, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Cancer letters   497   1 - 13   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Surgery is the only curative treatment option for pancreatic cancer, but patients often develop postoperative recurrence. Surgical invasiveness might be involved in the mechanism of recurrence. The associations among inflammation caused by surgery, neutrophils, and cancer metastasis were investigated. At first, neutrophil extracellular traps (NETs) were examined in clinical specimens, and NETs were observed around metastatic tumors. To explore how NETs were induced, neutrophils were cultured with pancreatic cancer or in cancer-conditioned medium. Neutrophils formed NETs when they were cultured with pancreatic cancer or even its conditioned medium. The effects of NETs on cancer cells were further investigated in vitro and in vivo. NETs induced the epithelial to mesenchymal transition in cancer cells and thereby promoted their migration and invasion. HMGB1 derived from NETs appeared to potentiate the malignancy of cancer cells. In a mouse model of liver metastasis with inflammation, NETs participated in the metastatic process by enhancing extravasation. Interestingly, thrombomodulin degraded HMGB1 and consequently inhibited the induction of NETs, thereby preventing pancreatic cancer metastasis to the liver. In conclusion, NETs interact reciprocally with pancreatic cancer cells, which play a pivotal role in inflammation-associated metastasis. Targeting NETs with thrombomodulin can be a novel strategy to improve the surgical outcome of pancreatic cancer patients.

    DOI: 10.1016/j.canlet.2020.10.015

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  • Extracellular vesicles shed from gastric cancer mediate protumor macrophage differentiation. 査読 国際誌

    Atene Ito, Shunsuke Kagawa, Shuichi Sakamoto, Kazuya Kuwada, Hiroki Kajioka, Masashi Yoshimoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Toshiyoshi Fujiwara

    BMC cancer   21 ( 1 )   102 - 102   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    BACKGROUND: Peritoneal dissemination often develops in gastric cancer. Tumor-associated macrophages (TAMs) are present in the peritoneal cavity of gastric cancer patients with peritoneal dissemination, facilitating tumor progression. However, the mechanism by which macrophages differentiate into tumor-associated macrophages in the peritoneal cavity is not well understood. In this study, the interplay between gastric cancer-derived extracellular vesicles (EVs) and macrophages was investigated. METHODS: The association between macrophages and EVs in peritoneal ascitic fluid of gastric cancer patients, or from gastric cancer cell lines was examined, and their roles in differentiation of macrophages and potentiation of the malignancy of gastric cancer were further explored. RESULTS: Immunofluorescent assays of the ascitic fluid showed that M2 macrophages were predominant along with the cancer cells in the peritoneal cavity. EVs purified from gastric cancer cells, as well as malignant ascitic fluid, differentiated peripheral blood mononuclear cell-derived macrophages into the M2-like phenotype, which was demonstrated by their morphology and expression of CD163/206. The macrophages differentiated by gastric cancer-derived EVs promoted the migration ability of gastric cancer cells, and the EVs carried STAT3 protein. CONCLUSION: EVs derived from gastric cancer play a role by affecting macrophage phenotypes, suggesting that this may be a part of the underlying mechanism that forms the intraperitoneal cancer microenvironment.

    DOI: 10.1186/s12885-021-07816-6

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  • Fibroblast activation protein targeted near infrared photoimmunotherapy (NIR PIT) overcomes therapeutic resistance in human esophageal cancer. 査読 国際誌

    Ryoichi Katsube, Kazuhiro Noma, Toshiaki Ohara, Noriyuki Nishiwaki, Teruki Kobayashi, Satoshi Komoto, Hiroaki Sato, Hajime Kashima, Takuya Kato, Satoru Kikuchi, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    Scientific reports   11 ( 1 )   1693 - 1693   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer-associated fibroblasts (CAFs) have an important role in the tumor microenvironment. CAFs have the multifunctionality which strongly support cancer progression and the acquisition of therapeutic resistance by cancer cells. Near-infrared photoimmunotherapy (NIR-PIT) is a novel cancer treatment that uses a highly selective monoclonal antibody (mAb)-photosensitizer conjugate. We developed fibroblast activation protein (FAP)-targeted NIR-PIT, in which IR700 was conjugated to a FAP-specific antibody to target CAFs (CAFs-targeted NIR-PIT: CAFs-PIT). Thus, we hypothesized that the control of CAFs could overcome the resistance to conventional chemotherapy in esophageal cancer (EC). In this study, we evaluated whether EC cell acquisition of stronger malignant characteristics and refractoriness to chemoradiotherapy are mediated by CAFs. Next, we assessed whether the resistance could be rescued by eliminating CAF stimulation by CAFs-PIT in vitro and in vivo. Cancer cells acquired chemoradiotherapy resistance via CAF stimulation in vitro and 5-fluorouracil (FU) resistance in CAF-coinoculated tumor models in vivo. CAF stimulation promoted the migration/invasion of cancer cells and a stem-like phenotype in vitro, which were rescued by elimination of CAF stimulation. CAFs-PIT had a highly selective effect on CAFs in vitro. Finally, CAF elimination by CAFs-PIT in vivo demonstrated that the combination of 5-FU and NIR-PIT succeeded in producing 70.9% tumor reduction, while 5-FU alone achieved only 13.3% reduction, suggesting the recovery of 5-FU sensitivity in CAF-rich tumors. In conclusion, CAFs-PIT could overcome therapeutic resistance via CAF elimination. The combined use of novel targeted CAFs-PIT with conventional anticancer treatments can be expected to provide a more effective and sensible treatment strategy.

    DOI: 10.1038/s41598-021-81465-4

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  • Real-Time Fluorescence Image-Guided Oncolytic Virotherapy for Precise Cancer Treatment. 招待 査読 国際共著 国際誌

    Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman

    International journal of molecular sciences   22 ( 2 )   879   2021年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Oncolytic virotherapy is one of the most promising, emerging cancer therapeutics. We generated three types of telomerase-specific replication-competent oncolytic adenovirus: OBP-301; a green fluorescent protein (GFP)-expressing adenovirus, OBP-401; and Killer-Red-armed OBP-301. These oncolytic adenoviruses are driven by the human telomerase reverse transcriptase (hTERT) promoter; therefore, they conditionally replicate preferentially in cancer cells. Fluorescence imaging enables visualization of invasion and metastasis in vivo at the subcellular level; including molecular dynamics of cancer cells, resulting in greater precision therapy. In the present review, we focused on fluorescence imaging applications to develop precision targeting for oncolytic virotherapy. Cell-cycle imaging with the fluorescence ubiquitination cell cycle indicator (FUCCI) demonstrated that combination therapy of an oncolytic adenovirus and a cytotoxic agent could precisely target quiescent, chemoresistant cancer stem cells (CSCs) based on decoying the cancer cells to cycle to S-phase by viral treatment, thereby rendering them chemosensitive. Non-invasive fluorescence imaging demonstrated that complete tumor resection with a precise margin, preservation of function, and prevention of distant metastasis, was achieved with fluorescence-guided surgery (FGS) with a GFP-reporter adenovirus. A combination of fluorescence imaging and laser ablation using a KillerRed-protein reporter adenovirus resulted in effective photodynamic cancer therapy (PDT). Thus, imaging technology and the designer oncolytic adenoviruses may have clinical potential for precise cancer targeting by indicating the optimal time for administering therapeutic agents; accurate surgical guidance for complete resection of tumors; and precise targeted cancer-specific photosensitization.

    DOI: 10.3390/ijms22020879

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  • Telomerase-specific oncolytic immunotherapy for promoting efficacy of PD-1 blockade in osteosarcoma. 査読 国際誌

    Yusuke Mochizuki, Hiroshi Tazawa, Koji Demiya, Miho Kure, Hiroya Kondo, Tadashi Komatsubara, Kazuhisa Sugiu, Joe Hasei, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancer immunology, immunotherapy   70 ( 5 )   1405 - 1417   2020年11月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Immune checkpoint inhibitors including anti-programmed cell death 1 (PD-1) antibody have recently improved clinical outcome in certain cancer patients; however, osteosarcoma (OS) patients are refractory to PD-1 blockade. Oncolytic virotherapy has emerged as novel immunogenic therapy to augment antitumor immune response. We developed a telomerase-specific replication-competent oncolytic adenovirus OBP-502 that induces lytic cell death via binding to integrins. In this study, we assessed the combined effect of PD-1 blockade and OBP-502 in OS cells. The expression of coxsackie and adenovirus receptor (CAR), integrins αvβ3 and αvβ5, and programmed cell death ligand 1 (PD-L1) was analyzed in two murine OS cells (K7M2, NHOS). The cytopathic activity of OBP-502 in both cells was analyzed using the XTT assay. OBP-502-induced immunogenic cell death was assessed by analyzing the level of extracellular ATP and high-mobility group box protein B1 (HMGB1). Subcutaneous tumor models for K7M2 and NHOS cells were used to evaluate the antitumor effect and number of tumor-infiltrating CD8+ cells in combination therapy. K7M2 and NHOS cells showed high expression of integrins αvβ3 and αvβ5, but not CAR. OBP-502 significantly suppressed the viability of both cells, in which PD-L1 expression and the release of ATP and HMGB1 were significantly increased. Intratumoral injection of OBP-502 significantly augmented the efficacy of PD-1 blockade on subcutaneous K2M2 and NHOS tumor models via enhancement of tumor-infiltrating CD8+  T cells. Our results suggest that telomerase-specific oncolytic virotherapy is a promising antitumor strategy to promote the efficacy of PD-1 blockade in OS.

    DOI: 10.1007/s00262-020-02774-7

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  • Boosting Replication and Penetration of Oncolytic Adenovirus by Paclitaxel Eradicate Peritoneal Metastasis of Gastric Cancer. 査読 国際誌

    Wataru Ishikawa, Satoru Kikuchi, Toshihiro Ogawa, Motoyasu Tabuchi, Hiroshi Tazawa, Shinji Kuroda, Kazuhiro Noma, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

    Molecular therapy oncolytics   18   262 - 271   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Peritoneal metastasis is the most frequent form of distant metastasis and recurrence in gastric cancer, and the prognosis is extremely poor due to the resistance of systemic chemotherapy. Here, we demonstrate that intraperitoneal (i.p.) administration of a green fluorescence protein (GFP)-expressing attenuated adenovirus with oncolytic potency (OBP-401) synergistically suppressed the peritoneal metastasis of gastric cancer in combination with paclitaxel (PTX). OBP-401 synergistically suppressed the viability of human gastric cancer cells in combination with PTX. PTX enhanced the antitumor effect of OBP-401 due to enhanced viral replication in cancer cells. The combination therapy increased induction of mitotic catastrophe, resulting in accelerated autophagy and apoptosis. Peritoneally disseminated nodules were selectively visualized as GFP-positive spots by i.p. administration of OBP-401 in an orthotopic human gastric cancer peritoneal dissemination model. PTX enhanced the deep penetration of OBP-401 into the disseminated nodules. Moreover, a non-invasive in vivo imaging system demonstrated that the combination therapy of i.p. OBP-401 administration with PTX significantly inhibited growth of peritoneal metastatic tumors and the amount of malignant ascites. i.p. virotherapy with PTX may be a promising treatment strategy for the peritoneal metastasis of gastric cancer.

    DOI: 10.1016/j.omto.2020.06.021

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  • Elimination of MYCN-Amplified Neuroblastoma Cells by Telomerase-Targeted Oncolytic Virus via MYCN Suppression. 査読 国際誌

    Terutaka Tanimoto, Hiroshi Tazawa, Takeshi Ieda, Hiroshi Nouso, Morimichi Tani, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara

    Molecular therapy oncolytics   18   14 - 23   2020年9月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Neuroblastoma (NB) is a primary malignant tumor of the peripheral sympathetic nervous system. High-risk NB is characterized by MYCN amplification and human telomerase reverse transcriptase (hTERT) rearrangement, contributing to hTERT activation and a poor outcome. For targeting hTERT-activated tumors, we developed two oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, in which the hTERT promoter drives expression of the viral E1 gene for tumor-specific virus replication. In this study, we demonstrate the therapeutic potential of the hTERT-driven oncolytic adenoviruses OBP-301 and OBP-702 using four human MYCN-amplified NB cell lines (IMR-32, CHP-134, NB-1, LA-N-5) exhibiting high hTERT expression. OBP-301 and OBP-702 exhibited a strong antitumor effect in association with autophagy in NB cells. Virus-mediated activation of E2F1 protein suppressed MYCN expression. OBP-301 and OBP-702 significantly suppressed the growth of subcutaneous CHP-134 tumors. Thus, these hTERT-driven oncolytic adenoviruses are promising antitumor agents for eliminating MYCN-amplified NB cells via E2F1-mediated suppression of MYCN protein.

    DOI: 10.1016/j.omto.2020.05.015

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  • FUCCI Real-Time Cell-Cycle Imaging as a Guide for Designing Improved Cancer Therapy: A Review of Innovative Strategies to Target Quiescent Chemo-Resistant Cancer Cells. 招待 査読 国際共著 国際誌

    Shuya Yano, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M Hoffman

    Cancers   12 ( 9 )   2655   2020年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Progress in chemotherapy of solid cancer has been tragically slow due, in large part, to the chemoresistance of quiescent cancer cells in tumors. The fluorescence ubiquitination cell-cycle indicator (FUCCI) was developed in 2008 by Miyawaki et al., which color-codes the phases of the cell cycle in real-time. FUCCI utilizes genes linked to different color fluorescent reporters that are only expressed in specific phases of the cell cycle and can, thereby, image the phases of the cell cycle in real-time. Intravital real-time FUCCI imaging within tumors has demonstrated that an established tumor comprises a majority of quiescent cancer cells and a minor population of cycling cancer cells located at the tumor surface or in proximity to tumor blood vessels. In contrast to most cycling cancer cells, quiescent cancer cells are resistant to cytotoxic chemotherapy, most of which target cells in S/G2/M phases. The quiescent cancer cells can re-enter the cell cycle after surviving treatment, which suggests the reason why most cytotoxic chemotherapy is often ineffective for solid cancers. Thus, quiescent cancer cells are a major impediment to effective cancer therapy. FUCCI imaging can be used to effectively target quiescent cancer cells within tumors. For example, we review how FUCCI imaging can help to identify cell-cycle-specific therapeutics that comprise decoy of quiescent cancer cells from G1 phase to cycling phases, trapping the cancer cells in S/G2 phase where cancer cells are mostly sensitive to cytotoxic chemotherapy and eradicating the cancer cells with cytotoxic chemotherapy most active against S/G2 phase cells. FUCCI can readily image cell-cycle dynamics at the single cell level in real-time in vitro and in vivo. Therefore, visualizing cell cycle dynamics within tumors with FUCCI can provide a guide for many strategies to improve cell-cycle targeting therapy for solid cancers.

    DOI: 10.3390/cancers12092655

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  • Oncolytic Virus-Mediated Targeting of the ERK Signaling Pathway Inhibits Invasive Propensity in Human Pancreatic Cancer. 査読 国際誌

    Takeshi Koujima, Hiroshi Tazawa, Takeshi Ieda, Hiroyuki Araki, Takuro Fushimi, Ryohei Shoji, Shinji Kuroda, Satoru Kikuchi, Ryuichi Yoshida, Yuzo Umeda, Fuminori Teraishi, Yasuo Urata, Hiroyuki Mizuguchi, Toshiyoshi Fujiwara

    Molecular therapy oncolytics   17   107 - 117   2020年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Pancreatic ductal adenocarcinoma (PDAC) cells have an exceptional ability to invade nerves through pronounced crosstalk between nerves and cancer cells; however, the mechanism of PDAC cell invasion remains to be elucidated. Here, we demonstrate the therapeutic potential of telomerase-specific oncolytic adenoviruses, OBP-301 and tumor suppressor p53-armed OBP-702, against human PDAC cells. Highly invasive PDAC cells exhibited higher levels of phosphorylated extracellular signal-regulated kinases 1 and 2 (ERK1/2) expression independent of KRAS expression; ERK1/2 inhibitor or small interfering RNA (siRNA) treatment significantly reduced the migration and invasion of PDAC cells, suggesting that the ERK signaling pathway is associated with the invasiveness of PDAC cells. OBP-702 infection suppressed ERK signaling and inhibited PDAC cell migration and invasion more efficiently than OBP-301. OBP-702 also effectively inhibited PDAC cell invasion even when invasiveness was enhanced by administration of motility stimulators, such as nerve and neurosecretory factors. Moreover, noninvasive whole-body imaging analyses showed that OBP-702 significantly suppressed tumor growth in an orthotopic PDAC xenograft model, although both viruses were equally effective against subcutaneous tumors, suggesting that OBP-702 can influence the orthotopic tumor microenvironment. Our data suggest that oncolytic virus-mediated disruption of ERK signaling is a promising antitumor strategy for attenuating the invasiveness of PDAC cells.

    DOI: 10.1016/j.omto.2020.03.016

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  • 骨肉腫に対する抗PD-1抗体の効果増強をめざした腫瘍融解ウイルス併用複合免疫療法の開発 招待

    望月 雄介, 田澤 大, 出宮 光二, 久禮 美穂, 長谷井 嬢, 中田 英二, 国定 俊之, 浦田 泰生, 藤原 俊義, 尾崎 敏文

    整形外科   71 ( 7 )   786 - 786   2020年6月

  • Immune Modulation by Telomerase-Specific Oncolytic Adenovirus Synergistically Enhances Antitumor Efficacy with Anti-PD1 Antibody. 査読 国際誌

    Nobuhiko Kanaya, Shinji Kuroda, Yoshihiko Kakiuchi, Kento Kumon, Tomoko Tsumura, Masashi Hashimoto, Toshiaki Morihiro, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Hiroyuki Mizuguchi, Yasuo Urata, Toshiyoshi Fujiwara

    Molecular therapy   28 ( 3 )   794 - 804   2020年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    The clinical benefit of monotherapy involving immune checkpoint inhibitors (ICIs) such as anti-programmed death-1 antibody (PD-1 Ab) is limited to small populations. We previously developed a telomerase-specific oncolytic adenovirus, Telomelysin (OBP-301), the safety of which was confirmed in a phase I clinical study. Here, we examined the potential of OBP-502, an OBP-301 variant, as an agent for inducing immunogenic cell death (ICD) and synergistically enhancing the efficacy of OBP-502 with PD-1 Ab using CT26 murine colon cancer and PAN02 murine pancreatic cancer cell lines. OBP-502 induced the release of ICD molecules such as adenosine triphosphate (ATP) and high-mobility group box protein 1 (HMGB1) from CT26 and PAN02 cells, leading to recruitment of CD8-positive lymphocytes and inhibition of Foxp3-positive lymphocyte infiltration into tumors. Combination therapy involving OBP-502 intratumoral administration and PD-1 Ab systemic administration significantly suppressed the growth of not only OBP-502-treated tumors but also tumors not treated with OBP-502 (so-called abscopal effect) in CT26 and PAN02 bilateral subcutaneous tumor models, in which active recruitment of CD8-positve lymphocytes was observed even in tumors not treated with OBP-502. This combined efficacy was similar to that observed in a CT26 rectal orthotopic tumor model involving liver metastases. In conclusion, telomerase-specific oncolytic adenoviruses are promising candidates for combined therapies with ICIs.

    DOI: 10.1016/j.ymthe.2020.01.003

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  • Bone and Soft-Tissue Sarcoma: A New Target for Telomerase-Specific Oncolytic Virotherapy. 招待 査読 国際誌

    Hiroshi Tazawa, Joe Hasei, Shuya Yano, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Cancers   12 ( 2 )   478   2020年2月

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    担当区分:筆頭著者, 責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adenovirus serotype 5 (Ad5) is widely and frequently used as a virus vector in cancer gene therapy and oncolytic virotherapy. Oncolytic virotherapy is a novel antitumor treatment for inducing lytic cell death in tumor cells without affecting normal cells. Based on the Ad5 genome, we have generated three types of telomerase-specific replication-competent oncolytic adenoviruses: OBP-301 (Telomelysin), green fluorescent protein (GFP)-expressing OBP-401 (TelomeScan), and tumor suppressor p53-armed OBP-702. These viruses drive the expression of the adenoviral E1A and E1B genes under the control of the hTERT (human telomerase reverse transcriptase-encoding gene) promoter, providing tumor-specific virus replication. This review focuses on the therapeutic potential of three hTERT promoter-driven oncolytic adenoviruses against bone and soft-tissue sarcoma cells with telomerase activity. OBP-301 induces the antitumor effect in monotherapy or combination therapy with chemotherapeutic drugs via induction of autophagy and apoptosis. OBP-401 enables visualization of sarcoma cells within normal tissues by serving as a tumor-specific labeling reagent for fluorescence-guided surgery via induction of GFP expression. OBP-702 exhibits a profound antitumor effect in OBP-301-resistant sarcoma cells via activation of the p53 signaling pathway. Taken together, telomerase-specific oncolytic adenoviruses are promising antitumor reagents that are expected to provide novel therapeutic options for the treatment of bone and soft-tissue sarcomas.

    DOI: 10.3390/cancers12020478

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  • Visualization of epithelial-mesenchymal transition in an inflammatory microenvironment-colorectal cancer network. 査読 国際誌

    Takeshi Ieda, Hiroshi Tazawa, Hiroki Okabayashi, Shuya Yano, Kunitoshi Shigeyasu, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Masahiko Nishizaki, Shunsuke Kagawa, Yasuhiro Shirakawa, Takashi Saitou, Takeshi Imamura, Toshiyoshi Fujiwara

    Scientific reports   9 ( 1 )   16378   2019年11月

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    担当区分:責任著者   記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Epithelial-mesenchymal transition (EMT) is a biological process by which epithelial cells acquire mesenchymal characteristics. In malignant tumors, EMT is crucial for acquisition of a mesenchymal phenotype with invasive and metastatic properties, leading to tumor progression. An inflammatory microenvironment is thought to be responsible for the development and progression of colorectal cancer (CRC); however, the precise role of inflammatory microenvironments in EMT-related CRC progression remains unclear. Here, we show the spatiotemporal visualization of CRC cells undergoing EMT using a fluorescence-guided EMT imaging system in which the mesenchymal vimentin promoter drives red fluorescent protein (RFP) expression. An inflammatory microenvironment including TNF-α, IL-1β, and cytokine-secreting inflammatory macrophages induced RFP expression in association with the EMT phenotype in CRC cells. In vivo experiments further demonstrated the distribution of RFP-positive CRC cells in rectal and metastatic tumors. Our data suggest that the EMT imaging system described here is a powerful tool for monitoring EMT in inflammatory microenvironment-CRC networks.

    DOI: 10.1038/s41598-019-52816-z

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  • トランスレーショナルリサーチとしての外科治療を補完する新たな集学的治療の開発研究 招待

    田澤 大, 田辺俊介, 香川俊輔, 白川靖博, 藤原俊義

    日本外科学会雑誌   120 ( 6 )   735 - 737   2019年11月

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    担当区分:筆頭著者, 責任著者   記述言語:日本語   掲載種別:研究論文(研究会,シンポジウム資料等)  

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  • Intraperitoneal cancer-immune microenvironment promotes peritoneal dissemination of gastric cancer 査読 国際誌

    Shuichi Sakamoto, Shunsuke Kagawa, Kazuya Kuwada, Atene Ito, Hiroki Kajioka, Yoshihiko Kakiuchi, Megumi Watanabe, Tetsuya Kagawa, Ryuichi Yoshida, Satoru Kikuchi, Shinji Kuroda, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Oncoimmunology   8 ( 12 )   e1671760   2019年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1080/2162402X.2019.1671760

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  • 蛍光イメージングによる新規がん治療戦略 招待

    矢野修也, 田澤 大, 香川俊輔, 藤原俊義

    メディカル・サイエンス・ダイジェスト   45 ( 7 )   427 - 429   2019年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • PD-L1 expression combined with microsatellite instability/CD8+ tumor infiltrating lymphocytes as a useful prognostic biomarker in gastric cancer. 査読 国際誌

    Toshiaki Morihiro, Shinji Kuroda, Nobuhiko Kanaya, Yoshihiko Kakiuchi, Tetsushi Kubota, Katsuyuki Aoyama, Takehiro Tanaka, Satoru Kikuchi, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Scientific reports   9 ( 1 )   4633   2019年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.1038/s41598-019-41177-2

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  • Activation of AZIN1 RNA editing is a novel mechanism that promotes invasive potential of cancer-associated fibroblasts in colorectal cancer. 査読 国際共著 国際誌

    Sho Takeda, Kunitoshi Shigeyasu, Yoshinaga Okugawa, Kazuhiro Yoshida, Yoshiko Mori, Shuya Yano, Kazuhiro Noma, Yuzo Umeda, Yoshitaka Kondo, Hiroyuki Kishimoto, Fuminori Teraishi, Takeshi Nagasaka, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Ajay Goel

    Cancer letters   444   127 - 135   2019年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adenosine-to-inosine (A-to-I) RNA editing is a recently described epigenetic modification, which is believed to constitute a key oncogenic mechanism in human cancers. However, its functional role in cancer-associated fibroblasts (CAFs) within the tumor microenvironment (TME) and its clinical significance remains unclear. Herein, we systematically analyzed a large cohort of 627 colorectal cancer (CRC) specimens, and investigated the expression pattern of ADAR1 and its biological significance on the antizyme inhibitor 1 (AZIN1) RNA editing levels. Both ADAR1 expression and AZIN1 RNA editing levels were significantly elevated in CRC tissues vs. normal mucosa, and these findings correlated with the increased expression of mesenchymal markers, Vimentin (ρ = 0.44) and Fibroblast activation protein (ρ = 0.38). Intriguingly, ADAR1 expression was specifically upregulated in both cancer cells and fibroblasts from cancerous lesions. Conditioned medium from cancer cells led to induction of ADAR1 expression and activation of AZIN1 RNA editing in fibroblasts (p < 0.05). Additionally, edited AZIN1 enhanced the invasive potential of fibroblasts. In conclusion, we provide novel evidence that hyper-editing of AZIN1 enhances the invasive potential of CAFs within the TME in colon and is an important predictor of tumor invasiveness in CRC.

    DOI: 10.1016/j.canlet.2018.12.009

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  • Cancer-associated fibroblasts (CAFs) promote the lymph node metastasis of esophageal squamous cell carcinoma. 査読 国際誌

    Hajime Kashima, Kazuhiro Noma, Toshiaki Ohara, Takuya Kato, Yuki Katsura, Satoshi Komoto, Hiroaki Sato, Ryoichi Katsube, Takayuki Ninomiya, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    International journal of cancer   144 ( 4 )   828 - 840   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Lymph node metastasis is a pathognomonic feature of spreading tumors, and overcoming metastasis is a challenge in attaining more favorable clinical outcomes. Esophageal cancer is an aggressive tumor for which lymph node metastasis is a strong poor prognostic factor, and the tumor microenvironment (TME), and cancer-associated fibroblasts (CAFs) in particular, has been implicated in esophageal cancer progression. CAFs play a central role in the TME and have been reported to provide suitable conditions for the progression of esophageal cancer, similar to their role in other malignancies. However, little is known concerning the relevance of CAFs to the lymph node metastasis of esophageal cancer. Here, we used clinical samples of esophageal cancer to reveal that CAFs promote lymph node metastasis and subsequently verified the intercellular relationships in vitro and in vivo using an orthotopic metastatic mouse model. In the analysis of clinical samples, FAP+ CAFs were strongly associated with lymph node metastasis rather than with other prognostic factors. Furthermore, CAFs affected the ability of esophageal cancer cells to acquire metastatic phenotypes in vitro; this finding was confirmed by data from an in vivo orthotopic metastatic mouse model showing that the number of lymph node metastases increased upon injection of cocultured cancer cells and CAFs. In summary, we verified in vitro and in vivo that the accumulation of CAFs enhances the lymph node metastasis of ESCC. Our data suggest that CAF targeted therapy can reduce lymph node metastasis and improve the prognosis of patients with esophageal cancer in the future.

    DOI: 10.1002/ijc.31953

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  • A Novel Combination Cancer Therapy with Iron Chelator Targeting Cancer Stem Cells via Suppressing Stemness. 査読 国際誌

    Yuki Katsura, Toshiaki Ohara, Kazuhiro Noma, Takayuki Ninomiya, Hajime Kashima, Takuya Kato, Hiroaki Sato, Satoshi Komoto, Toru Narusaka, Yasuko Tomono, Boyi Xing, Yuehua Chen, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

    Cancers   11 ( 2 )   177   2019年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Excess iron causes cancer and is thought to be related to carcinogenesis and cancer progression including stemness, but the details remain unclear. Here, we hypothesized that stemness in cancer is related to iron metabolism and that regulating iron metabolism in cancer stem cells (CSCs) may be a novel therapy. In this study, we used murine induced pluripotent stem cells that expressed specific stem cell genes such as Nanog, Oct3/4, Sox2, Klf4, and c-Myc, and two human cancer cell lines with similar stem cell gene expression. Deferasirox, an orally available iron chelator, suppressed expression of stemness markers and spherogenesis of cells with high stemness status in vitro. Combination therapy had a marked antitumor effect compared with deferasirox or cisplatin alone. Iron metabolism appears important for maintenance of stemness in CSCs. An iron chelator combined with chemotherapy may be a novel approach via suppressing stemness for CSC targeted therapy.

    DOI: 10.3390/cancers11020177

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  • Photoimmunotherapy for cancer-associated fibroblasts targeting fibroblast activation protein in human esophageal squamous cell carcinoma. 査読 国際共著 国際誌

    Shinichiro Watanabe, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Hiroaki Sato, Takuya Kato, Shinichi Urano, Ryoichi Katsube, Yuuri Hashimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    Cancer biology & therapy   20 ( 9 )   1234 - 1248   2019年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Cancer-associated fibroblasts (CAFs) are strongly implicated in tumor progression, including in the processes of tumorigenesis, invasion, and metastasis. The targeting of CAFs using various therapeutic approaches is a novel treatment strategy; however, the efficacy of such therapies remains limited. Recently, near-infrared photoimmunotherapy (NIR-PIT), which is a novel targeted therapy employing a cell-specific mAb conjugated to a photosensitizer, has been introduced as a new type of phototherapy. In this study, we have developed a novel NIR-PIT technique to target CAFs, by focusing on fibroblast activation protein (FAP), and we evaluate the treatment efficacy in vitro and in vivo. Esophageal carcinoma cells exhibited enhanced activation of fibroblasts, with FAP over-expressed in the cytoplasm and on the cell surface. FAP-IR700-mediated PIT showed induced rapid cell death specifically for those cells in vitro and in vivo, without adverse effects. This novel therapy for CAFs, designed as local control phototherapy, was safe and showed a promising inhibitory effect on FAP+ CAFs. PIT targeting CAFs via the specific marker FAP may be a therapeutic option for CAFs in the tumor microenvironment in the future.

    DOI: 10.1080/15384047.2019.1617566

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  • The epithelial-to-mesenchymal transition induced by tumor-associated macrophages confers chemoresistance in peritoneally disseminated pancreatic cancer 査読 国際誌

    Kazuya Kuwada, Shunsuke Kagawa, Ryuichi Yoshida, Shuichi Sakamoto, Atene Ito, Megumi Watanabe, Takeshi Ieda, Shinji Kuroda, Satoru Kikuchi, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Journal of experimental & clinical cancer research   37 ( 1 )   307   2018年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Background: The peritoneum is one of the most frequent metastatic sites in pancreatic cancer patients, and peritoneal dissemination makes this disease refractory due to aggressive progression and chemoresistance. Although the role of the tumor microenvironment in cancer development is recognized, the correlation between the peritoneal environment and refractoriness of peritoneal dissemination remains unclear. The intraperitoneal tumor-microenvironment and its potential role in the progression of peritoneal dissemination and chemo-refractoriness, focusing especially on macrophages, were investigated.
    Materials and methods: Peritoneal washes were obtained from pancreatic cancer patients, and cellular components were subjected to immunofluorescence assays. The effects of macrophages induced from monocytic THP-1 cells on pancreatic cancer cells were examined in co-culture conditions. The in vivo effects of macrophages on tumor growth and chemo-sensitivity were investigated by subcutaneously or intraperitoneally co-injecting cancer cells with macrophages into mice.
    Results: CD204-positive macrophages were present along with cancer cells in the peritoneal washes. In in vitro co-culture, tumor-associated macrophages affected pancreatic cancer cells, induced the epithelial-to-mesenchymal transition (EMT), and made them more resistant to chemotherapeutic agents. M2 macrophages promoted growth of both subcutaneous tumors and peritoneal dissemination in mice. Furthermore, co-inoculation of M2 macrophages conferred chemoresistance in the peritoneal dissemination mouse model, which significantly shortened their survival.
    Conclusion: Intraperitoneal tumor-associated macrophages potentially play an important role in promotion of peritoneal dissemination and chemoresistance of pancreatic cancer via EMT induction.

    DOI: 10.1186/s13046-018-0981-2

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  • Cancer-Associated Fibroblasts Affect Intratumoral CD8+ and FoxP3+ T Cells Via IL6 in the Tumor Microenvironment. 査読 国際誌

    Takuya Kato, Kazuhiro Noma, Toshiaki Ohara, Hajime Kashima, Yuki Katsura, Hiroaki Sato, Satoshi Komoto, Ryoichi Katsube, Takayuki Ninomiya, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    Clinical cancer research   24 ( 19 )   4820 - 4833   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Purpose: Cancer-associated fibroblasts (CAFs) in the tumor microenvironment (TME) play a central role in tumor progression. We investigated whether CAFs can regulate tumor-infiltrating lymphocytes (TILs) and their role in tumor immunosuppression.Experimental Design: A total of 140 cases of esophageal cancer were analyzed for CAFs and CD8+ or forkhead box protein 3 (FoxP3+) TILs by IHC. We analyzed cytokines using murine or human fibroblasts and cancer cells. Murine-derived fibroblasts and cancer cells were also inoculated into BALB/c or BALB/c-nu/nu mice and the tumors treated with recombinant IL6 or anti-IL6 antibody.Results: CD8+ TILs and CAFs were negatively correlated in intratumoral tissues (P < 0.001), whereas FoxP3+ TILs were positively correlated (P < 0.001) in esophageal cancers. Cocultured Colon26 cancer cells and fibroblasts resulted in accelerated tumor growth in BALB/c mice, along with decreased CD8+ and increased FoxP3+ TILs, compared with cancer cells alone. In vitro, IL6 was highly secreted in both murine and human cancer cell/fibroblast cocultures. IL6 significantly increased Colon26 tumor growth in immune-competent BALB/c (P < 0.001) with fewer CD8+ TILs than untreated tumors (P < 0.001), whereas no difference in BALB/c-nu/nu mice. In contrast, FoxP3+ TILs increased in IL6-treated tumors (P < 0.001). IL6 antibody blockade of tumors cocultured with fibroblasts resulted not only in regression of tumor growth but also in the accumulation of CD8+ TILs in intratumoral tissues.Conclusions: CAFs regulate immunosuppressive TIL populations in the TME via IL6. IL6 blockade, or targeting CAFs, may improve preexisting tumor immunity and enhance the efficacy of conventional immunotherapies. Clin Cancer Res; 24(19); 4820-33. ©2018 AACR.

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  • Integrated fluorescent cytology with nano-biologics in peritoneally disseminated gastric cancer 査読 国際誌

    Megumi Watanabe, Shunsuke Kagawa, Kazuya Kuwada, Yuuri Hashimoto, Kunitoshi Shigeyasu, Michihiro Ishida, Shuichi Sakamoto, Atene Ito, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Shuta Tomida, Ryuichi Yoshida, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

    Cancer science   109 ( 10 )   3263 - 3271   2018年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Gastric cancer patients positive for peritoneal cytology are at increased risk of tumor recurrence, but although a certain proportion of cytology-positive patients relapse rapidly with aggressive progression, others survive longer with conventional chemotherapies. This heterogeneity makes it difficult to stratify patients for more intensive therapy and poses a substantial challenge for the implementation of precision medicine. We developed a new approach to identify biologically malignant subpopulations in cytology-positive gastric cancer patients, using a green fluorescent protein (GFP)-expressing attenuated adenovirus in which the telomerase promoter regulates viral replication (TelomeScan, OBP-401). The fluorescence emitted from TelomeScan-positive cells was successfully quantified using a multi-mode microplate reader. We then analyzed clinical peritoneal washes obtained from 68 gastric cancer patients and found that patients positive for TelomeScan had a significantly worse prognosis. In 21 cytology-positive patients, the median survival time of those who were TelomeScan positive (235 days) was significantly shorter than that for those who were TelomeScan negative (671 days; P = 0.0062). This fluorescent virus-guided cytology detects biologically malignant cancer cells from the peritoneal washes of gastric cancer patients and may thus be useful for both therapy stratification and precision medicine approaches based on genetic profiling of disseminated cells.

    DOI: 10.1111/cas.13760

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  • 癌関連線維芽細胞が及ぼす腫瘍免疫逃避の解明 査読

    加藤 卓也, 野間 和広, 桂 佑貴, 佐藤 浩明, 河本 慧, 二宮 卓之, 大原 利章, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    癌と化学療法   45 ( 9 )   1279 - 1281   2018年9月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(株)癌と化学療法社  

    近年、免疫チェックポイント阻害薬をはじめがん免疫療法の発展により、飛躍的に予後の改善を認める癌腫が散見される。しかしながら、致命的な有害事象の発生や効果の得られる症例が限定的であることなど、克服すべき問題点も指摘されている。免疫チェックポイント阻害薬の治療効果予測因子として腫瘍浸潤リンパ球が注目されており、特に細胞傷害性T細胞の腫瘍内浸潤の程度が抗腫瘍効果に影響を与えていると報告されている。リンパ球の腫瘍浸潤においては、癌とがん微小環境の相互作用によって制御している可能性が指摘されている。そのなかで中心的な役割を担っている癌関連線維芽細胞(cancer-associated fibroblasts:CAFs)が注目されている。以前よりわれわれは、がん微小環境の強い関与を推測し、特にCAFsの作用に注目して癌の増殖・浸潤・血管新生・治療抵抗性について報告してきた。この度CAFsと腫瘍免疫に着目し、CAFsが寄与する腫瘍免疫抑制について検討している。今後、検討結果を随時報告する予定である。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2018&ichushi_jid=J00296&link_issn=&doc_id=20180920320008&doc_link_id=%2Fab8gtkrc%2F2018%2F004509%2F010%2F1279-1281%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2018%2F004509%2F010%2F1279-1281%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • HER2-targeted gold nanoparticles potentially overcome resistance to trastuzumab in gastric cancer 査読 国際誌

    Tetsushi Kubota, Shinji Kuroda, Nobuhiko Kanaya, Toshiaki Morihiro, Katsuyuki Aoyama, Yoshihiko Kakiuchi, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

    Nanomedicine : nanotechnology, biology, and medicine   14 ( 6 )   1919 - 1929   2018年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    An issue of concern is that no current HER2-targeted therapeutic agent is effective against Trastuzumab (Tmab)-resistant gastric cancer. Gold nanoparticles (AuNPs) are promising drug carriers with unique characteristics of a large surface area available for attachment of materials such as antibodies. Here, we created HER2-targeted AuNPs (T-AuNPs) and examined their therapeutic efficacy and cytotoxic mechanisms using HER2-postive Tmab-resistant (MKN7) or Tmab-sensitive (NCI-N87) gastric cancer cell lines. In vitro, T-AuNPs showed stronger cytotoxic effects than controls against MKN7 and NCI-N87 cells although Tmab had no effect on MKN7 cells. Autophagy played an important role in T-AuNP cytotoxic mechanisms, which was considered to be driven by internalization of T-AuNPs. Finally, T-AuNPs displayed potent antitumor effects against NCI-N87 and MKN7 subcutaneous tumors in in vivo mouse models. In conclusion, HER2-targeted AuNPs with conjugated Tmab is a promising strategy for the development of novel therapeutic agents to overcome Tmab resistance in gastric cancer.

    DOI: 10.1016/j.nano.2018.05.019

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  • 膵癌に対するウイルス療法の実用化に向けて 招待

    國府島 健, 田澤 大, 杭瀬 崇, 吉田 龍一, 楳田 祐三, 藤原 俊義

    消化器外科   41 ( 6 )   931 - 938   2018年5月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(株)へるす出版  

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  • Iron depletion is a novel therapeutic strategy to target cancer stem cells. 査読 国際誌

    Takayuki Ninomiya, Toshiaki Ohara, Kazuhiro Noma, Yuki Katsura, Ryoichi Katsube, Hajime Kashima, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Ling Chen, Tomonari Kasai, Masaharu Seno, Akihiro Matsukawa, Toshiyoshi Fujiwara

    Oncotarget   8 ( 58 )   98405 - 98416   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Adequate iron levels are essential for human health. However, iron overload can act as catalyst for the formation of free radicals, which may cause cancer. Cancer stem cells (CSCs), which maintain the hallmark stem cell characteristics of self-renewal and differentiation capacity, have been proposed as a driving force of tumorigenesis and metastases. In the present study, we investigated the role of iron in the proliferation and stemness of CSCs, using the miPS-LLCcm cell model. Although the anti-cancer agents fluorouracil and cisplatin suppressed the proliferation of miPS-LLCcm cells, these drugs did not alter the expression of stemness markers, including Nanog, SOX2, c-Myc, Oct3/4 and Klf4. In contrast, iron depletion by the iron chelators deferasirox and deferoxamine suppressed the proliferation of miPS-LLCcm cells and the expression of stemness markers. In an allograft model, deferasirox inhibited the growth of miPS-LLCcm implants, which was associated with decreased expression of Nanog and Sox2. Altogether, iron appears to be crucial for the proliferation and maintenance of stemness of CSCs, and iron depletion may be a novel therapeutic strategy to target CSCs.

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  • Therapeutic Cell-Cycle-Decoy Efficacy of a Telomerase-Dependent Adenovirus in an Orthotopic Model of Chemotherapy-Resistant Human Stomach Carcinomatosis Peritonitis Visualized With FUCCI Imaging 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    JOURNAL OF CELLULAR BIOCHEMISTRY   118 ( 11 )   3635 - 3642   2017年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    We have established an orthotopic nude-mouse model of gastric cancer carcinomatosis peritonitis, a recalcitrant disease in human patients. Human MKN45 poorly-differentiated human gastric cancer cells developed carcinomatosis peritonitis upon orthotopic transplantation in nude mice. The MKN45 cells expressed the fluorescent ubiquitination-based cell cycle indicator (FUCCI) that color codes the phases of the cell cycle. The intra-peritoneal tumors and ascites contained mostly quiescent G(1)/G(o) cancer cells visualized as red by FUCCI imaging. Cisplatinum (CDDP) treatment did not reduce bloody ascites, and larger tumors formed in the peritoneal cavity after CDDP treatment in an early-stage carcinomatosis peritonitis orthotopic mouse model. Paclitaxel-treated mice had reduced ascites, but also had large tumor masses in the peritonium after treatment with cancer cells mostly in G(0)/G(1), visualized by FUCCI red. In contrast, OBP-301 telomerase-dependent adenovirus-treated mice had no ascites and only small tumor nodules consisting of cancer cells mostly in S/G(2) phases in the early-stage carcinomatosis peritonitis model, visualized by FUCCI green. Furthermore, OBP-301 significantly reduced the size of tumors (P&lt;0.01) and ascites even in a late-stage carcinomatosis peritonitis model. These results suggest that quiescent peritoneally-disseminated gastric cancer cells are resistant to conventional chemotherapy, but OBP-301 significantly reduced the weight of the tumors and increased survival, suggesting clinical potential. J. Cell. Biochem. 118: 3635-3642, 2017. (c) 2016 Wiley Periodicals, Inc.

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  • Liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus with stealth effect on the immune system 査読 国際誌

    Katsuyuki Aoyama, Shinji Kuroda, Toshiaki Morihiro, Nobuhiko Kanaya, Tetsushi Kubota, Yoshihiko Kakiuchi, Satoru Kikuchi, Masahiko Nishizaki, Shunsuke Kagawa, Hiroshi Tazawa, Toshiyoshi Fujiwara

    SCIENTIFIC REPORTS   7 ( 1 )   2017年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Oncolytic virotherapy has the disadvantage of being unsuitable for systemic delivery due to immune elimination. Liposomal encapsulation is well-recognized to reduce immune elimination and enhance the stability of drugs in the bloodstream. In the present study, the potential of liposome-encapsulated plasmid DNA of telomerase-specific oncolytic adenovirus (TelomeScan) expressing GFP (Lipo-pTS) as an oncolytic adenoviral agent suitable for systemic delivery was investigated. Lipo-pTS, which has a diameter of 40-50 nm, showed potent antitumor effects on HCT116 colon carcinoma cells in vitro and in vivo. Tumor selectivity of Lipo-pTS was independent of coxsackie and adenovirus receptor (CAR). Importantly, Lipo-pTS reduced production of adenovirus-neutralizing antibodies (AdNAbs) after intravenous administration into immune-competent mice compared to TelomeScan, and even in the presence of AdNAbs, Lipo-pTS maintained strong cytotoxicity. In conclusion, Lipo-pTS has the potential to become an oncolytic adenoviral agent suitable for systemic delivery with the characteristics of CAR-independent antitumor activity and a stealth effect on the immune system.

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  • Role of zoledronic acid in oncolytic virotherapy: Promotion of antitumor effect and prevention of bone destruction 査読

    Yasuaki Yamakawa, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER SCIENCE   108 ( 9 )   1870 - 1880   2017年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY  

    Osteosarcoma is an aggressive malignant bone tumor that causes bone destruction. Although tumor-specific replicating oncolytic adenovirus OBP-301 induces an antitumor effect in an osteosarcoma tumor, it cannot prevent bone destruction. Zoledronic acid (ZOL) is a clinically available agent that inhibits bone destruction. In this study, we investigated the potential of combination therapy with OBP-301 and ZOL against osteosarcomas with bone destruction. The antitumor activity of OBP-301 and ZOL in monotherapy or combination therapy was assessed using three human osteosarcoma cell lines (143B, MNNG/HOS, SaOS-2). The cytotoxic effect of OBP-301 and/or ZOL was measured by assay of cell apoptosis. The effect of OBP-301 and ZOL on osteoclast activation was investigated. The potential of combination therapy against tumor growth and bone destruction was analyzed using an orthotopic 143B osteosarcoma xenograft tumor model. OBP-301 and ZOL decreased the viability of human osteosarcoma cells. Combination therapy with OBP-301 and ZOL displayed a synergistic antitumor effect, in which OBP-301 promoted apoptosis through suppression of anti-apoptotic myeloid cell leukemia 1 (MCL1). Combination therapy significantly inhibited tumor-mediated osteoclast activation, tumor growth and bone destruction compared to monotherapy. These results suggest that combination therapy of OBP-301 and ZOL suppresses osteosarcoma progression via suppression of MCL1 and osteoclast activation.

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  • Eradication of melanoma in vitro and in vivo via targeting with a Killer-Red-containing telomerase-dependent adenovirus 査読 国際共著 国際誌

    Kiyoto Takehara, Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    Cell Cycle   16 ( 16 )   1502 - 1508   2017年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    Melanoma is a highly recalcitrant cancer and transformative therapy is necessary for the cure of this disease. We recently developed a telomerase-dependent adenovirus containing the fluorescent protein Killer-Red. In the present report, we first determined the efficacy of Killer-Red adenovirus combined with laser irradiation on human melanoma cell lines in vitro. Cell viability of human melanoma cells was reduced in a dose-dependent and irradiation-time-dependent manner. We used an intradermal xenografted melanoma model in nude mice to determine efficacy of the Killer-Red adenovirus. Intratumoral injection of Killer-Red adenovirus, combined with laser irradiation, eradicated the melanoma indicating the potential of a new paradigm of cancer therapy.

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  • Impact of Autophagy in Oncolytic Adenoviral Therapy for Cancer 招待 査読 国際誌

    Hiroshi Tazawa, Shinji Kuroda, Joe Hasei, Shunsuke Kagawa, Toshiyoshi Fujiwara

    International Journal of Molecular Sciences   18 ( 7 )   1479   2017年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:MDPI AG  

    Oncolytic virotherapy has recently emerged as a promising strategy for inducing tumor-specific cell death. Adenoviruses are widely and frequently used in oncolytic virotherapy. The mechanism of oncolytic adenovirus-mediated tumor suppression involves virus-induced activation of the autophagic machinery in tumor cells. Autophagy is a cytoprotective process that produces energy via lysosomal degradation of intracellular components as a physiologic response to various stresses, including hypoxia, nutrient deprivation, and disruption of growth signaling. However, infection with oncolytic adenoviruses induces autophagy and subsequent death of tumor cells rather than enhancing their survival. In this review, we summarize the beneficial role of autophagy in oncolytic adenoviral therapy, including the roles of infection, replication, and cell lysis. Numerous factors are involved in the promotion and inhibition of oncolytic adenovirus-mediated autophagy. Furthermore, recent evidence has shown that oncolytic adenoviruses induce autophagy-related immunogenic cell death (ICD), which enhances the antitumor immune response by inducing the activation of danger signal molecules and thus represents a novel cancer immunotherapy. Understanding the precise role of oncolytic adenovirus-induced autophagy and ICD could enhance the therapeutic potential of oncolytic adenoviral therapy for treating various cancers.

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  • GFP labeling kinetics of triple-negative human breast cancer by a killer-reporter adenovirus in 3D GelfoamA (R) histoculture 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    In Vitro Cellular & Developmental Biology-Animal   53 ( 6 )   479 - 482   2017年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

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  • High-metastatic triple-negative breast-cancer variants selected in vivo become chemoresistant in vitro 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    In Vitro Cellular & Developmental Biology-Animal   53 ( 4 )   285 - 287   2017年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

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  • Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    CELL CYCLE   16 ( 5 )   406 - 414   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    We previously demonstrated that quiescent cancer cells in a tumor are resistant to conventional chemotherapy as visualized with a fluorescence ubiquitination cell cycle indicator (FUCCI). We also showed that proliferating cancer cells exist in a tumor only near nascent vessels or on the tumor surface as visualized with FUCCI and green fluorescent protein (GFP)-expressing tumor vessels. In the present study, we show the relationship between cell-cycle phase and chemotherapy-induced tumor angiogenesis using in vivo FUCCI real-time imaging of the cell cycle and nestin-driven GFP to detect nascent blood vessels. We observed that chemotherapy-treated tumors, consisting of mostly of quiescent cancer cells after treatment, had much more and deeper tumor vessels than untreated tumors. These newly-vascularized cancer cells regrew rapidly after chemotherapy. In contrast, formerly quiescent cancer cells decoyed to S/G(2) phase by a telomerase-dependent adenovirus did not induce tumor angiogenesis. The present results further demonstrate the importance of the cancer-cell position in the cell cycle in order that chemotherapy be effective and not have the opposite effect of stimulating tumor angiogenesis and progression.

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  • 骨肉腫に対する腫瘍溶解性ウイルス療法 招待

    杉生和久, 小松原将, 望月雄介, 田澤 大, 香川俊輔, 尾崎敏文, 藤原俊義

    PHARMSTAGE   16 ( 12 )   54 - 59   2017年3月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Enhanced Metastatic Recurrence Via Lymphatic Trafficking of a High-Metastatic Variant of Human Triple-Negative Breast Cancer After Surgical Resection in Orthotopic Nude Mouse Models 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Journal of Cellular Biochemistry   118 ( 3 )   559 - 569   2017年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    We previously developed and characterized a highly invasive and metastatic triple-negative breast cancer (TNBC) variant by serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Eventually, a highly invasive and metastatic variant of human TNBC was isolated after lymph node metastases was harvested and orthotopically re-implanted into the mammary gland of nude mice for two cycles. The variant thereby isolated is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present report, we observed that high-metastatic MDA-MB-231H-RFP cells produced significantly larger subcutaneous tumors compared with parental MDA-MB-231 cells in nude mice. Extensive lymphatic trafficking by high-metastatic MDA-MB-231 cells was also observed. High-metastatic MDA-MB-231 developed larger recurrent tumors 2 weeks after tumor resection compared with tumors that were not resected in orthotopic models. Surgical resection of the MDA-MB-231 high-metastatic variant primary tumor in orthotopic models also resulted in rapid and enhanced lymphatic trafficking of residual cancer cells and extensive lymph node and lung metastasis that did not occur in the non-surgical mice. These results suggest that surgical resection of high metastatic TNBC can greatly increase the malignancy of residual cancer. J. Cell. Biochem. 118: 559-569, 2017. (c) 2016 Wiley Periodicals, Inc.

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  • OBP-401-GFP telomerase-dependent adenovirus illuminates and kills high-metastatic more effectively than low-metastatic triple-negative breast cancer in vitro 査読 国際共著 国際誌

    S. Yano, K. Takehara, H. Kishimoto, H. Tazawa, Y. Urata, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

    Cancer Gene Therapy   24 ( 2 )   45 - 47   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Nature Publishing Group  

    We previously described the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared with 2 of 12 of the parental cell line. OBP-401 is a telomerase-dependent cancer-specific, green fluorescent protein (GFP)-expressing adenovirus. OBP-401 was used to infect parental MDA-MB-231P cells and high-metastatic MDA-MB-231H and MDA-MB-231HLN isolated from a lymph node metastasis and MDA-MB-231HLM isolated from a lung metastasis. Time-course imaging showed that OBP-401 labeled MDA-MB-231HP, MDA-MB-231HLN, and MDA-MB-231HLM cells more brightly than MDA-MB-231 parental cells. OBP-401 killed MDA-MB-231H, MDA-MB-231HLN, and MDA-MB-231HLM cells more efficiently than MDA-MB-231P parental cells. These results indicate that OBP-401 could infect, label and then kill high-metastatic MDA-MB-231 more efficiently than low-metastatic MDA-MB-231.

    DOI: 10.1038/cgt.2016.67

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  • Comparison of in vitro invasiveness of high- and low-metastatic triple-negative human breast cancer visualized by color-coded imaging 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    In Vitro Cellular & Developmental Biology-Animal   53 ( 2 )   96 - 98   2017年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    DOI: 10.1007/s11626-016-0092-3

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  • Comparison of Tumor Recurrence After Resection of Highly- and Poorly-Metastatic Triple-negative Breast Cancer in Orthotopic Nude-Mouse Models 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Michael Bouvet, Robert M. Hoffman

    Anticancer Research   37 ( 1 )   57 - 60   2017年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Background: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2, is a recalcitrant disease in need of effective therapy. We previously isolated highly-metastatic variants of the human TNBC cell line MDA-MB-231 using serial orthotopic implantation in nude mice. Materials and Methods: In the present report, we compared local and metastatic recurrence in lymph nodes in orthotopic nude-mouse models after bright-light surgery (BLS) of tumors from highly-metastatic variants or poorly-metastatic parental MDA-MB-231-RFP cells. Orthotopic tumors from parental MDA-MB-231 or highly-metastatic MDA-MB-231 were resected under bright light similar to an operating room. Results: After resection of primary tumors, local recurrence from highly-metastatic MDA-MB-231 cells grew more rapidly than did parental MDA-MB-231 cells. Lymph-node metastasis from highly-metastatic MDA-MB-231 cells occurred after primary tumor resection much more extensively than after parental MDAMB- 231 tumors were resected. Conclusion: The results of the present report suggest that conventional surgery under bright light was unable to control highly-metastatic compared with poorly-metastatic MDA-MB-231 TNBC.

    DOI: 10.21873/anticanres.11288

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  • 食道がんに対する放射線併用ウイルス療法の臨床研究 招待

    藤原俊義, 田澤大, 田邊俊介, 香川俊輔, 白川靖博

    日本臨床   75 ( 5 )   746 - 751   2017年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • HOZOT細胞を用いた腫瘍融解ウイルス製剤のDDS 招待

    田澤 大, 大西哲平, 香川俊輔, 中村修治, 藤原俊義

    BIO INDUSTRY   34 ( 4 )   16 - 23   2017年

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    担当区分:筆頭著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • HER2陽性胃癌に対する新たな治療戦略 査読

    金谷信彦, 黒田新士, 久保田哲史, 森廣俊昭, 菊地覚次, 西崎正彦, 田澤大, 香川俊輔, 藤原俊義

    癌と化学療法   44 ( 10 )   883 - 885   2017年

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Tumor-targeting adenovirus OBP-401 inhibits primary and metastatic tumor growth of triple-negative breast cancer in orthotopic nude-mouse models 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Oncotarget   7 ( 51 )   85273 - 85282   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IMPACT JOURNALS LLC  

    Our laboratory previously developed a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of the human MDA-MB-231 cell line in nude mice. The isolated variant was highly-invasive in the mammary gland and lymphatic channels and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. In the present study, the tumor-selective telomerase dependent OBP-401 adenovirus was injected intratumorally (i. t.) (1 x 10(8) PFU) when the high-metastatic MDA-MB-231 primary tumor expressing red fluorescent protein (MDA-MB-231-RFP) reached approximately 500 mm3 (diameter; 10 mm). The mockinfected orthotopic primary tumor grew rapidly. After i. t. OBP-401 injection, the growth of the orthotopic tumors was arrested. Six weeks after implantation, the fluorescent area and fluorescence intensity showed no increase from the beginning of treatment. OBP-401 was then injected into high-metastatic MDA-MB-231-RFP primary orthotopic tumor growing in mice which already had developed metastasis within lymphatic ducts. All 7 of 7 control mice subsequently developed lymph node metastasis. In contrast, none of 7 mice which received OBP-401 had lymph node metastasis. Seven of 7 control mice also had gross lung metastasis. In contrast, none of the 7 mice which received OBP-401 had gross lung metastasis. Confocal laser microscopy imaging demonstrated that all control mice had diffuse lung metastases. In contrast, all 7 mice which received OBP-401 only had a few metastatic cells in the lung. OBP-401 treatment significantly extended survival of the treated mice.

    DOI: 10.18632/oncotarget.13296

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  • In Vivo Selection of Intermediately- and Highly-Malignant Variants of Triple-negative Breast Cancer in Orthotopic Nude Mouse Models 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Anticancer Research   36 ( 12 )   6273 - 6277   2016年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Aim: Triple-negative breast cancer (TNBC), defined by the absence of receptors for estrogen, progesterone and human epithelial receptor 2 (HER2), is a recalcitrant disease in need of effective therapy. We previously isolated very-highly metastatic variants of the TNBC cell line MDA-MB-231 using serial orthotopic implantation of MDA-MB-231 human breast cancer cells in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (MDA-MB-231-RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation into the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for three or seven cycles in order to isolate intermediately, or highly-metastatic variants, respectively. Results: The degree of malignancy of isolated variants of MDA-MB-231 depends on the extent of orthotopic transplantation. Serial transplantation resulted in MDA-MB-231-RFP which significantly produced larger tumors compared with the parental MDA-MB-231-RFP. Serial orthotopic implantation for three cycles resulted in intermediately-metastatic variants of MDA-MB-231-RFP. MDA-MB-231-RFP serially orthotopically transplanted seven times significantly metastasized more to lymph nodes compared with parental MDA-MB-231-RFP cells and the intermediately-metastatic variant. The highly-metastatic variant MDA-MB-231-RFP cells significantly metastasized to the lung to a greater extent compared with parental MDA-MB-231-RFP and intermediate variants of MDA-MB-231-RFP. Conclusion: These results suggest that the number of serial orthotopic transplantations of MDA-MB-231-RFP correlates positively with tumor aggressiveness, and the intermediately- and highly-metastatic variants can serve as models of metastatic progression of TNBC.

    DOI: 10.21873/anticanres.11222

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  • Tumor-specific delivery of biologics by a novel T-cell line HOZOT 査読 国際誌

    Teppei Onishi, Hiroshi Tazawa, Yuuri Hashimoto, Makoto Takeuchi, Takeshi Otani, Shuji Nakamura, Fuminori Sakurai, Hiroyuki Mizuguchi, Hiroyuki Kishimoto, Yuzo Umeda, Yasuhiro Shirakawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Scientific Reports   6   38060   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    "Cell-in-cell" denotes an invasive phenotype in which one cell actively internalizes in another. The novel human T-cell line HOZOT, established from human umbilical cord blood, was shown to penetrate a variety of human cancer cells but not normal cells. Oncolytic viruses are emerging as biological therapies for human cancers; however, efficient viral delivery is limited by a lack of tumor-specific homing and presence of pre-existing or therapy-induced neutralizing antibodies. Here, we report a new, intriguing approach using HOZOT cells to transmit biologics such as oncolytic viruses into human cancer cells by cell-in-cell invasion. HOZOT cells were successfully loaded via human CD46 antigen with an attenuated adenovirus containing the fiber protein of adenovirus serotype 35 (OBP-401/F35), in which the telomerase promoter regulates viral replication. OBP-401/F35-loaded HOZOT cells were efficiently internalized into human cancer cells and exhibited tumor-specific killing by release of viruses, even in the presence of anti-viral neutralizing antibodies. Moreover, intraperitoneal administration of HOZOT cells loaded with OBP-401/F35 significantly suppressed peritoneally disseminated tumor growth in mice. This unique cell-in-cell property provides a platform for selective delivery of biologics into human cancer cells, which has important implications for the treatment of human cancers.

    DOI: 10.1038/srep38060

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  • Fluorescence-guided surgery of a highly-metastatic variant of human triple-negative breast cancer targeted with a cancer-specific GFP adenovirus prevents recurrence 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Oncotarget   7 ( 46 )   75635 - 75647   2016年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IMPACT JOURNALS LLC  

    We have previously developed a genetically-engineered GFP-expressing telomerase-dependent adenovirus, OBP-401, which can selectively illuminate cancer cells. In the present report, we demonstrate that targeting a triple-negative highinvasive human breast cancer, orthotopically-growing in nude mice, with OBP-401 enables curative fluorescence-guided surgery (FGS). OBP-401 enabled complete resection and prevented local recurrence and greatly inhibited lymph-node metastasis due to the ability of the virus to selectively label and subsequently kill cancer cells. In contrast, residual breast cancer cells become more aggressive after bright (white)light surgery (BLS). OBP-401-based FGS also improved the overall survival compared with conventional BLS. Thus, metastasis from a highly-aggressive triple-negative breast cancer can be prevented by FGS in a clinically-relevant mouse model.

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  • Iron depletion-induced downregulation of N-cadherin expression inhibits invasive malignant phenotypes in human esophageal cancer 査読 国際誌

    Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Shinichiro Watanabe, Hiroshi Tazawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    International Journal of Oncology   49 ( 4 )   1351 - 1359   2016年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPANDIDOS PUBL LTD  

    Esophageal carcinomas often have a poor prognosis due to early lymph node metastasis. Epithelial-mesenchymal transition (EMT) is strongly associated with the acquisition of cancer metastasis and invasion. However, there is no established treatment to eliminate the EMT of cancer cells. Iron is an essential element for both normal and cancer cells in humans. Recently, iron depletion has been discovered to suppress tumor growth. Therefore, we hypothesized that decreased iron conditions would regulate EMT phenotypes, as well as suppressing tumor growth. The human TE esophageal cancer cell lines and OE19 were used in our study. Decreased iron conditions were made using an iron-depletion diet in mice and the iron chelator deferasirox for cell studies. Migration and invasion abilities of cells were measured using migration, invasion, and sphere formation assays. Esophageal subcutaneous tumor growth was suppressed in decreased iron conditions. In vitro study showed that decreased iron conditions inhibited esophageal cancer cell proliferation as well as migration and invasion abilities, with downregulation of N-cadherin expression. Also, migration and invasion abilities were suppressed by inhibiting expression of N-cadherin. In conclusion, decreased iron conditions revealed a profound anticancer effect by the suppression of tumor growth and the inhibition of migration and invasion abilities via N-cadherin.

    DOI: 10.3892/ijo.2016.3640

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  • Efficacy of a Cell-Cycle Decoying Killer Adenovirus on 3-D Gelfoam (R)-Histoculture and Tumor-Sphere Models of Chemo-Resistant Stomach Carcinomatosis Visualized by FUCCI Imaging 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Hiroshi Tazawa, Hiroyuki Kishimoto, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    PLOS ONE   11 ( 9 )   e0162991   2016年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Stomach cancer carcinomatosis peritonitis (SCCP) is a recalcitrant disease. The goal of the present study was to establish an in vitro-in vivo-like imageable model of SCCP to develop cell-cycle-based therapeutics of SCCP. We established 3-D Gelfoam (R) histoculture and tumor-sphere models of SCCP. FUCCI-expressing MKN-45 stomach cancer cells were transferred to express the fluorescence ubiquinized cell-cycle indicator (FUCCI). FUCCI-expressing MKN-45 cells formed spheres on agarose or on Gelfoam (R) grew into tumor-like structures with G(0)/G(1) cancer cells in the center and S/G(2) cancer cells located in the surface as indicated by FUCCI imaging when the cells fluoresced red or green, respectively. We treated FUCCI-expressing cancer cells forming SCCP tumors in Gelfoam (R) histoculture with OBP-301, cisplatinum (CDDP), or paclitaxel. CDDP or paclitaxel killed only cycling cancer cells and were ineffective against G1/G2 MKN-45 cells in tumors growing on Gelfoam (R). In contrast, the telomerase-dependent adenovirus OBP-301 decoyed the MKN45 cells in tumors on Gelfoam (R) to cycle from G(0)/G(1) phase to S/G(2) phase and reduced their viability. CDDP-or paclitaxel-treated MKN-45 tumors remained quiescent and did not change in size. In contrast, OB-301 reduced the size of the MKN-45 tumors on Gelfoam 1. We examined the cell cycle-related proteins using Western blotting. CDDP increased the expression of p53 and p21 indicating cell cycle arrest. In contrast, OBP-301 decreased the expression of p53 and p21 Furthermore, OBP-301 increased the expression of E2F and pAkt as further indication of cell cycle decoy. This 3-D Gelfoam (R) histoculture and FUCCI imaging are powerful tools to discover effective therapy of SCCP such as OBP-301.

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  • p53 replacement therapy for cancer 招待 査読 国際誌

    Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Recent Results in Cancer Research   209   1 - 15   2016年9月

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    記述言語:英語   掲載種別:論文集(書籍)内論文   出版者・発行元:Springer New York LLC  

    Tumor suppressor gene (TSG) replacement therapy that involves various delivery systems is emerging as a promising antitumor strategy because malignant tumors develop through genetic alterations in TSGs. The most potent therapeutic TSG for tumor suppression is the multifunctional transcription factor p53 gene that regulates diverse cellular phenomena such as cell cycle arrest, senescence, apoptosis, and autophagy. Since the p53 gene is frequently inactivated by aberrant genetic regulation in human cancers, p53 replacement therapy is widely and frequently used as a potent antitumor strategy to restore wild-type p53 function in the p53-inactivated tumors. This chapter focuses on four types of p53 transfer systems: cationic liposome-DNA plasmid complexes, a replication-deficient adenovirus vector, a replication-competent adenovirus vector, and a protein transduction system. Moreover, we discuss recent advances in our understanding of the molecular basis of the p53-mediated cell death signaling pathway and therapeutic methods for enhancing tumor cell death and induction of bystander effects within tumor tissues in p53 replacement therapy. Exploration of the molecular mechanism underlying the p53-mediated tumor-suppressive network system and development of an effective strategy for enhancing p53-mediated cell death signaling pathways would lead to an improvement in the clinical outcome of patients with p53-inactivated cancers.

    DOI: 10.1007/978-3-319-42934-2_1

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  • In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation 査読 国際共著 国際誌

    Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Anticancer Research   36 ( 8 )   3817 - 3820   2016年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Aim: We describe the development of a highly-invasive, triple-negative breast cancer (TNBC) variant using serial orthotopic implantation of MDA-MB-231 human breast cancer in nude mice. Materials and Methods: MDA-MB-231 cells expressing red fluorescent protein (RFP) (1x10(7) cells/site) were initially injected subcutaneously in the flank of nude mice. After the subcutaneous tumors grew, they were harvested and cut into small pieces for orthotopic implantation in the right lower mammary gland. After the orthotopic tumors grew, they were resected and cut into small pieces and orthotopically reimplanted into the mammary gland of nude mice. The tumors grew and metastasized to lymph nodes. The lymph node metastases were harvested and cut into small pieces and orthotopically re-implanted into the mammary gland of nude mice. After the orthotopic tumors grew, the tumor was removed leaving residual cancer cells, which grew and metastasized to lymph nodes. The lymph node metastases were harvested, cut into pieces and orthotopically re-implanted into the mammary gland of nude mice for two cycles and then isolated. Results: The isolated variant is highly invasive in the mammary gland and metastasized to lymph nodes in 10 of 12 mice compared to 2 of 12 of the parental cell line. Conclusion: The availability of a highly invasive variant of TNBC targeting lymph nodes will be very useful for drug discovery of TNBC, a recalcitrant cancer and for mechanistic studies of its aggressiveness.

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  • Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas 査読 国際誌

    Shuhei Osaki, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Toshinori Omori, Kazuhisa Sugiu, Tadashi Komatsubara, Tomohiro Fujiwara, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshifumi Ozaki, Toshiyoshi Fujiwara

    SCIENTIFIC REPORTS   6   28953   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Osteosarcoma is a rare disease diagnosed as malignant bone tumor. It is generally refractory to chemotherapy, which contributes to its poor prognosis. The reversal of chemoresistance is a major clinical challenge to improve the prognostic outcome of osteosarcoma patients. We developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301 (telomelysin) and assessed its synergistic effects with chemotherapeutic agents (cisplatin and doxorubicin) using human osteosarcoma cell lines and a xenograft tumor model. The molecular mechanism underlying the chemosensitizing effect of OBP-301 was evaluated in aspects of apoptosis induction. OBP-301 inhibits anti-apoptotic myeloid cell leukemia 1 (MCL1) expression, which in turn leads to chemosensitization in human osteosarcoma cells. The siRNA-mediated knockdown of MCL1 expression sensitized human osteosarcoma cells to common chemotherapeutic agents. We also found that upregulation of microRNA-29 targeting MCL1 via virally induced transcriptional factor E2F-1 activation was critical for the enhancement of chemotherapy-induced apoptosis in osteosarcoma cells. Telomerase-specific oncolytic adenovirus synergistically suppressed the viability of human osteosarcoma cells in combination with chemotherapeutic agents. The combination treatment also significantly inhibited tumor growth, as compared to monotherapy, in an osteosarcoma xenograft tumor model. Our data suggest that replicative virus-mediated tumor-specific MCL1 ablation may be a promising strategy to attenuate chemoresistance in osteosarcoma patients.

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  • Iron depletion enhances the effect of sorafenib in hepatocarcinoma 査読 国際誌

    Shinichi Urano, Toshiaki Ohara, Kazuhiro Noma, Ryoichi Katsube, Takayuki Ninomiya, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Fumiaki Kimura, Kazuhiro Nouso, Akihiro Matsukawa, Kazuhide Yamamoto, Toshiyoshi Fujiwara

    Cancer Biology & Therapy   17 ( 6 )   648 - 656   2016年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    Human hepatocellular carcinoma (HCC) is known to have a poor prognosis. Sorafenib, a molecular targeted drug, is most commonly used for HCC treatment. However, its effect on HCC is limited in clinical use and therefore new strategies regarding sorafenib treatment are required. Iron overload is known to be associated with progression of chronic hepatitis and increased risk of HCC. We previously reported that iron depletion inhibited cancer cell proliferation and conversely induced angiogenesis. Indeed iron depletion therapy including iron chelator needs to be combined with anti-angiogenic drug for its anti-cancer effect. Since sorafenib has an anti-angiogenic effect by its inhibitory targeting VEGFR, we hypothesized that sorafenib could complement the anti-cancer effect of iron depletion. We retrospectively analyzed the relationship between the efficacy of sorafenib and serum iron-related markers in clinical HCC patients. In clinical cases, overall survival was prolonged in total iron binding capacity (TIBC) high- and ferritin low-patients. This result suggested that the low iron-pooled patients, who could have a potential of more angiogenic properties in/around HCC tumors, could be adequate for sorafenib treatment. We determined the effect of sorafenib (Nexavar (R)) and/or deferasirox (EXJADE (R)) on cancer cell viability, and on cell signaling of human hepatocarcinoma HepG2 and HLE cells. Both iron depletion by deferasirox and sorafenib revealed insufficient cytotoxic effect by each monotherapy, however, on the basis of increased angiogenesis by iron depletion, the addition of deferasirox enhanced anti-proliferative effect of sorafenib. Deferasirox was confirmed to increase vascular endothelial growth factor (VEGF) secretion into cellular supernatants by ELISA analysis. In in vivo study sorafenib combined with deferasirox also enhanced sorafenib-induced apoptosis. These results suggested that sorafenib combined with deferasirox could be a novel combination chemotherapy for HCC.

    DOI: 10.1080/15384047.2016.1177677

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  • Eradication of osteosarcoma by fluorescence-guided surgery with tumor labeling by a killer-reporter adenovirus 査読 国際共著 国際誌

    Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Journal of Orthopaedic Research   34 ( 5 )   836 - 844   2016年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    In a previous study, we developed fluorescence-guided surgery (FGS) for osteosarcoma using an orthotopic model with 143B human osteosarcoma cells expressing red fluorescent protein (RFP) implanted into the intramedullary cavity of the tibia in nude mice. The FGS-treated mice had a significantly higher disease-free survival (DFS) rate than the bright-light surgery (BLS). However, although FGS significantly reduced the recurrence of the primary tumor, it did not reduce lung metastasis. In the present study, we utilized the OBP-401 telomerase-dependent killer-reporter adenovirus, carrying green fluorescent protein (GFP), to label human osteosarcoma in situ in orthotopic mouse models. OBP-401-illuminated human osteosarcoma cell lines, 143B and MNNG/HOS cells in vitro and in vivo. OBP-401 tumor illumination enabled effective FGS of the 143B-derived orthotopic mouse model of human osteosarcoma model as well as FGS eradication of residual cancer cells after BLS. OBP-401-assisted FGS significantly inhibited local recurrence and lung metastasis after surgery, thereby prolonging DFS and overall survival (OS), achieving a very important improvement of therapeutic outcomes over our previously reported FGS study. These therapeutic benefits of FGS were demonstrated using a clinically-viable methodology of direct labeling of human osteosarcoma in situ with the OBP-401 killer-reporter adenovirus in contrast with previous reports, which used genetically engineered labeled cells or antibody-based fluorescent labels for FGS. (c) 2015 Orthopaedic Research Society. Published by Wiley Periodicals, Inc. J Orthop Res 34:836-844, 2016.

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  • Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer 査読 国際共著 国際誌

    Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Yasuhiro Shirakawa, Hiroshi Tazawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    Molecular Cancer Therapeutics   15 ( 3 )   402 - 411   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Peritoneal dissemination is the most frequent metastasis in gastric cancer and is associated with poor prognosis. The lack of particular target antigens in gastric cancer other than HER2 has hampered the development of treatments for peritoneal dissemination of gastric cancer. Wehypothesized that HER2-extracellular domain (HER2-ECD) gene transduction combined with trastuzumab-based photoimmunotherapy (PIT) might provide excellent and selective antitumor effects for peritoneal dissemination of gastric cancer. In vitro, adenovirus/HER2-ECD (Ad/HER2-ECD) efficiently transduced HER2-ECD into HER2-negative gastric cancer cells. Trastuzumab-IR700 (Tra-IR700)-mediated PIT induced selective cell death of HER2-ECD-transduced tumor cells. Ad/HER2-ECD also induced homogenous expression of HER2 in heterogeneous gastric cancer cells, resulting in uniform sensitivity of the cells to Tra-IR700-mediated PIT. Anti-HER2 PIT integrated with adenoviral HER2-ECD gene transfer was applied in mice bearing peritoneal dissemination of HER2-negative gastric cancer. Intraperitoneal administration of Ad/HER2-ECD and Tra-IR700 with PIT inhibited peritoneal metastasis and prolonged the survival of mice bearing MKN45. Furthermore, minimal side effects allowed the integrated therapy to be used repeatedly, providing better control of peritoneal dissemination. In conclusion, the novel therapy of molecular-targeted PIT integrated with gene transfer technology is a promising approach for the treatment of peritoneal dissemination in gastric cancer. (C) 2016 AACR.

    DOI: 10.1158/1535-7163.MCT-15-0644

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  • Fluvoxamine, an anti-depressant, inhibits human glioblastoma invasion by disrupting actin polymerization 査読 国際誌

    Keiichiro Hayashi, Hiroyuki Michiue, Hiroshi Yamada, Katsuyoshi Takata, Hiroki Nakayama, Fan-Yan Wei, Atsushi Fujimura, Hiroshi Tazawa, Akira Asai, Naohisa Ogo, Hiroyuki Miyachi, Tei-ichi Nishiki, Kazuhito Tomizawa, Kohji Takei, Hideki Matsui

    SCIENTIFIC REPORTS   6   23372   2016年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Glioblastoma multiforme (GBM) is the most common malignant brain tumor with a median survival time about one year. Invasion of GBM cells into normal brain is the major cause of poor prognosis and requires dynamic reorganization of the actin cytoskeleton, which includes lamellipodial protrusions, focal adhesions, and stress fibers at the leading edge of GBM. Therefore, we hypothesized that inhibitors of actin polymerization can suppress GBM migration and invasion. First, we adopted a drug repositioning system for screening with a pyrene-actin-based actin polymerization assay and identified fluvoxamine, a clinically used antidepressant. Fluvoxamine, selective serotonin reuptake inhibitor, was a potent inhibitor of actin polymerization and confirmed as drug penetration through the blood-brain barrier (BBB) and accumulation of whole brain including brain tumor with no drug toxicity. Fluvoxamine inhibited serum-induced ruffle formation, cell migration, and invasion of human GBM and glioma stem cells in vitro by suppressing both FAK and Akt/mammalian target of rapamycin signaling. Daily treatment of athymic mice bearing human glioma-initiating cells with fluvoxamine blocked tumor cell invasion and prolonged the survival with almost same dose of anti-depressant effect. In conclusion, fluvoxamine is a promising anti-invasive treatment against GBM with reliable approach.

    DOI: 10.1038/srep23372

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  • テロメラーゼ標的化がん治療・診断用アデノウイルス 招待

    田澤 大, 香川俊輔, 重安邦俊, 藤原俊義

    実験医学   34 ( 1 )   13 - 18   2016年1月

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    担当区分:筆頭著者   記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer 査読 国際誌

    Kiyoto Takehara, Hiroshi Tazawa, Naohiro Okada, Yuuri Hashimoto, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Yasuhiro Shirakawa, Nobuhiro Narii, Hiroyuki Mizuguchi, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Molecular Cancer Therapeutics   15 ( 1 )   199 - 208   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Photodynamic therapy (PDT) is a minimally invasive antitumor therapy that eradicates tumor cells through a photosensitizer-mediated cytotoxic effect upon light irradiation. However, systemic administration of photosensitizer often makes it difficult to avoid a photosensitive adverse effect. The red fluorescent protein KillerRed generates reactive oxygen species (ROS) upon green light irradiation. Here, we show the therapeutic potential of a novel tumor-specific replicating photodynamic viral agent (TelomeKiller) constructed using the human telomerase reverse transcriptase (hTERT) promoter. We investigated the light-induced antitumor effect of TelomeKiller in several types of human cancer cell lines. Relative cell viability was investigated using an XTT assay. The in vivo antitumor effect was assessed using subcutaneous xenografted tumor and lymph node metastasis models. KillerRed accumulation resulted in ROS generation and apoptosis in light-irradiated cancer cells. Intratumoral injection of TelomeKiller efficiently delivered the KillerRed protein throughout the tumors and exhibited a long-lasting antitumor effect with repeated administration and light irradiation in mice. Moreover, intratumorally injected TelomeKiller could spread into the regional lymph node area and eliminate micrometastasis with limited-field laser irradiation. Our results suggest that KillerRed has great potential as a novel photosensitizer if delivered with a tumor-specific virus-mediated delivery system. TelomeKiller-based PDT is a promising antitumor strategy to efficiently eradicate tumor cells. (C) 2015 AACR.

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  • Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy 査読 国際誌

    Masahiro Sugihara, Hiroshi Sadamori, Masahiro Nishibori, Yasuharu Sato, Hiroshi Tazawa, Susumu Shinoura, Yuzo Umeda, Ryuichi Yoshida, Daisuke Nobuoka, Masashi Utsumi, Kyotaro Ohno, Takeshi Nagasaka, Tadashi Yoshino, Hideo Kohka Takahashi, Takahito Yagi, Toshiyoshi Fujiwara

    American Journal of Surgery   211 ( 1 )   179 - 188   2016年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC  

    BACKGROUND: The purpose of this study is to determine the effects of anti-high mobility group box 1 (HMGB1) monoclonal antibody (mAb) on ischemia/reperfusion injury (IRI) and the mode of liver regeneration.
    METHODS: Rats underwent 70% hepatectomy with IRI caused by clamping the hepatoduodenal ligament for 20 minutes, followed by the administration of anti-HMGB1 mAb immediately before declamping the hepatoduodenal ligament. Five animals were used for each time point. We then evaluated IRI, regeneration parameters and the status of HMGB1 in remnant livers.
    RESULTS: The anti-HMGB1 mAb significantly ameliorated the degree of IRI in the remnant livers in association with the downregulation of HMGB1 protein. The ratio of Ki67-positive hepatocytes at 48 hours after 70% hepatectomy was significantly improved. Mean hepatocyte size was significantly reduced and cyclin-dependent kinase inhibitor 1 expression was significantly attenuated.
    CONCLUSIONS: Anti-HMGB1 mAb ameliorated IRI and improved the mode of liver regeneration after IRI followed by 70% hepatectomy in rats. (C) 2016 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.amjsurg.2015.06.025

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  • 宿主正常細胞である癌関連線維芽細胞を標的とした新たな食道癌治療法の開発 査読

    野間 和広, 賀島 肇, 二宮 卓之, 勝部 亮一, 渡邉 伸一郎, 大原 利章, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    癌と化学療法   42 ( 10 )   1228 - 1230   2015年10月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)   出版者・発行元:(株)癌と化学療法社  

    近年の分子細胞生化学の発展により、分子標的治療薬によって飛躍的に予後改善を認める癌腫もでてきている。また、bevacizumabの台頭にみられるように、がん微小環境を制御することでより抗腫瘍効果を上げる例もでてきており、新しい可能性を示唆している。癌とがん微小環境の相互作用については以前より多く報告されており、その中心的な役割を担っているのが癌関連線維芽細胞(cancer-associated fibroblasts:CAFs)といわれている。以前よりわれわれは、食道癌の進展におけるがん微小環境の強い関与を推測し、特にCAFの作用に注目し分子標的となり得るシグナルの解析を行ってきた。しかしながら、CAFの単一のシグナル阻害のみでは癌の治療においては不十分な可能性が考えられた。現在までに多くのCAF細胞におけるシグナルを標的とした治療法が提案されてきたが、未だ十分な結果を得ていない。光線免疫療法は、2011年にMitsunagaらにて発表された近赤外線光を用いた標的分子特異的癌治療である。われわれは、その細胞特異性に殺傷できるシステムに注目し、現在CAFそのものを制御すべくCAFに対する光線化学療法の開発、またその効果を検討している。今後検討結果を随時報告する予定である。(著者抄録)

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    その他リンク: https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J00296&link_issn=&doc_id=20151027380020&doc_link_id=%2Fab8gtkrc%2F2015%2F004210%2F021%2F1228-1230%26dl%3D0&url=http%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2015%2F004210%2F021%2F1228-1230%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

  • Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability 査読 国際共著 国際誌

    Keisuke Toda, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Takashi Kawai, Tomokazu Fuji, Fumitaka Taniguchi, Kazuya Yasui, Nobuhito Kubota, Yuko Takehara, Hiroshi Tazawa, Shunsuke Kagawa, Dong-Sheng Sun, Naoshi Nishida, Ajay Goel, Toshiyoshi Fujiwara

    CLINICAL EPIGENETICS   7 ( 1 )   73   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: The gene expressions of netrin-1 dependence receptors, DCC and UNC5C, are frequently downregulated in many cancers. We hypothesized that downregulation of DCC and UNC5C has an important growth regulatory function in gastric tumorigenesis.
    Results: In the present study, a series of genetic and epigenetic analyses for DCC and UNC5C were performed in a Japanese cohort of 98 sporadic gastric cancers and corresponding normal gastric mucosa specimens. Loss of heterozygosity (LOH) analyses and microsatellite instability (MSI) analysis was applied to determine chromosomal instability (CIN) and MSI phenotypes, respectively. More than 5 % methylation in the DCC and UNC5C promoters were found in 45 % (44/98) and 32 % (31/98) gastric cancers, respectively, and in 9 % (9/105) and 5 % (5/105) normal gastric mucosa, respectively. Overall, 70 % (58 of 83 informative cases) and 51 % (40 of 79 informative cases) of gastric cancers harbored either LOH or aberrant methylation in the DCC and UNC5C genes, respectively. In total, 77 % (51 of 66 informative cases) of gastric cancers showed cumulative defects in these two dependence receptors and were significantly associated with chromosomal instability. Both DCC and UNC5C were inactivated in 97 % of CIN-positive gastric cancers and in 55 % of CIN-negative gastric cancers.
    Conclusions: Defect in netrin receptors is a common feature in gastric cancers. DCC alterations are apparent in the early stages, and UNC5C alterations escalate with the progression of the disease, suggesting that the cumulative alterations of netrin-1 receptors was a late event in gastric cancer progression and emphasizing the importance of this growth regulatory pathway in gastric carcinogenesis.

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  • Experimental Curative Fluorescence-guided Surgery of Highly Invasive Glioblastoma Multiforme Selectively Labeled With a Killer-reporter Adenovirus 査読 国際共著 国際誌

    Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Michael Bouvet, Yasuo Urata, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    Molecular Therapy   23 ( 7 )   1182 - 1188   2015年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Fluorescence-guided surgery (FGS) of cancer is an area of intense current interest. However, although benefits have been demonstrated with FGS, curative strategies need to be developed. Glioblastoma multiforme (GBM) is one of the most invasive of cancers and is not totally resectable using standard bright-light surgery (BLS) or current FGS strategies. We report here a curative strategy for FGS of GBM. In this study, telomerase-dependent adenovirus OBP-401 infection brightly and selectively labeled GBM with green fluorescent protein (GFP) for FGS in orthotopic nude mouse models. OBP-401-based FGS enabled curative resection of GBM without recurrence for at least 150 days, compared to less than 30 days with BLS.

    DOI: 10.1038/mt.2015.63

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  • Targeting tumors with a killer-reporter adenovirus for curative fluorescence-guided surgery of soft-tissue sarcoma 査読 国際共著 国際誌

    Shuya Yano, Shinji Miwa, Hiroyuki Kishimoto, Fuminari Uehara, Hiroshi Tazawa, Makoto Toneri, Yukihiko Hiroshima, Mako Yamamoto, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Oncotarget   6 ( 15 )   13133 - 13148   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:IMPACT JOURNALS LLC  

    Fluorescence-guided surgery (FGS) of cancer is an area of intense interest. However, FGS of cancer has not yet been shown to be curative due to residual microscopic disease. Human fibrosarcoma HT1080 expressing red fluorescent protein (RFP) was implanted orthotopically in the quadriceps femoris muscle of nude mice. The tumor-bearing mice were injected with high and low-dose telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401, which labeled the tumor with GFP. Fluorescence-guided surgery (FGS) or bright light surgery (BLS) was then performed. OBP-401 could label soft-tissue sarcoma (STS) with GFP in situ, concordant with RFP. OBP-401-based FGS resulted in superior resection of STS in the orthotopic model of soft-tissue sarcoma, compared to BLS. High-dose administration of OBP-401 enabled FGS without residual sarcoma cells or local or metastatic recurrence, due to its dual effect of cancer-cell labeling with GFP and killing. High-dose OBP-401 based-FGS improved disease free survival (p = 0.00049) as well as preserved muscle function compared with BLS. High-dose OBP-401-based FGS could cure STS, a presently incurable disease. Since the parent virus of OBP-401, OBP-301, has been previously proven safe in a Phase I clinical trial, it is expected the OBP-401-FGS technology described in the present report should be translatable to the clinic in the near future.

    DOI: 10.18632/oncotarget.3811

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  • MicroRNA as a molecular target for gastrointestinal cancers 招待 査読 国際誌

    Hiroshi Tazawa, Takeshi Nagasaka, Shunsuke Kagawa, Toshiyoshi Fujiwara

    TRANSLATIONAL GASTROINTESTINAL CANCER   4 ( 3 )   219 - 235   2015年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    DOI: 10.3978/j.issn.2224-4778.2015.04.01

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  • Fluorescence virus-guided capturing system of human colorectal circulating tumour cells for non-invasive companion diagnostics 査読 国際共著 国際誌

    Kunitoshi Shigeyasu, Hiroshi Tazawa, Yuuri Hashimoto, Yoshiko Mori, Masahiko Nishizaki, Hiroyuki Kishimoto, Takeshi Nagasaka, Shinji Kuroda, Yasuo Urata, Ajay Goel, Shunsuke Kagawa, Toshiyoshi Fujiwara

    GUT   64 ( 4 )   627 - 635   2015年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BMJ PUBLISHING GROUP  

    Background Molecular-based companion diagnostic tests are being used with increasing frequency to predict their clinical response to various drugs, particularly for molecularly targeted drugs. However, invasive procedures are typically required to obtain tissues for this analysis. Circulating tumour cells (CTCs) are novel biomarkers that can be used for the prediction of disease progression and are also important surrogate sources of cancer cells. Because current CTC detection strategies mainly depend on epithelial cell-surface markers, the presence of heterogeneous populations of CTCs with epithelial and/or mesenchymal characteristics may pose obstacles to the detection of CTCs.
    Methods We developed a new approach to capture live CTCs among millions of peripheral blood leukocytes using a green fluorescent protein (GFP)-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401, TelomeScan).
    Results Our biological capturing system can image epithelial and mesenchymal tumour cells with telomerase activities as GFP-positive cells. After sorting, direct sequencing or mutation-specific PCR can precisely detect different mutations in KRAS, BRAF and KIT genes in epithelial, mesenchymal or epithelial-mesenchymal transition-induced CTCs, and in clinical blood samples from patients with colorectal cancer.
    Conclusions This fluorescence virus-guided viable CTC capturing method provides a non-invasive alternative to tissue biopsy or surgical resection of primary tumours for companion diagnostics.

    DOI: 10.1136/gutjnl-2014-306957

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  • Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional Gelfoam (R) histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging 査読 国際共著 国際誌

    Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminaru Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Cell Cycle   14 ( 6 )   808 - 819   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS INC  

    The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We previously reported monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor, intravitally in live mice, using a fluorescence ubiquitination-based cell-cycle indicator (FUCCI). Approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after cessation of chemotherapy. These results suggested why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. In the present report, we used FUCCI imaging and Gelfoam (R) collagen-sponge-gel histoculture, to demonstrate in real time, that the cell-cycle phase distribution of cancer cells in Gelfoam (R) and in vivo tumors is highly similar, whereby only the surface cells proliferate and interior cells are quiescent in G(0)/G(1). This is in contrast to 2D culture where most cancer cells cycle. Similarly, the cancer cells responded similarly to toxic chemotherapy in Gelfoam (R) culture as in vivo, and very differently than cancer cells in 2D culture which were much more chemosensitive. Gelfoam (R) culture of FUCCI-expressing cancer cells offers the opportunity to image the cell cycle of cancer cells continuously and to screen for novel effective therapies to target quiescent cells, which are the majority in a tumor and which would have a strong probability to be effective in vivo.

    DOI: 10.1080/15384101.2014.1000685

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  • Biological Ablation of Sentinel Lymph Node Metastasis in Submucosally Invaded Early Gastrointestinal Cancer 査読 国際共著 国際誌

    Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Masahiko Nishizaki, Takeshi Nagasaka, Yasuhiro Shirakawa, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

    Molecular Therapy   23 ( 3 )   501 - 509   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Currently, early gastrointestinal cancers are treated endoscopically, as long as there are no lymph node metastases. However, once a gastrointestinal cancer invades the submucosal layer, the lymph node metastatic rate rises to higher than 10%. Therefore, surgery is still the gold standard to remove regional lymph nodes containing possible metastases. Here, to avoid prophylactic surgery, we propose a less-invasive biological ablation of lymph node metastasis in subnnucosally invaded gastrointestinal cancer patients. We have established an orthotopic early rectal cancer xenograft model with spontaneous lymph node metastasis by implantation of green fluorescent protein (GFP)-labeled human colon cancer cells into the submucosal layer of the murine rectum. A solution containing telomerase-specific oncolytic adenovirus was injected into the peritumoral submucosal space, followed by excision of the primary rectal tumors mimicking the endoscopic submucosal dissection (ESD) technique. Seven days after treatment, GFP signals had completely disappeared indicating that sentinel lymph node metastasis was selectively eradicated. Moreover, biologically treated mice were confirmed to be relapse-free even 4 weeks after treatment. These results indicate that virus-mediated biological ablation selectively targets lymph node metastasis and provides a potential alternative to surgery for subnnucosal invasive gastrointestinal cancer patients.

    DOI: 10.1038/mt.2014.244

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  • Loss of p53 in stromal fibroblasts enhances tumor cell proliferation through nitric-oxide-mediated cyclooxygenase 2 activation 査読 国際共著 国際誌

    S. Wada, Y. Matsushita, H. Tazawa, W. Aoi, Y. Naito, A. Higashi, H. Ohshima, T. Yoshikawa

    Free Radical Research   49 ( 3 )   269 - 278   2015年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:TAYLOR & FRANCIS LTD  

    Overexpression of cyclooxygenase 2 (COX-2) by stromal fibroblasts plays a critical role in the early stage of carcinogenesis. COX-2 expression is thought to be positively or negatively regulated by inflammatory chemical mediators or tumor suppressors. In this study, the contributions of inducible nitric oxide synthase (iNOS) and p53 to COX-2 expression were examined using mouse embryonic fibroblasts (MEFs) from wild-type, p53-deficient, iNOS-deficient, and p53/iNOS-deficient mice. These MEFs were treated with 1 mu g/mL of lipopolysaccharide and 100 IU/mL of interferon gamma for up to 72 h. iNOS and COX-2 expression were analyzed by Western blotting. iNOS was induced earlier (16 h) in p53-deficient MEFs than in wild-type MEFs (48 h). Elevated expression of COX-2 was sustained for a longer duration in the p53-deficient MEFs. In contrast, COX-2 expression was reduced earlier in the iNOS-deficient MEFs. Addition of an exogenous NO donor (0.8 mM of S-nitroso-L-glutathione) to the iNOS-deficient MEFs augmented COX-2 expression. Co-culture with stimulated p53-deficient MEFs promoted cell proliferation of mouse rectal polyploid carcinoma CMT93 cells, but treatment with a COX-2-specific inhibitor counteracted this effect. These results suggest that loss of function of the p53 gene in stromal fibroblasts enhances COX-2 expression by enhancing iNOS expression and the resultant production of NO, contributing to the promotion of tumor growth.

    DOI: 10.3109/10715762.2014.997230

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  • Viral transduction of the HER2-extracellular domain expands trastuzumab-based photoimmunotherapy for HER2-negative breast cancer cells 査読 国際誌

    Kyoko Shimoyama, Shunsuke Kagawa, Michihiro Ishida, Shinichiro Watanabe, Kazuhiro Noma, Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Shunsuke Tanabe, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

    Breast Cancer Research and Treatment   149 ( 3 )   597 - 605   2015年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    The prognosis of HER2-positive breast cancer has been improved by trastuzumab therapy, which features high specificity and limited side effects. However, trastuzumab-based therapy has shortcomings. Firstly, HER2-targeted therapy is only applicable to HER2-expressing tumors, which comprise only 20-25 % of primary breast cancers. Secondly, many patients who initially respond to trastuzumab ultimately develop disease progression. To overcome these problems, we employed virus-mediated HER2 transduction and photoimmunotherapy (PIT) which involves trastuzumab conjugated with a photosensitizer, trastuzumab-IR700, and irradiation of near-infrared light. We hypothesized that the gene transduction technique together with PIT would expand the range of tumor entities suitable for trastuzumab-based therapy and improve its antitumor activity. The HER2-extracellular domain (ECD) was transduced by the adenoviral vector, Ad-HER2-ECD, and PIT with trastuzumab-IR700 was applied in the HER2-negative cancer cells. Ad-HER2-ECD can efficiently transduce HER2-ECD into HER2-negative human cancer cells. PIT with trastuzumab-IR700 induced direct cell membrane destruction of Ad-HER2-ECD-transduced HER2-negative cancer cells. Novel combination of viral transduction of a target antigen and an antibody-based PIT would expand and potentiate molecular-targeted therapy even for target-negative or attenuated cancer cells.

    DOI: 10.1007/s10549-015-3265-y

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  • Multidisciplinary cancer therapy with telomerase-specific oncolytic adenovirus 招待 査読 国際誌

    Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

    Current Cancer Therapy Reviews   11 ( 3 )   178 - 187   2015年

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:Bentham Science Publishers B.V.  

    A multidisciplinary approach of combining surgery, chemotherapy and radiotherapy has remained the accepted standard management for various types of human cancer. However, many new treatment options have recently become available, including molecular targeted therapies, immunotherapies and oncolytic virotherapies. Replication-selective tu-mor-specific viruses have been designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. We constructed an attenuated adenovirus 5 vector, telomelysin (OBP-301), in which the telomerase-specific promoter drives expression of viral replication-inducible E1 genes. Although telomelysin alone exhibited substantial antitumor effects both in animal models and in clinical trials, telomelysin has the potential to be the first-in-class oncolytic virus for combination therapy based on our current understanding of the molecular mechanisms. Telomelysin sensitizes human cancer cells to ionizing radiation by inhibiting the radiation-induced DNA repair machinery, and also eliminates radio-resistant quiescent cancer stem-like cells by promoting cell cycle entry. A clinical trial of intratumoral administration of telomelysin with radiotherapy in esophageal cancer patients is currently underway. This article reviews recent highlights in the rapidly evolving field of multidisciplinary therapy with telomelysin.

    DOI: 10.2174/1573394712666160128201822

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  • Molecular diagnosis and therapy for occult peritoneal metastasis in gastric cancer patients 招待 査読 国際誌

    Shunsuke Kagawa, Kunitoshi Shigeyasu, Michihiro Ishida, Megumi Watanabe, Hiroshi Tazawa, Takeshi Nagasaka, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    World Journal of Gastroenterology   20 ( 47 )   17796 - 17803   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BAISHIDENG PUBLISHING GROUP INC  

    To apply an individualized oncological approach to gastric cancer patients, the accurate diagnosis of disease entities is required. Peritoneal metastasis is the most frequent mode of metastasis in gastric cancer, and the tumor-node-metastasis classification includes cytological detection of intraperitoneal cancer cells as part of the staging process, denoting metastatic disease. The accuracy of cytological diagnosis leaves room for improvement; therefore, highly sensitive molecular diagnostics, such as an enzyme immunoassay, reverse transcription polymerase chain reaction, and virus-guided imaging, have been developed to detect minute cancer cells in the peritoneal cavity. Molecular targeting therapy has also been spun off from basic research in the past decade. Although conventional cytology is still the mainstay, novel approaches could serve as practical complementary diagnostics to cytology in near future. (C) 2014 Baishideng Publishing Group Inc. All rights reserved.

    DOI: 10.3748/wjg.v20.i47.17796

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  • Establishment of a Non-Invasive Semi-Quantitative Bioluminescent Imaging Method for Monitoring of an Orthotopic Esophageal Cancer Mouse Model 査読 国際誌

    Shinji Kuroda, Tetsushi Kubota, Katsuyuki Aoyama, Satoru Kikuchi, Hiroshi Tazawa, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    PLOS ONE   9 ( 12 )   e114562   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Orthotopic models of various types of tumors are widely used in anti-tumor therapeutic experiments in preclinical studies. However, there are few ways to appropriately monitor therapeutic effect in orthotopic tumor models, especially for tumors invisible from the outside. In this study we aimed to establish a non-invasive semi-quantitative bioluminescent imaging method of monitoring an orthotopic esophageal cancer mouse model. We confirmed that the TE8 esophageal cancer cell line implanted orthotopically into the abdominal esophagus of nu/nu mice (n=5) developed not only a main tumor at the implanted site, but also local lymph node metastases and peritoneal disseminations within 6 weeks after inoculation. We established a TE8 cell line that stably expressed the firefly luciferase gene (TE8-Luc). We showed that TE8-Luc cells implanted subcutaneously into nu/nu mice (n=5) grew over time until 5 weeks after inoculation. Tumor volume was strongly correlated with luminescent intensity emitted from the tumor, which was quantified using the IVIS imaging system. We then showed that TE8-Luc cells implanted orthotopically into the mouse abdominal esophagus (n=8) also formed a tumor and that the luminescent intensity of such a tumor, as detected by IVIS, increased over time until 7 weeks after inoculation and was therefore likely to reflect tumor progression. We therefore propose that this orthotopic esophageal cancer model, monitored using the non-invasive semi-quantitative IVIS imaging system, will be useful for in vivo therapeutic experiments against esophageal cancer. This experimental setting is expected to contribute to the development of novel therapeutic technologies for esophageal cancer in preclinical studies.

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  • Tumor-targeting Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle as visualized by FUCCI imaging and become sensitive to chemotherapy 査読 国際共著 国際誌

    Shuya Yano, Yong Zhang, Ming Zhao, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Cell Cycle   13 ( 24 )   3958 - 3963   2014年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LANDES BIOSCIENCE  

    Quiescent cancer cells are resistant to cytotoxic agents which target only proliferating cancer cells. Time-lapse imaging demonstrated that tumor-targeting Salmonella typhimurium A1-R (A1-R) decoyed cancer cells in monolayer culture and in tumor spheres to cycle from G(0)/G(1) to S/G(2)/M, as demonstrated by fluorescence ubiquitination-based cell cycle indicator (FUCCI) imaging. A1-R infection of FUCCI-expressing subcutaneous tumors growing in nude mice also decoyed quiescent cancer cells, which were the majority of the cells in the tumors, to cycle from G(0)/G(1) to S/G(2)/M, thereby making them sensitive to cytotoxic agents. The combination of A1-R and cisplatinum or paclitaxel reduced tumor size compared with A1-R monotherapy or cisplatinum or paclitaxel alone. The results of this study demonstrate that A1-R can decoy quiescent cancer cells to cycle to S/G(2)/M and sensitize them to cytotoxic chemotherapy. These results suggest a new paradigm of bacterial-decoy chemotherapy of cancer.

    DOI: 10.4161/15384101.2014.964115

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  • Spatial-temporal FUCCI imaging of each cell in a tumor demonstrates locational dependence of cell cycle dynamics and chemoresponsiveness 査読 国際共著 国際誌

    Shuya Yano, Yong Zhang, Shinji Miwa, Yasunori Tome, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Cell Cycle   13 ( 13 )   2110 - 2119   2014年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LANDES BIOSCIENCE  

    The phase of the cell cycle can determine whether a cancer cell can respond to a given drug. We report here on the results of monitoring of real-time cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination cell cycle indicator (FUCCI) before, during, and after chemotherapy. In nascent tumors in nude mice, approximately 30% of the cells in the center of the tumor are in G(0)/G(1) and 70% in S/G(2)/M. In contrast, approximately 90% of cancer cells in the center and 80% of total cells of an established tumor are in G(0)/G(1) phase. Similarly, approximately 75% of cancer cells far from (&gt;100 mu m) tumor blood vessels of an established tumor are in G(0)/G(1). Longitudinal real-time imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, had little effect on quiescent cancer cells, which are the vast majority of an established tumor. Moreover, resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Our results suggest why most drugs currently in clinical use, which target cancer cells in S/G(2)/M, are mostly ineffective on solid tumors. The results also suggest that drugs that target quiescent cancer cells are urgently needed.

    DOI: 10.4161/cc.29156

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  • ANTITUMOR EFFECT OF TELOMERASE-SPECIFIC ONCOLYTIC ADENOVIRUS ON HUMAN BONE AND SOFT TISSUE SARCOMA CELLS 査読

    Hiroshi Tazawa, Tsuyoshi Sasaki, Jo Hasei, Yuuri Hashimoto, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   261 - 262   2014年7月

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    記述言語:英語   掲載種別:研究論文(研究会,シンポジウム資料等)   出版者・発行元:WILEY-BLACKWELL  

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  • テロメラーゼ活性依存的腫瘍融解ウイルスによるがん治療 招待

    田澤 大, 矢野修也, 香川俊輔, 白川靖博, 藤原俊義

    腫瘍内科   13 ( 6 )   817 - 823   2014年6月

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    記述言語:日本語   掲載種別:研究論文(学術雑誌)  

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  • Establishment of a pancreatic stem cell line from fibroblast-derived induced pluripotent stem cells 査読 国際誌

    Takashi Kuise, Hirofumi Noguchi, Hiroshi Tazawa, Takashi Kawai, Masaya Iwamuro, Issei Saitoh, Hitomi Usui Kataoka, Masami Watanabe, Yasufumi Noguchi, Toshiyoshi Fujiwara

    Biomedical Engineering Online   13   64   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BIOMED CENTRAL LTD  

    Background: For cell therapies to treat diabetes, it is important to produce a sufficient number of pancreatic endocrine cells that function similarly to primary islets. Induced pluripotent stem (iPS) cells represent a potentially unlimited source of functional pancreatic endocrine cells. However, the use of iPS cells for laboratory studies and cell-based therapies is hampered by their high tumorigenic potential and limited ability to generate pure populations of differentiated cell types in vitro. The purpose of this study was to establish a pancreatic stem cell line from iPS cells derived from mouse fibroblasts.
    Methods: Mouse iPS cells were induced to differentiate into insulin-producing cells by a multi-step differentiation protocol, which was conducted as described previously with minor modifications. Selection of the pancreatic stem cell was based on morphology and Pdx1 expression. The pancreatic potential of the pancreatic stem cells was evaluated using a reverse transcription PCR, real-time PCR, immunofluorescence, and a glucose challenge test. To assess potential tumorigenicity of the pancreatic stem cells, the cells were injected into the quadriceps femoris muscle of the left hindlimb of nude mice.
    Results: The iPS-derived pancreatic stem cells expressed the transcription factor -Pdx1- a marker of pancreatic development, and continued to divide actively beyond passage 80. Endocrine cells derived from these pancreatic stem cells expressed insulin and pancreatic genes, and they released insulin in response to glucose stimulation. Mice injected with the pancreatic stem cells did not develop tumors, in contrast to mice injected with an equal number of iPS cells.
    Conclusion: This strategy provides a new approach for generation of insulin-producing cells that is more efficient and safer than using iPS cells. We believe that this approach will help to develop a patient-specific cell transplantation therapy for diabetes in the near future.

    DOI: 10.1186/1475-925X-13-64

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  • Fascin regulates chronic inflammation-related human colon carcinogenesis by inhibiting cell anoikis 査読 国際誌

    Yusuke Kanda, Tokuichi Kawaguchi, Yasuhiro Kuramitsu, Takao Kitagawa, Tokushige Kobayashi, Norihiko Takahashi, Hiroshi Tazawa, Hasem Habelhah, Jun-ichi Hamada, Masanobu Kobayashi, Mio Hirahata, Kunishige Onuma, Mitsuhiko Osaki, Kazuyuki Nakamura, Tomoyuki Kitagawa, Masuo Hosokawa, Futoshi Okada

    Proteomics   14 ( 9 )   1031 - 1041   2014年5月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    By a proteomics-based approach, we identified an overexpression of fascin in colon adenocarcinoma cells (FPCKpP-3) that developed from nontumorigenic human colonic adenoma cells (FPCK-1-1) and were converted to tumorigenic by foreign-body-induced chronic inflammation in nude mice. Fascin overexpression was also observed in the tumors arising from rat intestinal epithelial cells (IEC 6) converted to tumorigenic in chronic inflammation which was induced in the same manner. Upregulation of fascin expression in FPCK-1-1 cells by transfection with sense fascin cDNA converted the cells tumorigenic, whereas antisense fascin-cDNA-transfected FPCKpP-3 cells reduced fascin expression and lost their tumor-forming ability in vivo. The tumorigenic potential by fascin expression was consistent with their ability to survive and grow in the three-dimensional multicellular spheroids. We found that resistance to anoikis (apoptotic cell death as a consequence of insufficient cell-to-substrate interactions), which is represented by the three-dimensional growth of solid tumors in vivo, was regulated by fascin expression through caspase-dependent apoptotic signals. From these, we demonstrate that fascin is a potent suppressor to caspase-associated anoikis and accelerator of the conversion of colonic adenoma cells into adenocarcinoma cells by chronic inflammation.

    DOI: 10.1002/pmic.201300414

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  • Invading cancer cells are predominantly in G(0)/G(1) resulting in chemoresistance demonstrated by real-time FUCCI imaging 査読 国際共著 国際誌

    Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    Cell Cycle   13 ( 6 )   953 - 960   2014年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LANDES BIOSCIENCE  

    Invasive cancer cells are a critical target in order to prevent metastasis. In the present report, we demonstrate real-time visualization of cell cycle kinetics of invading cancer cells in 3-dimensional (3D) Gelfoam (R) histoculture, which is in vivo-like. A fluorescence ubiquitination cell cycle indicator (FUCCI) whereby G(0)/G(1) cells express a red fluorescent protein and S/G(2)/M cells express a green fluorescent protein was used to determine the cell cycle position of invading and non-invading cells. With FUCCI 3D confocal imaging, we observed that cancer cells in G(0)/G(1) phase in Gelfoam (R) histoculture migrated more rapidly and further than cancer cells in S/G(2)/M phases. Cancer cells ceased migrating when they entered S/G(2)/M phases and restarted migrating after cell division when the cells re-entered G(0)/G(1). Migrating cancer cells also were resistant to cytotoxic chemotherapy, since they were preponderantly in G(0)/G(1), where cytotoxic chemotherapy is not effective. The results of the present report suggest that novel therapy targeting G(0)/G(1) cancer cells should be developed to prevent metastasis.

    DOI: 10.4161/cc.27818

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  • A Genetically Engineered Oncolytic Adenovirus Decoys and Lethally Traps Quiescent Cancer Stem-like Cells in S/G(2)/M Phases 査読 国際共著 国際誌

    Shuya Yano, Hiroshi Tazawa, Yuuri Hashimoto, Yasuhiro Shirakawa, Shinji Kuroda, Masahiko Nishizaki, Hiroyuki Kishimoto, Futoshi Uno, Takeshi Nagasaka, Yasuo Urata, Shunsuke Kagawa, Robert M. Hoffman, Toshiyoshi Fujiwara

    CLINICAL CANCER RESEARCH   19 ( 23 )   6495 - 6505   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Purpose: Because chemoradiotherapy selectively targets proliferating cancer cells, quiescent cancer stem-like cells are resistant. Mobilization of the cell cycle in quiescent leukemia stem cells sensitizes them to cell death signals. However, it is unclear that mobilization of the cell cycle can eliminate quiescent cancer stem-like cells in solid cancers. Thus, we explored the use of a genetically-engineered telomerase-specific oncolytic adenovirus, OBP-301, to mobilize the cell cycle and kill quiescent cancer stem-like cells.
    Experimental Design: We established CD133(+) cancer stem-like cells from human gastric cancer MKN45 and MKN7 cells. We investigated the efficacy of OBP-301 against quiescent cancer stem-like cells. We visualized the treatment dynamics of OBP-301 killing of quiescent cancer stem-like cells in dormant tumor spheres and xenografts using a fluorescent ubiquitination cell-cycle indicator (FUCCI).
    Results: CD133(+) gastric cancer cells had stemness properties. OBP-301 efficiently killed CD133(+) cancer stem-like cells resistant to chemoradiotherapy. OBP-301 induced cell-cycle mobilization from G(0)-G(1) to S/G(2)/M phases and subsequent cell death in quiescent CD133(+) cancer stem-like cells by mobilizing cell-cycle-related proteins. FUCCI enabled visualization of quiescent CD133(+) cancer stem-like cells and proliferating CD133(-) non-cancer stem-like cells. Three-dimensional visualization of the cell-cycle behavior in tumor spheres showed that CD133(+) cancer stem-like cells maintained stemness by remaining in G(0)-G(1) phase. We showed that OBP-301 mobilized quiescent cancer stem-like cells in tumor spheres and xenografts into S/G(2)/M phases where they lost viability and cancer stem-like cell properties and became chemosensitive.
    Conclusion: Oncolytic adenoviralinfection is an effective mechanism of cancer cell killing in solid cancer and can be a new therapeutic paradigm to eliminate quiescent cancer stem-like cells. Clin Cancer Res; 19(23); 6495-505. (C) 2013 AACR.

    DOI: 10.1158/1078-0432.CCR-13-0742

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  • Oncolytic Adenovirus-Induced Autophagy: Tumor-Suppressive Effect and Molecular Basis 査読 国際誌

    Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Acta Medica Okayama   67 ( 6 )   333 - 342   2013年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OKAYAMA UNIV MED SCHOOL  

    Autophagy is a catabolic process that produces energy through lysosomal degradation of intracellular organelles. Autophagy functions as a cytoprotective factor under physiological conditions such as nutrient deprivation, hypoxia, and interruption of growth factors. On the other hand, infection with pathogenic viruses and bacteria also induces autophagy in infected cells. Oncolytic virotherapy with replication-competent viruses is thus a promising strategy to induce tumor-specific cell death. Oncolytic adenoviruses induce autophagy and subsequently contribute to cell death rather than cell survival in tumor cells. We previously developed a telomerase-specific replication-competent oncolytic adenovirus, OBP-301, which induces cell lysis in tumor cells with telomerase activities. OBP-301-mediated cytopathic activity is significantly associated with induction of autophagy biomarkers. In this review, we focus on the tumor-suppressive role and molecular basis of autophagic machinery induced by oncolytic adenoviruses. Addition of tumor-specific promoters and modification of the fiber knob of adenoviruses supports the oncolytic adenovirus-mediated autophagic cell death. Autophagy is cooperatively regulated by the El-dependent activation pathway, E4-dependent inhibitory pathway, and microRNA-dependent fine-tuning. Thus, future exploration of the functional role and molecular mechanisms underlying oncolytic adenovirus-induced autophagy would provide novel insights and improve the therapeutic potential of oncolytic adenoviruses.

    DOI: 10.18926/AMO/52006

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  • Advances in adenovirus-mediated p53 cancer gene therapy 査読 国際誌

    Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Expert Opinion on Biological Therapy   13 ( 11 )   1569 - 1583   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    Introduction: The tumor suppressor p53 gene regulates diverse cellular processes, such as cell-cycle arrest, senescence, apoptosis and autophagy, and it is frequently inactivated by genetic alterations in ∼ 50% of all types of human cancers. To restore wild-type p53 function in p53-inactivated tumors, adenovirus-mediated p53 gene therapy has been developed as a promising antitumor strategy in preclinical experiments and clinical studies. Areas covered: This review focuses on the clinical relevance of replication-deficient adenovirus vectors that carry the wild-type p53 gene (Ad-p53
    Advexin, Gendicine and SCH-58500) in clinical studies of patients with various cancers and the future perspectives regarding conditionally replicating adenovirus vectors expressing the wild-type p53 gene (CRAd-p53
    AdDelta24-p53, SG600-p53, OBP-702) in preclinical experiments. Moreover, the recent advances in our understanding of the molecular basis for the p53-mediated tumor suppression network induced by Ad-p53 and CRAd-p53 vectors and the combination therapies for promoting the therapeutic potential of adenovirus-mediated p53 gene therapy are discussed. Expert opinion: Exploration of the molecular mechanism underlying the p53-mediated tumor suppression network and the effective strategy for enhancing the p53-mediated cell death signaling pathway would provide novel insights into the improvement of clinical outcome in p53-based cancer gene therapy. © 2013 Informa UK, Ltd.

    DOI: 10.1517/14712598.2013.845662

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  • Chronic inflammation-derived nitric oxide causes conversion of human colonic adenoma cells into adenocarcinoma cells 査読 国際誌

    Hiroshi Tazawa, Tokuichi Kawaguchi, Tokushige Kobayashi, Yasuhiro Kuramitsu, Sayori Wada, Yoshiko Satomi, Hoyoku Nishino, Masanobu Kobayashi, Yusuke Kanda, Mitsuhiko Osaki, Tomoyuki Kitagawa, Masuo Hosokawa, Futoshi Okada

    EXPERIMENTAL CELL RESEARCH   319 ( 18 )   2835 - 2844   2013年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER INC  

    It has been suggested that nitric oxide (NO) derived from chronically inflamed tissues is a cause of carcinogenesis. We herein demonstrated that administration of an inducible NO synthase inhibitor, aminoguanidine, significantly suppressed the tumorigenic conversion of human colonic adenoma (FPCK-1-1) cells into adenocarcinoma (FPCK/Inflam) cells accelerated by foreign body-induced chronic inflammation in nude mice. To determine whether NO directly promotes carcinogenesis, we exposed FPCK-1-1 cells continuously to chemically generated NO (FPCK/NO), and periodically examined their tumorigenicity. FPCK/NO cells formed tumors, whereas vehicle-treated cells (FPCK/NaOH) did not. We selected a tumorigenic population from FPCK/NO cells kept it in three-dimensional (3D) culture where in vivo-like multicellular spheroidal growth was expected. FPCK/Inflam cells developed large spheroids whereas FPCK/NO cells formed tiny but growing compact aggregates in 3D culture. Meanwhile, FPCK-1-1 and FPCK/NaOH cells underwent anoikis (apoptotic cell death consequential on insufficient cell-to-substrate interactions) through activation of caspase 3. The survived cells in the 3D culture (FPCK/NO/3D), which were derived from FPCK/NO cells, showed a similar tumor incidence to that of FPCK/Inflam cells. These results showed that NO was one of the causative factors for the acceleration of colon carcinogenesis, especially in the conversion from adenoma to adenocarcinoma in the chronic inflammatory environment. (C) 2013 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.yexcr.2013.08.006

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  • Dual Programmed Cell Death Pathways Induced by p53 Transactivation Overcome Resistance to Oncolytic Adenovirus in Human Osteosarcoma Cells 査読 国際誌

    Joe Hasei, Tsuyoshi Sasaki, Hiroshi Tazawa, Shuhei Osaki, Yasuaki Yamakawa, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Teppei Onishi, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Molecular Cancer Therapeutics   12 ( 3 )   314 - 325   2013年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Tumor suppressor p53 is a multifunctional transcription factor that regulates diverse cell fates, including apoptosis and autophagy in tumor biology. p53 overexpression enhances the antitumor activity of oncolytic adenoviruses; however, the molecular mechanism of this occurrence remains unclear. We previously developed a tumor-specific replication-competent oncolytic adenovirus, OBP-301, that kills human osteosarcoma cells, but some human osteosarcoma cells were OBP-301-resistant. In this study, we investigated the antitumor activity of a p53-expressing oncolytic adenovirus, OBP-702, and the molecular mechanism of the p53-mediated cell death pathway in OBP-301-resistant human osteosarcoma cells. The cytopathic activity of OBP-702 was examined in OBP-301-sensitive (U2OS and HOS) and OBP-301-resistant (SaOS-2 and MNNG/HOS) human osteosarcoma cells. The molecular mechanism in the OBP-702-mediated induction of two cell death pathways, apoptosis and autophagy, was investigated in OBP-301-resistant osteosarcoma cells. The antitumor effect of OBP-702 was further assessed using an orthotopic OBP-301-resistant MNNG/HOS osteosarcoma xenograft tumor model. OBP-702 suppressed the viability of OBP-301-sensitive and -resistant osteosarcoma cells more efficiently than OBP-301 or a replication-deficient p53-expressing adenovirus (Ad-p53). OBP-702 induced more profound apoptosis and autophagy when compared with OBP-301 or Ad-p53. E1A-mediated miR-93/106b upregulation induced p21 suppression, leading to p53-mediated apoptosis and autophagy in OBP-702-infected cells. p53 overexpression enhanced adenovirus-mediated autophagy through activation of damage-regulated autophagy modulator (DRAM). Moreover, OBP-702 suppressed tumor growth in an orthotopic OBP-301-resistant MNNG/HOS xenograft tumor model. These results suggest that OBP-702-mediated p53 transactivation is a promising antitumor strategy to induce dual apoptotic and autophagic cell death pathways via regulation of miRNA and DRAM in human osteosarcoma cells. Mol Cancer Ther; 12(3); 314-25. (C)2012 AACR.

    DOI: 10.1158/1535-7163.MCT-12-0869

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  • A simple detection system for adenovirus receptor expression using a telomerase-specific replication-competent adenovirus 国際誌

    T. Sasaki, H. Tazawa, J. Hasei, S. Osaki, T. Kunisada, A. Yoshida, Y. Hashimoto, S. Yano, R. Yoshida, S. Kagawa, F. Uno, Y. Urata, T. Ozaki, T. Fujiwara

    GENE THERAPY   20 ( 1 )   112 - 118   2013年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Adenovirus serotype 5 (Ad5) is frequently used as an effective vector for induction of therapeutic transgenes in cancer gene therapy or of tumor cell lysis in oncolytic virotherapy. Ad5 can infect target cells through binding with the coxsackie and adenovirus receptor (CAR). Thus, the infectious ability of Ad5-based vectors depends on the CAR expression level in target cells. There are conventional methods to evaluate the CAR expression level in human target cells, including flow cytometry, western blotting and immunohistochemistry. Here, we show a simple system for detection and assessment of functional CAR expression in human tumor cells, using the green fluorescent protein (GFP)-expressing telomerase-specific replication-competent adenovirus OBP-401. OBP-401 infection induced detectable GFP expression in CAR-expressing tumor cells, but not in CAR-negative tumor cells, nor in CAR-positive normal fibroblasts, 24 h after infection. OBP-401-mediated GFP expression was significantly associated with CAR expression in tumor cells. OBP-401 infection detected tumor cells with low CAR expression more efficiently than conventional methods. OBP-401 also distinguished CAR-positive tumor tissues from CAR-negative tumor and normal tissues in biopsy samples. These results suggest that GFP-expressing telomerase-specific replication-competent adenovirus is a very potent diagnostic tool for assessment of functional CAR expression in tumor cells for Ad5-based antitumor therapy. Gene Therapy (2013) 20, 112-118; doi:10.1038/gt.2011.213; published online 12 January 2012

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  • Genetically engineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis 査読 国際誌

    Hiroshi Tazawa, Shuya Yano, Ryosuke Yoshida, Yasumoto Yamasaki, Tsuyoshi Sasaki, Yuuri Hashimoto, Shinji Kuroda, Masaaki Ouchi, Teppei Onishi, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Toshiyoshi Fujiwara

    International Journal of Cancer   131 ( 12 )   2939 - 2950   2012年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-BLACKWELL  

    Autophagy is known to have a cytoprotective role under various cellular stresses; however, it also results in robust cell death as an important safeguard mechanism that protects the organism against invading pathogens and unwanted cancer cells. Autophagy is regulated by cell signalling including microRNA (miRNA), a post-transcriptional regulator of gene expression. Here, we show that genetically engineered telomerase-specific oncolytic adenovirus induced miR-7 expression, which is significantly associated with its cytopathic activity in human cancer cells. Virus-mediated miR-7 upregulation depended on enhanced expression of the E2F1 protein. Ectopic expression of miR-7 suppressed cell viability and induced autophagy by inhibiting epidermal growth factor receptor (EGFR) expression. Our results suggest that oncolytic adenovirus induces autophagic cell death through an E2F1-miR-7-EGFR pathway in human cancer cells, providing a novel insight into the molecular mechanism of an anticancer virotherapy.

    DOI: 10.1002/ijc.27589

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  • Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2-extracellular domain in human cancer cells 査読 国際誌

    Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Shuya Yano, Teppei Onishi, Tsuyoshi Sasaki, Yasuhiro Shirakawa, Hiroyuki Kishimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Cancer Immunology Immunotherapy   61 ( 11 )   1905 - 1916   2012年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:SPRINGER  

    Trastuzumab, a humanized antibody targeting HER2, exhibits remarkable therapeutic efficacy against HER2-positive breast and gastric cancers; however, acquired resistance presents a formidable obstacle to long-term tumor responses in the majority of patients. Here, we show the mechanism of resistance to trastuzumab in HER2-positive human cancer cells and explore the molecular sensitization by exogenous expression of HER2-extracellular domain (ECD) in HER2-negative or trastuzumab-resistant human cancer cells. We found that long-term exposure to trastuzumab induced resistance in HER2-positive cancer cells; HER2 expression was downregulated, and antibody-dependent cellular cytotoxicity (ADCC) activity was impaired. We next examined the hypothesis that trastuzumab-resistant cells could be re-sensitized by the transfer of non-functional HER2-ECD. Exogenous HER2-ECD expression induced by the stable transfection of a plasmid vector or infection with a replication-deficient adenovirus vector had no apparent effect on the signaling pathway, but strongly enhanced ADCC activity in low HER2-expressing or trastuzumab-resistant human cancer cells. Our data indicate that restoration of HER2-ECD expression sensitizes HER2-negative or HER2-downregulated human cancer cells to trastuzumab-mediated ADCC, an outcome that has important implications for the treatment of human cancers.

    DOI: 10.1007/s00262-012-1249-x

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  • A novel apoptotic mechanism of genetically engineered adenovirus-mediated tumour-specific p53 overexpression through E1A-dependent p21 and MDM2 suppression 査読 国際誌

    Yasumoto Yamasaki, Hiroshi Tazawa, Yuuri Hashimoto, Toru Kojima, Shinji Kuroda, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Hiroyuki Mizuguchi, Akira Ohtsuru, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    EUROPEAN JOURNAL OF CANCER   48 ( 14 )   2282 - 2291   2012年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Oncolytic viruses engineered to replicate in tumour cells but not in normal cells could be used as tumour-specific vectors carrying the therapeutic genes. We previously developed a telomerase-specific oncolytic adenovirus, OBP-301, that causes cell death in human cancer cells with telomerase activities. Here, we further modified OBP-301 to express the wild-type p53 tumour suppressor gene (OBP-702), and investigated whether OBP-702 induces stronger antitumour activity than OBP-301. The antitumour effect of OBP-702 was compared to that of OBP-301 on OBP-301-sensitive (H358 and H460) and OBP-301-resistant (T.Tn and HSC4) human cancer cells. OBP-702 suppressed the viability of both OBP-301-sensitive and OBP-301-resistant cancer cells more efficiently than OBP-301. OBP-702 caused increased apoptosis compared to OBP-301 or a replication-deficient adenovirus expressing the p53 gene (Ad-p53) in H358 and T.Tn cells. Adenovirus E1A-mediated p21 and MDM2 downregulation was involved in the apoptosis caused by OBP-702. Moreover, OBP-702 significantly suppressed tumour growth in subcutaneous tumour xenograft models compared to monotherapy with OBP-301 or Ad-p53. Our data demonstrated that OBP-702 infection expressed adenovirus E1A and then inhibited p21 and MDM2 expression, which in turn efficiently induced apoptotic cell death. This novel apoptotic mechanism suggests that the p53-expressing OBP-702 is a promising antitumour reagent for human cancer and could improve the clinical outcome. (C) 2011 Elsevier Ltd. All rights reserved.

    DOI: 10.1016/j.ejca.2011.12.020

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  • Synergistic Interaction of Telomerase-Specific Oncolytic Virotherapy and Chemotherapeutic Agents for Human Cancer 招待 査読 国際誌

    Toshiyoshi Fujiwara, Shunsuke Kagawa, Hiroshi Tazawa

    Current Pharmaceutical Biotechnology   13 ( 9 )   1809 - 1816   2012年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BENTHAM SCIENCE PUBL LTD  

    Replication-selective tumor-specific viruses present a novel approach for treatment of neoplastic disease. These vectors are designed to induce virus-mediated lysis of tumor cells after selective viral propagation within the tumor. Telomerase activation is considered to be a critical step in carcinogenesis through the maintenance of telomeres, and its activity correlates closely with human telomerase reverse transcriptase (hTERT) expression. We constructed an attenuated adenovirus 5 vector, in which the hTERT promoter element drives expression of E1 genes, OBP-301 (Telomelysin). Since only tumor cells that express telomerase activity would activate this promoter, the hTERT proximal promoter allows for preferential expression of viral genes in tumor cells, leading to selective viral replication and oncolytic cell death. OBP-301 alone exhibited substantial antitumor effects both in animal models and in clinical trials; data regarding combination therapy with OBP-301 and chemotherapeutic agents are preliminary but encouraging. This article reviews synergistic interaction of virotherapy and chemotherapy, and illustrates the potential application for the treatment of human cancer.

    DOI: 10.2174/138920112800958887

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  • The hTERT Promoter Enhances the Antitumor Activity of an Oncolytic Adenovirus under a Hypoxic Microenvironment 査読 国際誌

    Yuuri Hashimoto, Hiroshi Tazawa, Fuminori Teraishi, Toru Kojima, Yuichi Watanabe, Futoshi Uno, Shuya Yano, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    PLOS ONE   7 ( 6 )   e39292   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:PUBLIC LIBRARY SCIENCE  

    Hypoxia is a microenvironmental factor that contributes to the invasion, progression and metastasis of tumor cells. Hypoxic tumor cells often show more resistance to conventional chemoradiotherapy than normoxic tumor cells, suggesting the requirement of novel antitumor therapies to efficiently eliminate the hypoxic tumor cells. We previously generated a tumor-specific replication-competent oncolytic adenovirus (OBP-301: Telomelysin), in which the human telomerase reverse transcriptase (hTERT) promoter drives viral E1 expression. Since the promoter activity of the hTERT gene has been shown to be upregulated by hypoxia, we hypothesized that, under hypoxic conditions, the antitumor effect of OBP-301 with the hTERT promoter would be more efficient than that of the wild-type adenovirus 5 (Ad5). In this study, we investigated the antitumor effects of OBP-301 and Ad5 against human cancer cells under a normoxic (20% oxygen) or a hypoxic (1% oxygen) condition. Hypoxic condition induced nuclear accumulation of the hypoxia-inducible factor-1 alpha and upregulation of hTERT promoter activity in human cancer cells. The cytopathic activity of OBP-301 was significantly higher than that of Ad5 under hypoxic condition. Consistent with their cytopathic activity, the replication of OBP-301 was significantly higher than that of Ad5 under the hypoxic condition. OBP-301-mediated E1A was expressed within hypoxic areas of human xenograft tumors in mice. These results suggest that the cytopathic activity of OBP-301 against hypoxic tumor cells is mediated through hypoxia-mediated activation of the hTERT promoter. Regulation of oncolytic adenoviruses by the hTERT promoter is a promising antitumor strategy, not only for induction of tumor-specific oncolysis, but also for efficient elimination of hypoxic tumor cells.

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  • A protein transduction method using oligo-arginine (3R) for the delivery of transcription factors into cell nuclei 査読 国際誌

    Takashi Hitsuda, Hiroyuki Michiue, Mizuki Kitamatsu, Atsushi Fujimura, Feifei Wang, Takahiro Yamamoto, Xiao-Jian Han, Hiroshi Tazawa, Atsuhito Uneda, Iori Ohmori, Tei-ichi Nishiki, Kazuhito Tomizawa, Hideki Matsui

    Biomaterials   33 ( 18 )   4665 - 4672   2012年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI LTD  

    Protein transduction with cell-penetrating peptides such as poly-arginine and HIV TAT peptides is widely used to deliver proteins, peptides, siRNA and biologically active compounds. It has been thought that poly-arginine peptides transduce proteins in a manner dependent on the number of arginine residues and oligo-peptides such as three arginines (3R) are ineffective. Here we showed that 3R-fused proteins were effectively delivered and functioned in cells co-treated with pyrenebutyrate, a counteranion bearing an aromatic hydrophobic moiety. Little 3R was transduced in glioma cells without pyrenebutyrate whereas the oligo-arginine was effectively delivered with pyrenebutyrate. Enhanced green fluorescence protein (eGFP) fused with 3R was effectively delivered into various kinds of cells including primary cultured cells and suspended cells in the presence of pyrenebutyrate. p53 fused with 3R (3R-p53) was delivered into glioma cells without pyrenebutyrate but could not be translocated into the ncleus. In contrast, 3R-p53 was observed in nuclei of glioma cells when co-applied with pyrenebutyrate. Although 3R-p53 was delivered less effectively than 11R-p53 with pyrenebutyrate, its transcriptional activity was higher than that of 11R-p53. Moreover, a single administration of 3R-p53 with pyrenebutyrate significantly inhibited the growth of cancer cells. These results suggest protein transduction using an oligo-arginine (3R) with pyrenebutyrate to be a good tool for the delivery of functional transcription factors and a promising method of treating cancer. (C) 2012 Elsevier Ltd. All rights reserved.

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  • Preclinical Evaluation of Telomerase-Specific Oncolytic Virotherapy for Human Bone and Soft Tissue Sarcomas 査読 国際誌

    Tsuyoshi Sasaki, Hiroshi Tazawa, Jo Hasei, Toshiyuki Kunisada, Aki Yoshida, Yuuri Hashimoto, Shuya Yano, Ryosuke Yoshida, Futoshi Uno, Shunsuke Kagawa, Yuki Morimoto, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    Clinical Cancer Research   17 ( 7 )   1828 - 1838   2011年4月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    Purpose: Tumor-specific replication-selective oncolytic virotherapy is a promising antitumor therapy for induction of cell death in tumor cells but not of normal cells. We previously developed an oncolytic adenovirus, OBP-301, that kills human epithelial malignant cells in a telomerase-dependent manner. Recent evidence suggests that nonepithelial malignant cells, which have low telomerase activity, maintain telomere length through alternative lengthening of telomeres (ALT). However, it remains unclear whether OBP-301 is cytopathic for nonepithelial malignant cells. Here, we evaluated the antitumor effect of OBP-301 on human bone and soft tissue sarcoma cells.
    Experimental Design: The cytopathic activity of OBP-301, coxsackie and adenovirus receptor (CAR) expression, and telomerase activity were examined in 10 bone (OST, U2OS, HOS, HuO9, MNNG/HOS, SaOS-2, NOS-2, NOS-10, NDCS-1, and OUMS-27) and in 4 soft tissue (CCS, NMS-2, SYO-1, and NMFH-1) sarcoma cell lines. OBP-301 antitumor effects were assessed using orthotopic tumor xenograft models. The fiber-modified OBP-301 (termed OBP-405) was used to confirm an antitumor effect on OBP-301-resistant sarcomas.
    Results: OBP-301 was cytopathic for 12 sarcoma cell lines but not for the non-CAR-expressing OUMS27 and NMFH-1 cells. Sensitivity to OBP-301 was dependent on CAR expression and not on telomerase activity. ALT-type sarcomas were also sensitive to OBP-301 because of upregulation of human telomerase reverse transcriptase (hTERT) mRNA following virus infection. Intratumoral injection of OBP-301 significantly suppressed the growth of OST and SYO-1 tumors. Furthermore, fiber-modified OBP-405 showed antitumor effects on OBP-301-resistant OUMS-27 and NMFH-1 cells.
    Conclusions: A telomerase-specific oncolytic adenovirus is a promising antitumor reagent for the treatment of bone and soft tissue sarcomas. Clin Cancer Res; 17(7); 1828-38. (C) 2011 AACR.

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  • MicroRNAs as potential target gene in cancer gene therapy of gastrointestinal tumors 査読 国際誌

    Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Expert Opinion on Biological Therapy   11 ( 2 )   145 - 155   2011年2月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INFORMA HEALTHCARE  

    Introduction: MicroRNA (miRNA) is a small non-coding RNA, which negatively regulates the expression of many target genes, thereby contributing to the modulation of diverse cell fates. Recent advances in molecular biology have revealed the potential role of miRNAs in tumor initiation, progression and metastasis. Aberrant regulation of miRNAs has been frequently reported in a variety of cancers, including gastrointestinal tumors, suggesting that cancer-related miRNAs are promising as novel biomarkers for tumor diagnosis and are potential target genes for cancer gene therapy against gastrointestinal tumors.
    Areas covered: The review focuses on the role of specific miRNAs (miR-192/194/215 and miR-7) in the differentiation of gastrointestinal epithelium and on the role of tumor-suppressive (miR-34, miR-143, miR-145) and oncogenic miRNAs (miR-21, miR-17-92 cluster) in gastrointestinal tumors. Furthermore, the potential role of miRNAs as novel biomarkers and target genes for cancer gene therapy against gastrointestinal tumors are discussed. We will also outline the potential clinical application of miRNAs for tumor diagnosis and cancer gene therapy against gastrointestinal tumors.
    Expert opinion: Exploration of tumor-related miRNAs would provide important opportunities for the development of novel cancer gene therapies aimed at normalizing the critical miRNAs that are deregulated in gastrointestinal tumors.

    DOI: 10.1517/14712598.2011.542749

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  • Telomerase-Dependent Oncolytic Adenovirus Sensitizes Human Cancer Cells to Ionizing Radiation via Inhibition of DNA Repair Machinery 査読 国際誌

    Shinji Kuroda, Toshiya Fujiwara, Yasuhiro Shirakawa, Yasumoto Yamasaki, Shuya Yano, Futoshi Uno, Hiroshi Tazawa, Yuuri Hashimoto, Yuichi Watanabe, Kazuhiro Noma, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Cancer Research   70 ( 22 )   9339 - 9348   2010年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    The inability to repair DNA double-strand breaks (DSB) leads to radiosensitization, such that ionizing radiation combined with molecular inhibition of cellular DSB processing may greatly affect treatment of human cancer. As a variety of viral products interact with the DNA repair machinery, oncolytic virotherapy may improve the therapeutic window of conventional radiotherapy. Here, we describe the mechanistic basis for synergy of irradiation and OBP-301 (Telomelysin), an attenuated type-5 adenovirus with oncolytic potency that contains the human telomerase reverse transcriptase promoter to regulate viral replication. OBP-301 infection led to E1B55kDa viral protein expression that degraded the complex formed by Mre11, Rad50, and NBS1, which senses DSBs. Subsequently, the phosphorylation of cellular ataxia-telangiectasia mutated protein was inhibited, disrupting the signaling pathway controlling DNA repair. Thus, tumor cells infected with OBP-301 could be rendered sensitive to ionizing radiation. Moreover, by using noninvasive whole-body imaging, we showed that intratumoral injection of OBP-301 followed by regional irradiation induces a substantial antitumor effect, resulting from tumor cell-specific radiosensitization, in an orthotopic human esophageal cancer xenograft model. These results illustrate the potential of combining oncolytic virotherapy and ionizing radiation as a promising strategy in the management of human cancer. Cancer Res; 70(22); 9339-48. (C) 2010 AACR.

    DOI: 10.1158/0008-5472.CAN-10-2333

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  • In Vivo Biological Purging for Lymph Node Metastasis of Human Colorectal Cancer by Telomerase-Specific Oncolytic Virotherapy 査読

    Toru Kojima, Yuichi Watanabe, Yuuri Hashimoto, Shinji Kuroda, Yasumoto Yamasaki, Shuya Yano, Masaaki Ouchi, Hiroshi Tazawa, Futoshi Uno, Shunsuke Kagawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    ANNALS OF SURGERY   251 ( 6 )   1079 - 1086   2010年6月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    Background/Objective: The aim of this study was to develop a less invasive way of targeting lymph node metastasis for the treatment of human gastrointestinal cancer. Lymphatic invasion is a major route for cancer cell dissemination, and adequate treatment of locoregional lymph nodes is required for curative treatment in patients with malignancies.
    Methods: Human telomerase reverse transcription (hTERT) is the catalytic subunit of telomerase, which is highly active in cancer cells but quiescent in most normal somatic cells. OBP-301 (Telomelysin) is an attenuated adenovirus with oncolytic potency that contains the hTERT promoter element to regulate viral replication. We examined whether OBP-301 injected into the primary tumor might be useful for purging micrometastasis from regional lymph nodes in an orthotopic colorectal cancer model.
    Results: OBP-301 was intratumorally injected into HT29 tumors orthotopically implanted into the rectum in BALB/c nu/nu mice. By using a highly sensitive quantitative PCR analysis that targets the human-specific Alu sequence, we showed that OBP-301 caused viral spread into the regional lymphatic area and selectively replicated in neoplastic lesions, resulting in tumor-cell-specific death in metastatic lymph nodes. Moreover, although the surgical removal of primary tumors increased the tendency of lymph node metastasis, preoperative intratumoral injection of virus significantly reduced lymph node metastasis.
    Conclusions: Our results indicate that intratumoral injection of OBP-301 mediates effective in vivo purging of metastatic tumor cells from regional lymph nodes, which may help optimize treatment of human cancer, especially gastrointestinal malignancies.

    DOI: 10.1097/SLA.0b013e3181deb69d

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  • A simple biological imaging system for detecting viable human circulating tumor cells 査読

    Toru Kojima, Yuuri Hashimoto, Yuichi Watanabe, Shunsuke Kagawa, Futoshi Uno, Shinji Kuroda, Hiroshi Tazawa, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    JOURNAL OF CLINICAL INVESTIGATION   119 ( 10 )   3172 - 3181   2009年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC CLINICAL INVESTIGATION INC  

    The presence of circulating tumor cells (CTCs) in the peripheral blood is associated with short survival, making the detection of CTCs clinically useful as a prognostic factor of disease outcome and/or a surrogate marker of treatment response. Recent technical advances in immunocytometric analysis and quantitative real-time PCR have made it possible to detect a few CTCs in the blood; however, there is no sensitive assay to specifically detect viable CTCs. Here, we report what we believe to be a new approach to visually detect live human CTCs among millions of peripheral blood leukocytes, using a telomerase-specific replication-selective adenovirus expressing GFP. First, we constructed a GFP-expressing attenuated adenovirus, in which the telomerase promoter regulates viral replication (OBP-401; TelomeScan). We then used OBP-401 to establish a simple ex vivo method that was able to detect viable human CTCs in the peripheral blood. The detection method involved a 3-step procedure, including the lysis of rbc, the subsequent addition of OBP-401 to the cell pellets, and an automated scan using fluorescence microscopy. OBP-401 infection increased the signal-to-background ratio as a tumor-specific probe, because the fluorescent signal was amplified only in viable, infected human tumor cells, by viral replication. This GFP-expressing virus-based method is remarkably simple and allows precise enumeration of CTCs.

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  • Lipopolysaccharide induces aberrant hypermethylation of Hic-1 in mouse embryonic fibroblasts lacking p53 gene 査読

    Masayuki Tatemichi, Harumi Hata, Hiroshi Tazawa, Toshio Nakadate

    ANTICANCER RESEARCH   28 ( 4B )   2101 - 2108   2008年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:INT INST ANTICANCER RESEARCH  

    Background: The present study asked whether continuous administration with lipopolysaccharide (LPS), a potent inflammatory agent, induces aberrant methylation in the promoter region of tumor suppressor genes and p53 and/or inducible nitric oxide synthase (iNOS) genes involved in its aberrant methylation. Materials and Methods: Mouse embryonic fibroblasts (MEFs) were prepared from mice harboring four different genotypes (p53(+/+)iNOS(+/+), p53(+/+)iNOS(-/-), p53(-/-)iNOS(+/+) and p53(-/-)iNOS(-/-)). The MEFs were immortalized by 3T3 procedure and continuously cultured under a medium containing LPS or LPS plus interferon (IFN) gamma during 40 passages. The methylation status in the CpG site of hypermethylated in cancer-1 (Hic-1) exon 1a and p16 promoter region was monitored using bisulfite-sequencing methods. Results: LPS and LPS plus IFN-gamma induced de novo methylation in the CpG sites of the Hic-1 gene. This site was methylated only in p53(-/-) MEFs, and the mRNA expression of Hic-1 decreased in p53(-/-) MEFs compared to p53(+/+) MEFs. The methylation patterns of Hic-1, however, were not affected by iNOS gene status. The promoter region of p16 was methylated by increasing the passage, even under the control medium, with LPS administration promoting methylation, particularly in MEFs lacking the iNOS gene. However, the methylation pattern was not significantly different between the p53 genotypes. Conclusion: Our preliminary study suggests that LPS induces de novo methylation in the CpG site in MEFs. For the Hic-1 gene, but not p16, the p53 gene might protect against aberrant methylation. The iNOS gene might not be involved in methylation of the Hic-1 gene, whereas the promoter region of p16 could be prone to methylation in MEFs lacking the iNOS gene.

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  • Tumor-suppressive miR-34a induces senescence-like growth arrest through modulation of the E2F pathway in human colon cancer cells 査読

    Hiroshi Tazawa, Naoto Tsuchiya, Masashi Izumiya, Hitoshi Nakagama

    PROCEEDINGS OF THE NATIONAL ACADEMY OF SCIENCES OF THE UNITED STATES OF AMERICA   104 ( 39 )   15472 - 15477   2007年9月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATL ACAD SCIENCES  

    Accumulating evidence suggests a role for microRNAs in human carcinogenesis as novel types of tumor suppressors or oncogenes. However, their precise biological role remains largely elusive. In the present study, we aimed to identify microRNA species involved in the regulation of cell proliferation. Using quantitative RT-PCR analysis, we demonstrated that miR-34a was highly up-regulated in a human colon cancer cell line, HCT 116, treated with a DNA-damaging agent, adriamycin. Transient introduction of miR-34a into two human colon cancer cell lines, HCT 116 and RKO, caused complete suppression of cell proliferation and induced senescence-like phenotypes. Moreover, miR-34a also suppressed in vivo growth of HCT 116 and RKO cells in tumors in mice when complexed and administered with atelocollagen for drug delivery. Gene-expression microarray and immunoblot analyses revealed down-regulation of the E2F pathway by miR-34a introduction. Up-regulation of the p53 pathway was also observed. Furthermore, 9 of 25 human colon cancers (36%) showed decreased expression of miR-34a compared with counterpart normal tissues. Our results provide evidence that miR-34a functions as a potent suppressor of cell proliferation through modulation of the E2F signaling pathway. Abrogation of miR-34a function could contribute to aberrant cell proliferation, leading to colon cancer development.

    DOI: 10.1073/pnas.0707351104

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  • Mouse strain differences in inflammatory responses of colonic mucosa induced by dextran sulfate sodium cause differential susceptibility to PhIP-induced large bowel carcinogenesis 査読

    Masako Nakanishi, Hiroshi Tazawa, Naoto Tsuchiya, Takashi Sugimura, Takuji Tanaka, Hitoshi Nakagama

    CANCER SCIENCE   98 ( 8 )   1157 - 1163   2007年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:BLACKWELL PUBLISHING  

    In mice, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces a high incidence of malignant lymphoma and leukemia, but exhibits little, if any, carcinogenic activity in the large intestine after long-term exposure. However, recent studies have revealed that colonic adenocarcinomas can be efficiently and rapidly induced by combined treatment with PhIP and dextran sulfate sodium (DSS), a potent inducer of colitis. In the present study, the authors investigated the effects of inflammation on PhIP-induced carcinogenesis using two mouse strains, C57BL/6J and MSM/Ms, showing distinct temporal profiles of inflammatory responses to DSS. A long-term carcinogenesis experiment conducted with a single i.g. administration of PhIP (200 mg/kg body weight), followed by DSS treatment in drinking water for 4-6 days, revealed an increase in tumor incidence in C57BL/6J mice in accordance with the DSS intake. In contrast, neoplastic lesions were rarely observed in the MSM/Ms strain. From the short-term exposure to DSS for 4 days, C57BL/6J mice demonstrated severe chronic colitis, accompanied by hyperplastic cryptal epithelium and extensive cellular infiltration. Splenomegaly and swelling of mesenteric lymph nodes were also evident for over 1 month as chronic symptoms of systemic immunological disturbance. However, no inflammatory lesions were detected in MSM/Ms mice. The present results provide strong evidence that prolonged chronic inflammatory responses induced by DSS are directly responsible for the observed enhancement of PhIP-induced large bowel carcinogenicity.

    DOI: 10.1111/j.1349-7006.2007.00528.x

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  • Mouse strain differences in inflammatory responses of colonic mucosa induced by dextran sulfate sodium cause differential susceptibility to PhIP-induced large bowel carcinogenesis 査読

    Masako Nakanishi, Hiroshi Tazawa, Naoto Tsuchiya, Takashi Sugimura, Takuji Tanaka, Hitoshi Nakagama

    Cancer Science   98 ( 8 )   1157 - 1163   2007年8月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)  

    In mice, 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) induces a high incidence of malignant lymphoma and leukemia, but exhibits little, if any, carcinogenic activity in the large intestine after long-term exposure. However, recent studies have revealed that colonic adenocarcinomas can be efficiently and rapidly induced by combined treatment with PhIP and dextran sulfate sodium (DSS), a potent inducer of colitis. In the present study, the authors investigated the effects of inflammation on PhIP-induced carcinogenesis using two mouse strains, C57BL/6J and MSM/Ms, showing distinct temporal profiles of inflammatory responses to DSS. A long-term carcinogenesis experiment conducted with a single i.g. administration of PhIP (200 mg/kg body weight), followed by DSS treatment in drinking water for 4-6 days, revealed an increase in tumor incidence in C57BL/6J mice in accordance with the DSS intake. In contrast, neoplastic lesions were rarely observed in the MSM/Ms strain. From the short-term exposure to DSS for 4 days, C57BL/6J mice demonstrated severe chronic colitis, accompanied by hyperplastic cryptal epithelium and extensive cellular infiltration. Splenomegaly and swelling of mesenteric lymph nodes were also evident for over 1 month as chronic symptoms of systemic immunological disturbance. However, no inflammatory lesions were detected in MSM/Ms mice. The present results provide strong evidence that prolonged chronic inflammatory responses induced by DSS are directly responsible for the observed enhancement of PhIP-induced large bowel carcinogenicity. © 2007 Japanese Cancer Association.

    DOI: 10.1111/j.1349-7006.2007.00528.x

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  • Oxidative and nitrative stress caused by subcutaneous implantation of a foreign body accelerates sarcoma development in Trp53(+/-) mice 査読

    Hiroshi Tazawa, Masayuki Tatemichi, Tomohiro Sawa, Isabelle Gilibert, Ning Ma, Yusuke Hiraku, Lawrence A. Donehower, Hiroko Ohgaki, Shosuke Kawanishi, Hiroshi Ohshima

    CARCINOGENESIS   28 ( 1 )   191 - 198   2007年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:OXFORD UNIV PRESS  

    Chronic inflammation is a recognized risk factor for human cancer at various sites because of persistent oxidative and nitrative tissue damage. Trp53(+/-) mice show the predisposition to tumor development, such as sarcomas and lymphomas, compared with Trp53(+/+) mice. We investigated the effects of chronic inflammation, especially oxidative and nitrative stress, induced by subcutaneous implantation of a plastic plate (10 x 5 x 1 mm) as a foreign body on tumorigenesis in Trp53(+/-) and Trp53(+/+) mice. The plastic plates were implanted at the age of about 11 weeks. Thirty out of 38 Trp53(+/-) mice (79%) developed sarcomas around the implant (mean time of tumor appearance was 45.8 +/- 12.0 weeks of age), whereas only one of 10 Trp53(+/+) mice with an implant (10%) developed a tumor, at 56 weeks. No sarcomas developed at a sham-operation site. Two of 10 Trp53(+/-) mice with no implant (20%) also developed three sarcomas spontaneously at 77, 81 and 84 weeks. Increased immunostaining for markers of oxidative and nitrative stress (8-oxo-7,8-dihydro-2'-deoxyguanosine, 8-nitroguanine and 3-nitrotyrosine) and expression of inducible nitric oxide synthase in tumor cells and inflammatory cells were detected in implant-induced sarcomas compared with spontaneous sarcomas in Trp53(+/-) mice. Furthermore, p53 loss of heterozygosity was observed in 26 out of 29 implant-induced sarcomas (90%). These results indicate that implanted foreign bodies significantly enhanced sarcoma development in Trp53(+/-) mice, and this may be associated with increased oxidaive and nitrative stress. Loss of the remaining wild-type p53 allele and loss of p53 function appears to be, at least in part, underlying molecular mechanisms during the development of sarcomas at the implantation site in Trp53(+/-) mice. Such implant-induced sarcoma development in Trp53(+/-) mice could be useful for studying molecular mechanisms and developing new strategies for chemoprevention in human carcinogenesis induced by chronic inflammation and/or foreign bodies.

    DOI: 10.1093/carcin/bgl128

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  • The role of nicotinamide adenine dinucleotide phosphate oxidase-derived reactive oxygen species in the acquisition of metastatic ability of tumor cells 査読

    F Okada, M Kobayashi, H Tanaka, T Kobayashi, H Tazawa, Y Iuchi, K Onuma, M Hosokawa, MC Dinauer, NH Hunt

    AMERICAN JOURNAL OF PATHOLOGY   169 ( 1 )   294 - 302   2006年7月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    We examined the role of phagocyte-derived oxygen radicals in tumor cell acquisition of metastatic phenotype by comparing gp91(phox-/-) mice and C57BL/6J wild-type (WT) mice. The gp91(phox-/-) mouse is deficient in the gp91(phox) gene, an essential subunit of the phagocyte nicotinamide adenine dinucleotide phosphate oxidase that generates superoxide anion. QR-32 fibrosarcoma cells are nonmetastatic but are converted into metastatic tumors once in contact with foreign body (gelatin sponge)-induced phagocytes in vivo. Compared to QR-32 cells co-implanted with the foreign body in WT mice, those in gp91(phox-/-) mice exhibited reduced metastasis. There was no difference in the incidence of primary tumors after injection of B16BL6 melanoma cells in WT and gp91(phox-/-) mice. However, after resection of the primary tumors, metastases; were reduced in gp91(phox-/-) mice. Thymosin beta 4 gene expression and cell motility/invasion were seen in the tumors from WT mice but not in those from gp91(Phox-/-) mice. Adoptive transfer of phagocytes from WT mice, but not those from gp91(phox-/-) mice, restored the metastatic ability of tumors grown in gp91(phox-/-) mice. These findings show that tumor metastatic behavior can primarily be endowed by phagocyte-derived superoxide anion and its oxidative metabolites, which are generated through activation of nicotinamide adenine dinucleotide phosphate oxidase.

    DOI: 10.2353/ajpath.2006.060073

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  • Prevention of inflammation-mediated acquisition of metastatic properties of benign mouse fibrosarcoma cells by administration of an orally available superoxide dismutase

    F Okada, H Shionoya, M Kobayashi, T Kobayashi, H Tazawa, K Onuma, Y Iuchi, N Matsubara, T Ijichi, B Dugas, M Hosokawa

    BRITISH JOURNAL OF CANCER   94 ( 6 )   854 - 862   2006年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:NATURE PUBLISHING GROUP  

    Weakly tumorigenic and nonmetastatic QR- 32 cells derived from a fibrosarcoma in C57BL6 mouse are converted to malignant cells once they have grown after being coimplanted with a gelatine sponge which induces inflammation. We administered a newly developed peroral superoxide dismutase ( SOD), oxykine, and as control vehicle, gliadin and saline, starting 2 days before the coimplantation and continued daily throughout the experiment. In the oxykine group, tumour incidence was lower ( 41%) than in the gliadin or saline group ( 83 and 79%, respectively). The inhibitory effect of oxykine was lost when an individual component of oxykine was administered, that is, SOD alone and gliadin alone. The effect was also abolished when administered by intraperitoneal route. When perfused in situ with nitroblue tetrazolium, an indicator of superoxide formation, the tumour masses from gliadin and saline groups displayed intense formazan deposition, whereas, those from oxykine group had less deposition. Enzymatic activity of SOD was also increased in oxykine group. Arising tumour cells in gliadin and saline groups acquired metastatic phenotype, but those in oxykine group showed reduced metastatic ability. These results suggested that the orally active SOD derivative prevented tumour progression promoted by inflammation, which is thought to be through scavenging inflammatory cell- derived superoxide anion.

    DOI: 10.1038/sj.bjc.6603016

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  • Involvement of reactive nitrogen oxides for acquisition of metastatic properties of benign tumors in a model of inflammation-based tumor progression 査読

    F Okada, H Tazawa, T Kobayashi, M Kobayashi, M Hosokawa

    NITRIC OXIDE-BIOLOGY AND CHEMISTRY   14 ( 2 )   122 - 129   2006年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ACADEMIC PRESS INC ELSEVIER SCIENCE  

    The cells of a weakly tumorigenic and non-metastatic murine fibrosarcoma (QR-32) are converted into highly malignant tumors (acquiring metastatic potential) once they have grown in vivo after being co-implanted with gelatin sponge which induces inflammation. In the present study, we examined whether nitric oxide (NO) is involved in the inflammation-based tumor progression by administrating a specific inhibitor to inducible nitric oxide synthase, aminoguanidine (AG). First, we co-implanted 1 x 10(5) QR-32 cells with gelatin sponge (10 x 5 x 3 mm piece) into a subcutaneous space in C57BL6 mice. Administration of AG in drinking water (1%) had started 2 days before the tumor implantation and continued until the termination of the experiment. The incidence of tumor formation and the tumor growth did not differ between AG-treated group and -untreated group. On day 28,. we excised the arising tumors to establish culture cell lines for evaluation of their acquisition of metastatic phenotype in other normal mice. Metastasis incidence and the number of metastatic colonies were significantly reduced in the tumor cell lines obtained from AG-treated mice compared to those from non-treated mice (p &lt; 0.05). Immunohistochemical analysis demonstrated that inducible nitric oxide synthase and nitrotyrosine in the inflamed lesion were reduced in the AG-administered mice. However, intensity of 8-hydroxy-2-deoxyguanosine was not different between the groups. These results showed that nitric oxide and its reactive nitrogen oxide species cooperatively play a pivotal role in the progression of benign tumor cells in inflamed lesions. (c) 2005 Elsevier Inc. All rights reserved.

    DOI: 10.1016/j.niox.2005.06.009

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  • Prevention of human cancer by modulation of chronic inflammatory processes 査読

    H Ohshima, H Tazawa, BS Sylla, T Sawa

    MUTATION RESEARCH-FUNDAMENTAL AND MOLECULAR MECHANISMS OF MUTAGENESIS   591 ( 1-2 )   110 - 122   2005年12月

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    記述言語:英語   出版者・発行元:ELSEVIER SCIENCE BV  

    Chronic inflammation induced by biological, chemical and physical factors has been associated with increased risk of human cancer at various sites. Inflammation facilitates the initiation of normal cells and their growth and progression to malignancy through production of pro-inflammatory cytokines and diverse reactive oxygen and nitrogen species. These also activate signaling molecules involved in inflammation and carcinogenesis such as nuclear transcription factor (NF-kappa B), inducible nitric oxide synthase (iNOS) and cyclooxygenase-2 (COX-2). Several chemopreventive agents act through inhibition of signaling pathways (e.g. NF-kappa B), inhibition of oxidant-generating enzymes (e.g. NOS) and mediators of inflammation (c,g, COX-2), scavenging reactive oxygen and nitrogen species, and modulation of xenobiotic-metabolizing enzymes (especially phase 11 enzyme induction). Some anti-inflammatory drugs have been tested in clinical trials to prevent human cancer at several sites, Better understanding of the molecular mechanisms by which chronic inflammation increases cancer risk will lead to further development of new strategies for cancer prevention at many sites. (c) 2005 Elsevier B.V. All rights reserved.

    DOI: 10.1016/j.mrfmmm.2005.03.030

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  • Increased risk of intestinal type of gastric adenocarcinoma in Japanese women associated with long forms of CCTTT pentanucleotide repeat in the inducible nitric oxide synthase promoter 査読

    M Tatemichi, T Sawa, Gilibert, I, H Tazawa, T Katoh, H Ohshima

    CANCER LETTERS   217 ( 2 )   197 - 202   2005年1月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:ELSEVIER SCI IRELAND LTD  

    Tandem repeat number polymorphism of a CCTTT pentanucleotide in the promoter region of the inducible nitric oxide synthase gene (iNOS) and a polymorphism of the interleukin-1beta (IL-1B) promoter at position -31 were analyzed in DNA samples from 181 Japanese control subjects and 158 gastric cancer patients, including 96 intestinal type and 62 diffuse type. An association between the intestinal type of gastric adenocarcinoma and higher promoter activity of the iNOS gene was found in women, especially those having higher promoter activity of the IL-1B gene and without a history of smoking. Our results imply that chronic inflammation caused by excess nitric oxide generated by iNOS contributes to Helicobacter pylori-induced gastric cancer. (C) 2004 Elsevier Ireland Ltd. All rights reserved.

    DOI: 10.1016/j.canlet.2004.09.002

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  • Suppression of thymic lymphomas and increased nonthymic lymphomagenesis in TRP53-deficient mice lacking inducible nitric oxide synthase gene 査読

    M Tatemichi, H Tazawa, M Masuda, M Saleem, S Wada, LA Donehower, H Ohgaki, H Ohshima

    INTERNATIONAL JOURNAL OF CANCER   111 ( 6 )   819 - 828   2004年10月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:WILEY-LISS  

    Trp53-deficient mice spontaneously develop lymphomas, mainly of thymic origin, although the molecular mechanism remains largely unknown. As several interaction effects between p53 and iNOS have been reported, we hypothesized that iNOS activity in the thymus is causally linked to lymphomagenesis in Trp53-deficient mice. We therefore created mouse strains with different combinations of the Trp53 and iNOS genes. Western blot and histologic analyses showed that the iNOS protein was constitutively expressed in the thymus independently of Trp53 status and its expression was enhanced in Trp53(+/-) and Trp53(-/-) mice compared to Trp53(+/+) mice. Homozygous disruption of iNOS decreased the incidence of thymic lymphomas by almost 40% (p = 0.087) and 90% (p &lt; 0.05) in Trp53(-/-) and Trp53(+/-) mice, respectively, compared to the respective iNOS wild-type mice but significantly (p &lt; 0.05) increased the development of nonthymic lymphomas in Trp53(-/-) and Trp53(+/-) mice. Although iNOS gene disruption did not affect the phenotype of thymic lymphomas, absence of the iNOS gene shifted the spectrum of nonthymic lymphoma from the B-cell to the T-cell lineage. RT-PCR analysis revealed enhanced expression of IL-10, which could have a promoting effect on lymphomagenesis, even without any stimulation, in the spleen of aging mice with the gene combinations Trp53(-/-)iNOS(-/-) and Trp53(+/-)iNOS(-/-) but not Trp53(-/-)iNOS(+/+) or Trp53(+/-)iNOS(+/+). These results suggest that iNOS could increase the development of thymic lymphomas in Trp53-deficient mice. While iNOS may have protective effects against nonthymic lymphomagenesis, the regulation of cytokine production by iNOS may be involved in the underlying mechanism of anti-lymphomagenesis effects in the peripheral lymphoid organ. (C) 2004 Wiley-Liss, Inc.

    DOI: 10.1002/ijc.20350

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  • Infiltration of neutrophils is required for acquisition of metastatic phenotype of benign murine fibrosarcoma cells - Implication of inflammation-associated carcinogenesis and tumor progression 査読

    H Tazawa, F Okada, T Kobayashi, M Tada, Y Mori, Y Une, F Sendo, M Kobayashi, M Hosokawa

    AMERICAN JOURNAL OF PATHOLOGY   163 ( 6 )   2221 - 2232   2003年12月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    QR-32 tumor cells, a clone derived from a murine fibrosarcoma, are poorly tumorigenic and nonmetastatic when injected into syngeneic C57BL/6 mice. However, they are converted to highly malignant ones once they have grown in vivo after being co-implanted in a subcutaneous site with a foreign body, a gelatin sponge. Early phase of inflammation induced by the gelatin sponge participates in the conversion and histological analysis shows predominant infiltration of neutrophils. The objective of this study was to determine whether the depletion of the infiltrating neutrophils has any effect on the tumor progression. Intraperitoneal administration of a monoclonal anti-granulocyte antibody, RB6-8C5 (RB6), depleted neutrophils from both the peripheral blood circulation and the local inflamed site in mice with co-implantation of QR-32 tumor cells and gelatin sponge. The RB6 administration did not inhibit either tumor development or growth of QR-32 tumor cells. In contrast, tumor cell lines established from RB6-administered mice showed a significant decrease in metastatic incidence as compared with the tumor cell lines obtained from the mice with administration of control rat IgG or saline. Metastatic ability was significantly suppressed when RB6 had been administered in the early phase (from day - 2 to day 6 after implantation); however, the administration in the middle (from day 6 to day 14) or late (from day 14 to day 22) phase did not affect the metastatic ability. We confirmed the phenomena by using integrin beta(2) knockout mice that had impaired neutrophil infiltration into inflamed sites. In the knockout mice, neutrophils hardly infiltrated into the gelatin sponge and the tumors showed dramatically suppressed metastatic phenotype as compared with those in wild-type mice or nude mice. Immunohistochemical analysis demonstrated that expressions of 8-hydroxy-2'-deoxyguanosine and nitrotyrosine were parallel to those in the presence of neutrophils. These results suggested that inflammation, especially when neutrophils infiltrate into tumor tissue, is primarily important for benign tumor cells to acquire metastatic phenotype.

    DOI: 10.1016/S0002-9440(10)63580-8

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  • Thymosin-beta 4 regulates motility and metastasis of malignant mouse fibrosarcoma cells 査読

    T Kobayashi, F Okada, N Fujii, N Tomita, S Ito, H Tazawa, T Aoyama, SK Choi, T Shibata, H Fujita, M Hosokawa

    AMERICAN JOURNAL OF PATHOLOGY   160 ( 3 )   869 - 882   2002年3月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:AMER SOC INVESTIGATIVE PATHOLOGY, INC  

    We identified a thymosin-beta4 gene overexpression in malignant mouse fibrosarcoma. cells (QRsP-30) that were derived from clonal. weakly tumorigenic and nonmetastatic QR-32 cells by using a differential display method. Thymosin-beta4 is known as a 4.9-kd polypeptide that interacts with G-actin and functions as a major actin-sequestering protein in cells. All of the six malignant fibrosarcoma cell lines that have been independently converted from QR-32 cells expressed high levels of thymosin-beta4 mRNA and its expression in tumor cells was correlated with tumorigenicity and metastatic potential. Up-regulation of thymosin-beta4 in QR-32 cells (32-S) transfected with sense thymosin-beta4 cDNA converted the cells to develop tumors and formed numerous lung metastases in syngeneic C57BL/6 mice. in contrast, antisense thymosin-beta4 cDNA-transfected QRsP-30 (30-AS) cells reduced thymosin-beta4 expression, and significantly lost tumor formation and metastases to distant organs. Vector-alone transfected cells (32-V or 30-V cells) behaved like their parental cells. We observed that tumor cell motility, cell shape, and F-actin organization is regulated in proportion to the level of thymosin-beta4 expression. These findings indicate that thymosin-beta4 molecule regulates fibrosarcoma cell tumorigenicity and metastasis through actin-based cytoskeletal organization.

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  • Conversion of human colonic adenoma cells to adenocarcinoma cells through inflammation in nude mice 査読

    F Okada, T Kawaguchi, H Habelhah, T Kobayashi, H Tazawa, N Takeichi, T Kitagawa, M Hosokawa

    LABORATORY INVESTIGATION   80 ( 11 )   1617 - 1628   2000年11月

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    記述言語:英語   掲載種別:研究論文(学術雑誌)   出版者・発行元:LIPPINCOTT WILLIAMS & WILKINS  

    The roles of inflammation in the malignant progression of tumors during multistep carcinogenesis have been much discussed but remain to be elucidated. To determine the direct contribution of inflammation to colon carcinogenesis, we established a new model of progression of human colonic adenoma cells using a nude mouse; the progression is accelerated by coimplantation of a plastic plate. The FPCK-1-1 cell line, derived from a colonic polyp in a patient with familial adenomatous polyposis, is nontumorigenic when injected subcutaneously into nude mice in a cell suspension of up to 5 x 10(6) cells per mouse. However implantation of 1 x 10(5) FPCK-1-1 cells attached to a plastic plate induced first acute and then chronic inflammation, and formed progressively growing tumors that were histologically determined as moderately differentiated adenocarcinoma in 65% of mice. Moreover cell lines established from the growing tumors were found to be tumorigenic when injected into mice even without a plastic plate. The tumor arising from the adenoma cells implanted attached to a plastic plate was surrounded by highly proliferating fibrous stroma. This fibrous tissue was considered essential for malignant progression, rather than for attachment to the plastic plate substrate, because the tumors were formed after injection of FPCK-1-1 cells into the fibrous tissue from which the plastic plate had been removed before the cell injection. The conditioned medium (CM) obtained from the fibroblasts derived from a plastic plate-associated stromal tissue was found to contain factors that stimulated growth of FPCK-1-1 cells, but not of the derivative progressor cell lines. The factor was stable to heating and neuraminidase treatment, but labile to trypsin treatment. The main growth-potentiating activity was contained in the fraction larger than 100 kDa. In contrast, the activity to promote FPCK-1-1 cell growth was not present in the CM of subcutaneous fibroblasts from untreated nude mice or the fibroblast cell lines C3H10T 1/2 and NIH3T3. These results demonstrated that inflammation-associated stroma promoted the conversion of colonic adenoma cells to adenocarcinoma cells.

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    その他リンク: http://orcid.org/0000-0003-4733-1037

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    長谷井 嬢, 尾崎修平, 山川泰明, 田澤 大, 香川俊輔, 尾崎敏文, 藤原俊義( 担当: 共著 ,  範囲: 骨軟部肉腫に対するテロメラーゼ依存性増殖型腫瘍融解ウイルスを用いた治療戦略)

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  • 骨肉腫に対するp53誘導性腫瘍融解ウイルスを用いたアブスコパル効果・ワクチン効果の誘導

    出宮 光二, 田澤 大, 近藤 宏也, 久禮 美穂, 長谷井 嬢, 中田 英二, 国定 俊之, 藤原 俊義, 尾崎 敏文

    日本整形外科学会雑誌   94 ( 8 )   S1855 - S1855   2020年9月

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)   出版者・発行元:(公社)日本整形外科学会  

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  • がん関連線維芽細胞由来IL-6制御による免疫応答の効率化バイオマーカーとしてのIL-6の可能性

    西脇 紀之, 野間 和広, 大原 利章, 河崎 健人, 赤井 正明, 小林 照貴, 加藤 卓也, 前田 直見, 菊地 覚次, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本分子腫瘍マーカー研究会プログラム・講演抄録   40回   72 - 73   2020年9月

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)   出版者・発行元:日本分子腫瘍マーカー研究会  

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  • 肝内胆管癌における免疫微小環境と治療予後の関連性

    小西 大輔, 吉田 一博, 楳田 祐三, 重安 邦俊, 矢野 修也, 武田 正, 吉田 龍一, 杭瀬 崇, 藤 智和, 安井 和也, 松田 達雄, 田澤 大, 白川 靖博, 八木 孝仁, 藤原 俊義

    日本外科学会定期学術集会抄録集   120回   SF - 3   2020年8月

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)   出版者・発行元:(一社)日本外科学会  

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  • EMT-MET可視化バイオセンサーを用いてhybridE/M状態での化学療法抵抗性をリアルタイムイメージングにより解き明かす

    三村直毅, 矢野修也, 矢野修也, 田澤大, 家田偉史, 岡林大樹, 重安邦俊, 重安邦俊, 武田正, 吉田一博, 寺石文則, 寺石文則, 楳田祐三, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • 大腸癌微小環境におけるRNA編集の可能性と展望

    武田正, 重安邦俊, 重安邦俊, 小松泰浩, 高橋一剛, 畑七々子, 吉田一博, 矢野修也, 矢野修也, 近藤喜太, 寺石文則, 寺石文則, 楳田祐三, 田澤大, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • 癌微小環境が引き起こす腫瘍免疫抑制の解明“Drug repositioning′′による免疫応答賦活化の可能性

    西脇紀之, 野間和広, 赤井正明, 小林照貴, 鳴坂徹, 河本慧, 加藤卓也, 前田直見, 田辺俊介, 大原利章, 田澤大, 白川靖博, 藤原俊義

    日本外科学会定期学術集会(Web)   120th   2020年

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  • 大腸癌化学放射線療法で活性化されるRNA編集によるネオアンチゲンの人工的生成

    小松泰浩, 重安邦俊, 重安邦俊, 武田正, 高橋一剛, 畑七々子, 吉田一博, 矢野修也, 矢野修也, 大原利章, 野間和広, 楳田祐三, 黒田新士, 黒田新士, 近藤喜太, 寺石文則, 寺石文則, 田澤大, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • Fibroblast activation protein-α(FAP)を標的とした癌関連線維芽細胞(CAFs)に対する光免疫療法~Sunrise of targeting tumor microenvironment therapy~

    小林照貴, 野間和広, 赤井正明, 西脇紀之, 鳴坂徹, 河本慧, 前田直見, 大原利章, 田辺俊介, 田澤大, 白川靖博, 藤原俊義

    日本外科学会定期学術集会(Web)   120th   2020年

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  • 癌関連線維芽細胞由来IL-6制御による免疫応答の効率化-“Drug repositioning“による癌治療の可能性-

    西脇紀之, 野間和広, 大原利章, 小林照貴, 菊地覚次, 菊地覚次, 田澤大, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • 新世代の外科医の苦悩と挑戦

    西脇紀之, 野間和広, 赤井正明, 小林照貴, 鳴坂徹, 河本慧, 大原利章, 田澤大, 藤原俊義

    日本外科学会定期学術集会(Web)   120th   2020年

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  • 癌関連線維芽細胞を標的とした光免疫療法の新たな開発

    小林照貴, 野間和広, 河崎健人, 赤井正明, 西脇紀之, 大原利章, 田澤大, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020年

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    記述言語:日本語   掲載種別:研究発表ペーパー・要旨(全国大会,その他学術会議)  

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  • 胃癌サブタイプと癌関連線維芽細胞の相互作用

    李云成, 田澤大, 野間和広, 大原利章, 黒田新士, 黒田新士, 菊地覚次, 菊地覚次, 香川俊輔, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   79th   2020年

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  • 骨肉腫に対する抗PD-1抗体と腫瘍融解アデノウイルスの複合免疫療法

    望月 雄介, 田澤 大, 出宮 光二, 久禮 美穂, 長谷井 嬢, 中田 英二, 国定 俊之, 浦田 泰生, 藤原 俊義, 尾崎 敏文

    日本整形外科学会雑誌   93 ( 8 )   S1672 - S1672   2019年9月

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    記述言語:日本語   出版者・発行元:(公社)日本整形外科学会  

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  • 骨肉腫に対するテロメラーゼ特異的腫瘍融解ウイルスを用いた複合免疫療法(Combination immunotherapy with telomerase-specific oncolytic adenovirus for osteosarcoma)

    出宮 光二, 田澤 大, 望月 雄介, 久禮 美穂, 近藤 宏也, 長谷井 嬢, 国定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   78回   J - 1001   2019年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • 骨肉腫に対するp53誘導性腫瘍融解ウイルス療法のアブスコパル効果

    出宮 光二, 田澤 大, 久禮 美穂, 望月 雄介, 長谷井 嬢, 中田 英二, 国定 俊之, 浦田 泰生, 藤原 俊義, 尾崎 敏文

    日本整形外科学会雑誌   93 ( 8 )   S1673 - S1673   2019年9月

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    記述言語:日本語   出版者・発行元:(公社)日本整形外科学会  

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  • 鉄キレート剤による幹細胞性制御による新規食道癌治療法(Stemness control by iron chelator is a novel therapeutic strategy for esophageal cancer treatment) 査読

    鳴坂 徹, 大原 利章, 桂 佑貴, 野間 和広, 西脇 紀之, 河本 慧, 田澤 大, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   78回   P - 1077   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • がん関連線維芽細胞(CAFs)による腫瘍免疫抑制のメカニズムについて(Exploring the mechanism of cancer-associated fibroblasts(CAFs) induced immunosuppression in tumor microenvironment) 査読

    西脇 紀之, 野間 和広, 小林 照貴, 鳴坂 徹, 河本 慧, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   78回   P - 3083   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • がん組織の生体イメージング: 現場を押さえろ! 細胞周期の可視化から見えてきた難治性がん細胞の存在と新規治療戦略(In vivo microscopy of cancer tissues: catch the scene! Fluorescence-guided novel therapeutic strategy for therapy-refractory tumor cells identified by cell cycle imaging) 査読

    矢野 修也, 田澤 大, 重安 邦俊, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   78回   IS3 - 5   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • AZIN1 RNA編集は大腸癌微小環境の再構成を促進し癌の進展に寄与する新たなメカニズムである(AZIN1 RNA editing is a novel mechanism that enhances malignant potential of colorectal cancer microenvironment) 査読

    武田 正, 重安 邦俊, 吉田 一博, 母里 淑子, 矢野 修也, 近藤 喜太, 野間 和広, 寺石 文則, 楳田 祐三, 岸本 浩行, 田澤 大, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   78回   E - 2079   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 化学放射線療法は線維芽細胞の活性化を介して食道癌細胞の悪性度を向上させる(Chemoradiotherapy promotes malignancy of cancer cells via activating fibroblasts in esophageal squamous cell carcinomas) 査読

    河本 慧, 野間 和広, 小林 照貴, 西脇 紀之, 鳴坂 徹, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   78回   E - 1038   2019年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 細胞周期の可視化から見えてきた難治性がん細胞の存在と新規治療戦略

    矢野修也, 矢野修也, 田澤大, 重安邦俊, 香川俊輔, 藤原俊義

    日本癌学会学術総会抄録集(Web)   78th   2019年

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  • 癌関連線維芽細胞が放出するIL-6が腫瘍内に浸潤するCD8+ならびにFoxP3+T細胞に影響を与える(Cancer-associated fibroblasts affect the intra-tumoral infiltration of CD8+ and FoxP3+ T cells via IL-6)

    加藤 卓也, 野間 和広, 佐藤 浩明, 河本 慧, 大原 利章, 田澤 大, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   77回   1860 - 1860   2018年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 骨肉腫に対する抗PD-1抗体とテロメラーゼ特異的ウイルス療法による新規治療戦略(Novel therapeutic strategy with anti-PD-1 antibody and telomerase-specific oncolytic virotherapy in osteosarcoma)

    望月 雄介, 田澤 大, 出宮 光二, 小松原 将, 杉生 和久, 長谷井 嬢, 国定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   77回   1813 - 1813   2018年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • p53誘導性腫瘍融解ウイルス療法は骨肉腫に強力な免疫原性細胞死を誘導する(Oncolytic adenoviral therapy with p53 transactivation induces profound immunogenic cell death in osteosarcoma)

    出宮 光二, 田澤 大, 望月 雄介, 小松原 将, 杉生 和久, 長谷井 嬢, 国定 俊之, 浦田 泰生, 尾崎 敏文, 藤原 俊義

    日本癌学会総会記事   77回   2251 - 2251   2018年9月

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    記述言語:英語   出版者・発行元:(一社)日本癌学会  

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  • 鉄キレート剤の幹細胞性制御による新規癌治療法(Stemness control by iron chelator is a novel strategy for cancer treatment) 査読

    大原 利章, 桂 佑貴, 野間 和広, 鳴坂 徹, 佐藤 浩明, 河本 慧, 加藤 卓也, 田澤 大, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   77回   2318 - 2318   2018年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 消化管がん治療の新展開 食道癌におけるがん細胞及びがん関連線維芽細胞に対するDual-targeting Photoimmunotherapy(Developments in gastrointestinal cancer treatments Dual-targeting Photoimmunotherapy for esophageal cancer and cancer-associated fibroblasts in tumor microenvironment) 査読

    佐藤 浩明, 野間 和広, 鳴坂 徹, 河本 慧, 大原 利章, 田澤 大, 藤原 俊義

    日本癌学会総会記事   77回   96 - 96   2018年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 炎症性微小環境-大腸がんクロストークにおけるEMTイメージング(Visualization of epithelial-mesenchymal transition in inflammatory microenvironment-colorectal cancer crosstalk) 査読

    田澤 大, 家田 偉史, 矢野 修也, 重安 邦俊, 黒田 新士, 大原 利章, 野間 和広, 岸本 浩行, 西崎 正彦, 香川 俊輔, 斎藤 卓, 今村 健志, 藤原 俊義

    日本癌学会総会記事   77回   1204 - 1204   2018年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 癌関連線維芽細胞が引き起こす腫瘍免疫抑制の解明 腫瘍浸潤リンパ球とIL-6と代謝の観点から 査読

    加藤 卓也, 野間 和広, 賀島 肇, 桂 佑貴, 佐藤 浩明, 河本 慧, 二宮 卓之, 大原 利章, 田澤 大, 白川 靖博, 稲垣 優, 岩垣 博巳, 藤原 俊義

    日本がん免疫学会総会プログラム・抄録集   22回   95 - 95   2018年7月

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    記述言語:日本語   出版者・発行元:日本がん免疫学会  

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  • 外科学の新知見(2)がんの早期診断に向けて がん特異的蛍光ウイルス製剤を用いた簡便な循環がん細胞(CTC)の遺伝子プロファイリング技術の開発 査読

    重安 邦俊, 田澤 大, 橋本 悠里, 母里 淑子, 西崎 正彦, 岸本 浩行, 永坂 岳司, 黒田 新士, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   118回   282 - 282   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 腫瘍融解ウイルス併用放射線療法による食道癌治療成績向上への取り組み

    田辺 俊介, 白川 靖博, 前田 直見, 二宮 卓之, 黒田 新士, 野間 和広, 楳田 祐三, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   118回   944 - 944   2018年4月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • Molecular radiosensitization of p53-armed telomerase-dependent oncolytic adenovirus against human soft-tissue sarcoma

    Tadashi Komatsubara, Hiroshi Tazawa, Yusuke Mochizuki, Kazuhisa Sugiu, Toshinori Omori, Yasuaki Yamakawa, Syuhei Osaki, Joe Hasei, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER SCIENCE   109   454 - 454   2018年1月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY  

    Web of Science

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  • 食道癌におけるがん細胞及びがん関連線維芽細胞に対するDual-targeting Photoimmunotherapy

    佐藤浩明, 野間和宏, 鳴坂徹, 河本慧, 大原利章, 田澤大, 白川靖博, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   29th   2018年

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  • 鉄キレート剤の幹細胞性制御による新規癌治療法の確立

    大原利章, 大原利章, 桂佑貴, 野間和広, 鳴坂徹, 二宮卓之, 友野靖子, 田澤大, 香川俊輔, 白川靖博, 松川昭博, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   29th   2018年

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  • 骨肉腫に対するp53誘導性腫瘍融解ウイルス療法による免疫原性細胞死の誘導効果

    出宮光二, 田澤大, 田澤大, 望月雄介, 小松原将, 長谷井嬢, 中田英二, 国定俊之, 浦田泰生, 藤原俊義, 尾崎敏文

    日本整形外科学会雑誌   92 ( 8 )   2018年

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  • 骨肉腫におけるテロメラーゼ特異的腫瘍融解ウイルスと抗PD-1抗体を用いた複合免疫療法

    望月雄介, 田澤大, 出宮光二, 小松原将, 長谷井嬢, 中田英二, 国定俊之, 浦田泰生, 藤原俊儀, 尾崎敏文

    日本整形外科学会雑誌   92 ( 6 )   2018年

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  • 軟部肉腫に対するp53発現腫瘍融解アデノウイルスによるアポトーシス抑制遺伝子発現の制御を介した放射線感受性増感作用の検討

    小松原将, 出宮光二, 望月雄介, 長谷井嬢, 吉田晶, 中田英二, 国定俊之, 浦田泰生, 田澤大, 藤原俊義, 尾崎敏文

    日本整形外科学会雑誌   92 ( 8 )   2018年

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  • Novel therapeutic strategy for human epidermal growth factor receptor 2-positive gastric cancer

    Nobuhiko Kanaya, Shinji Kuroda, Tetsushi Kubota, Toshiaki Morihiro, Satoru Kikuchi, Masahiko Nishizaki, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Japanese Journal of Cancer and Chemotherapy   44 ( 10 )   883 - 885   2017年10月

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    記述言語:日本語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    Trastuzumab (Tmab), a humanized monoclonal antibody that selectively targets human epidermal growth factor receptor 2 (HER2), is currently used in the clinical setting for the treatment of both breast and gastric cancer. While Tmab has shown improvements in patient prognoses, acquired resistance to this agent remains an issue. While some novel HER2-targeted agents have been approved for clinical use in breast cancer, no such agent has shown treatment efficacy for gastric malignancies with Tmab-resistance. Nanotechnology, which has progressed rapidly, has been applied to medical fields in recent years. Gold nanopartides, which are characterized by their in vivo stability and ease of surface modification, have been reported to show efficacy as the carriers of therapeutic agents, such as drugs, antibodies, peptides, and nucleic acids. In this work, we developed Tmab-conjugated gold nanopartides and demonstrate their efficacy for the treatment of HER2-positive, Tmab-resistant gastric cancer cell lines. Our findings demonstrate that Tmab-conjugated gold nanopartides have the potential to be a novel HER2-targeted therapeutic agent.

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  • 抗体結合磁性ナノ粒子による温熱療法 癌播種病変への治療応用へ向けて

    香川 哲也, 岸本 浩行, 松三 雄騎, 田澤 大, 大原 利章, 永坂 岳司, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   76回   P - 2368   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 癌関連線維芽細胞(CAFs)により放出されるIL-6が腫瘍免疫抑制を引き起こす 査読

    加藤 卓也, 野間 和広, 賀島 肇, 桂 佑貴, 佐藤 浩明, 二宮 卓之, 大原 利章, 田澤 大, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   76回   P - 1260   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • バイオイメージングの創薬、診断、治療への展開 EMT-がん微小環境ネットワークの蛍光生細胞イメージングシステム 査読

    家田 偉史, 田澤 大, 菊地 覚次, 黒田 新士, 大原 利章, 野間 和広, 岸本 浩行, 永坂 岳司, 西崎 正彦, 香川 俊輔, 今村 健志, 藤原 俊義

    日本癌学会総会記事   76回   S15 - 7   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 大腸癌におけるAZIN1のRNA編集に関する新しい知見

    重安 邦俊, 武田 正, 奥川 喜永, 問山 裕二, 永坂 岳司, 田澤 大, 香川 俊輔, Goel Ajay, 藤原 俊義

    日本癌学会総会記事   76回   E - 2079   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 鉄キレート剤特異的な腫瘍幹細胞性抑制効果の検討 査読

    桂 佑貴, 大原 利章, 賀島 肇, 佐藤 浩明, 加藤 卓也, 二宮 卓之, 野間 和広, 友野 靖子, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   76回   E - 1014   2017年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Hyperthermia at the single-cell level for disseminated cancer disease with immuno-magnetic nanoparticles 査読

    Tetsuya Kagawa, Hiroyuki Kishimoto, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Takeshi Nagasaka, Satoshi Nohara, Ichiro Kato, Adarsh Sandhu, Hiromichi Aono, Toshiyoshi Fujiwara

    American Association for Cancer Research   77 ( 13 )   2017年7月

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    記述言語:英語  

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  • 臨床応用を目指した消化器外科領域の基礎研究・橋渡し研究 膵癌に対するテロメラーゼ特異的腫瘍融解ウイルス療法

    國府島 健, 田澤 大, 杭瀬 崇, 信岡 大輔, 吉田 龍一, 楳田 祐三, 浦田 泰生, 香川 俊輔, 八木 孝仁, 藤原 俊儀

    日本消化器外科学会総会   72回   WS14 - 8   2017年7月

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    記述言語:日本語   出版者・発行元:(一社)日本消化器外科学会  

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  • 癌関連線維芽細胞は食道癌のリンパ節転移を促進するか~臨床検体の解析と同所移植モデルを用いた検証~

    賀島肇, 野間和広, 佐藤浩明, 桂佑貴, 加藤卓也, 大原利章, 田澤大, 白川靖博, 藤原俊義

    日本がん転移学会学術集会・総会プログラム抄録集   26th   2017年

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  • Real-time in-vivo image-guided cell-cycle perturbation to increase tumor chemosensitivity

    Shuya Yano, Hiroshi Tazawa, Hiroyuki Kishimoto, Shunsuke Kagawa, Yoshihiko Kadowaki, Nobuhiro Ishido, Takahiro Okamoto, Yasuo Urata, Kiyoto Takehara, Robert M. Hoffman, Toshiyoshi Fujiwara

    MOLECULAR CANCER RESEARCH   14   2016年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1557-3125.CELLCYCLE16-PR14

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  • Novel HER2-Targeted therapy combined with gold nanoparticles

    Tetsushi Kubota, Shinji Kuroda, Toshiaki Morihiro, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    Japanese Journal of Cancer and Chemotherapy   43 ( 10 )   1237 - 1239   2016年10月

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    記述言語:日本語   掲載種別:書評論文,書評,文献紹介等   出版者・発行元:Japanese Journal of Cancer and Chemotherapy Publishers Inc.  

    Trastuzumab (Tmab) is a humanized monoclonal antibody that binds to the human epidermal growth factor receptor 2 (HER2). It is clinically used for HER2-positive breast and gastric cancers
    however, the use of Tmab is restricted to tumors expressing high levels of HER2 (accounting for only 20% of tumors), and Tmab cannot be used for tumors resistant to Tmab. Although novel HER2-Targeted agents have been developed to treat Tmab-resistant tumors, none of these have shown clinical efficacy in gastric cancer patients. Recent developments in nanotechnology have had a significant impact on the field of medicine. Gold nanoparticles (AuNPs), which show characteristics such as in vivo stability and ease of surface functionali- zation, have been developed as therapeutic and contrast agents for medical applications. Previous studies show that AuNPs exert cytotoxic effects through autophagy and apoptosis
    therefore, AuNPs in combination with tumor-Targeting antibodies are attractive therapeutic agents. In this study, we developed HER2-Targeted AuNPs (Tmab-AuNPs) and showed that they had a potent antitumor effect on Tmab-resistant cell lines. In addition, Tmab-AuNPs were effective against HER2-negative gastric cancer cell lines when HER2 was artificially overexpressed. Thus, our results indicate that Tmab-AuNPs may overcome the shortcomings of Tmab-based therapy.

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  • p53活性化能を有するテロメラーゼ標的型ウイルス療法による腹腔内胃癌微小環境の浄化作用

    田澤 大, 堀 直人, 國府島 健, 谷本 光隆, 家田 偉史, 渡邉 めぐみ, 黒田 新士, 西崎 正彦, 浦田 泰生, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   75回   E - 2069   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 食道癌において癌関連繊維芽細胞が腫瘍転移に及ぼす影響の検証 査読

    賀島 肇, 野間 和広, 桂 佑貴, 加藤 卓也, 勝部 亮一, 二宮 卓之, 大原 利章, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   75回   P - 3151   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 癌関連線維芽細胞(CAFs)が及ぼす腫瘍免疫逃避の解明 CAFsと腫瘍浸潤リンパ球の検討 査読

    加藤 卓也, 野間 和広, 賀島 肇, 桂 佑貴, 二宮 卓之, 大原 利章, 田澤 大, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   75回   E - 1068   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 鉄代謝は癌幹細胞の新規治療ターゲットとなり得る 査読

    大原 利章, 二宮 卓之, 桂 佑貴, 賀島 肇, 加藤 卓也, 野間 和広, 田澤 大, 藤原 俊義

    日本癌学会総会記事   75回   E - 1109   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 炎症性微小環境によって誘導されるEMTの蛍光生細胞イメージングシステム 査読

    家田 偉史, 田澤 大, 菊地 覚次, 黒田 新士, 大原 利章, 野間 和広, 岸本 浩行, 永坂 岳司, 西崎 正彦, 香川 俊輔, 今村 健志, 藤原 俊義

    日本癌学会総会記事   75回   J - 3053   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 抗体結合磁性ナノ粒子による腫瘍選択的な細胞内温熱療法の開発 査読

    香川 哲也, 岸本 浩行, 田澤 大, 大原 利章, 永坂 岳司, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   75回   P - 3307   2016年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Comprehensive analysis of intrahepatic cholangiocarcinoma based on viral infections and mutational status in the IDH1/2 and KRAS genes

    Kazuya Yasui, Takeshi Nagasaka, Yuzo Umeda, Tomokazu Fuji, Fumitaka Taniguchi, Toshiaki Toshima, Keisuke Kimura, Takashi Kawai, Yoshiko Mori, Hiroshi Tazawa, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-3172

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  • Iron control is a novel therapeutic target of cancer stem cells

    Toshiaki Ohara, Takayuki Ninomiya, Kazuhiro Noma, Hajime Kashima, Yuki Katsura, Takuya Kato, Yasuko Tomono, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-2510

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  • A novel circulating cell free DNA-based assay in colorectal cancer patients during treatment with systematic chemotherapy

    Toshiaki Toshima, Takeshi Nagasaka, Yoshiko Mori, Takashi Kawai, Tomokazu Fuji, Fumitaka Taniguchi, Keisuke Kimura, Kazuya Yasui, Hiroyuki Kishimoto, Yuzo Umeda, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-510

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  • Tumor suppressor p53 reactivation by oncolytic adenovirus reverses chemoresistance in human osteosarcomas

    Kazuhisa Sugiu, Hiroshi Tazawa, Joe Hasei, Shuhei Osaki, Yasuaki Yamakawa, Toshinori Omori, Tadashi Komatsubara, Kouji Uotani, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-4677

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  • Suppression of MYCN-driven neuroblastoma malignant phenotype by telomerasetargeted tumor suppressor p53 transactivation

    Terutaka Tanimoto, Hiroshi Tazawa, Hiroshi Noso, Takanori Oyama, Yasuo Urata, Shunsuke Kagawa, Takuo Noda, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-2448

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  • Micro RNAs as promising therapeutic targets for anti-metastatic therapy in colorectal cancer

    Takashi Kawai, Takeshi Nagasaka, Yoshiko Mori, Tomokazu Fuji, Fumitaka Taniguchi, Keisuke Kimura, Toshiaki Toshima, Kazuya Yasui, Yuzo Umeda, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-1078

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  • Functional analysis of tumor associated macrophage utilizing virus-guided fluorescent imaging of pancreatic cancer cells in the peritoneal cavity

    Kazuya Kuwada, Shunsuke Kagawa, Megumi Watanabe, Shuichi Sakamoto, Satoru Kikuchi, Shinji Kuroda, Ryuichi Yoshida, Hiroshi Tazawa, Tetuya Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-4156

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  • Correlation of FAP(fibroblast activation protein)-expressing cancer associated fibroblasts (CAFs) and tumor metastasis in esophageal carcinoma

    Hajime Kashima, Kazuhiro Noma, Yuki Katsura, Takuya Kato, Ryoichi Katsube, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-1560

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  • Virally enhanced p53 reactivation impairs KRAS-driven pancreatic cancer invasion

    Takeshi Koujima, Hiroshi Tazawa, Takeshi Leda, Kazuya Kuwada, Terutaka Tanimoto, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-3748

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  • A novel live imaging system for inflammation-induced epithelial-mesenchymal transition in colorectal cancers

    Takeshi Ieda, Hiroshi Tazawa, Satoru Kikuchi, Shinji Kuroda, Toshiaki Ohara, Kazuhiro Noma, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-1613

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  • Prognostic correlation of tumor-infiltrating lymphocytes (TILs) and cancer associated fibroblasts (CAFs) in patients with human esophageal carcinoma

    Takuya Kato, Kazuhiro Noma, Yuki Katsura, Hajime Kashima, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-4160

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  • PD-L1 expression as a predictive factor for recurrence pattern and prognosis in curatively resected gastric cancer

    Toshiaki Morihiro, Shinji Kuroda, Tetsushi Kubota, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-2649

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  • Novel HER2-targeted gold nanoparticles; integration of antibody therapy and nanotechnology

    Tetsushi Kubota, Shinji Kuroda, Toshiaki Morihiro, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-4747

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  • PD-1 and PD-L1 expression patterns and DNA mismatch repair status for precision management of patients with gastric cancer

    Keisuke Kimura, Takeshi Nagasaka, Yoshiko Mori, Takashi Kawai, Tomokazu Fuji, Fumitaka Taniguchi, Kazuya Yasui, Toshiaki Toshima, Yuzo Umeda, Hiroshi Tazawa, Ajay Goel, Toshiyoshi Fujiwara

    CANCER RESEARCH   76   2016年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2016-2317

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  • MGMT Inactivation Arrest Tumor Growth and Serves As a Promising Predictive Biomarker for Treatment Response in Colorectal Cancer

    Yoshiko Mori, Takeshi Nagasaka, Hiroshi Tazawa, Yuzo Umeda, Kunitoshi Shigeyasu, Kazuhiro Yoshida, Ajay Goel, Toshiyoshi Fujiwara

    GASTROENTEROLOGY   150 ( 4 )   S1013 - S1013   2016年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

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  • 鉄コントロールによる新規がん幹細胞治療 査読

    二宮 卓之, 大原 利章, 加藤 卓也, 賀島 肇, 野間 和広, 田澤 大, 田辺 俊介, 香川 俊輔, 白川 靖博, 藤原 俊義

    日本外科学会定期学術集会抄録集   116回   PS - 8   2016年4月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 癌関連線維芽細胞が食道癌の浸潤と転移に及ぼす影響の検証

    賀島肇, 野間和広, 桂佑貴, 加藤卓也, 大原利章, 田澤大, 白川靖博, 香川俊輔, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   27th   2016年

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  • 鉄コントロールによる新規がん幹細胞治療 査読

    二宮 卓之, 大原 利章, 勝部 亮一, 賀島 肇, 加藤 卓也, 野間 和広, 田澤 大, 香川 俊輔, 水谷 昭文, 笠井 智成, 妹尾 昌治, 藤原 俊義

    日本癌学会総会記事   74回   IS4 - 6   2015年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • ヒト癌細胞におけるEMT可視化生体イメージング技術の開発 査読

    家田 偉史, 田澤 大, 菊池 覚次, 黒田 新士, 大原 利章, 野間 和広, 岸本 浩行, 永坂 岳司, 西崎 正彦, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   74回   P - 2028   2015年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Phase I/II trial of endoscopic intratumoral administration of OBP-301, a novel telomerase-specific oncolytic virus, with radiation in elderly esophageal cancer patients

    Shunsuke Tanabe, Hiroshi Tazawa, Shunsuke Kagawa, Kazuhiro Noma, Kiyoto Takehara, Takeshi Koujima, Hajime Kashima, Takuya Kato, Shinji Kuroda, Satoru Kikuchi, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-CT123

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  • A novel tumor-specific oncolytic biological therapy against invasive pancreatic cancer

    Takeshi Koujima, Hiroshi Tazawa, Naoto Hori, Shuta Tamura, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-3535

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  • Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells: a preliminary clinical study as a potential clinical biomarker

    Megumi Watanabe, Shunsuke Kagawa, Kazuya Kuwata, Michihiro Ishida, Yuuri Hashimoto, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Yasuo Urata, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-3412

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  • HER2-targeted gold nanoparticles produce potent antitumor effects on human gastric cancer cells

    Tetsushi Kubota, Shinji Kuroda, Katsuyuki Aoyama, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-5520

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  • A novel photoimmunotherapy targeting cancer-associated fibroblasts (CAFs) overcomes therapeutic resistance in human esophageal cancer

    Ryoichi Katsube, Kazuhiro Noma, Shinichiro Watanabe, Shinichi Urano, Takayuki Ninomiya, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Hisataka Kobayashi, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-401

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  • Preclinical evaluation of radiotherapy in combination with radio-sensitizing telomerase-specific oncolytic virus for human bone and soft tissue sarcomas

    Toshinori Omori, Yasuaki Yamakawa, Joe Hasei, Hiroshi Tazawa, Shuhei Osaki, Tusyoshi Sasaki, Kazuhisa Sugiu, Tomohiro Fujiwara, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-1794

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  • Iron control is a novel therapeutic target of cancer stem cells

    Takayuki Ninomiya, Toshiaki Ohara, Hajime Kashima, Ryoichi Katsube, Kazuhiro Noma, Yasuko Tomono, Akifumi Mizutani, Tomonari Kasai, Masaharu Seno, Shinji Kuroda, Hiroyuki Kishimoto, Hiroshi Tazawa, Yasuhiro Shirakawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-4243

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  • Differentiated gastric cancer cells have a potential to induce cancer-associated fibroblasts

    Yuncheng Li, Hiroshi Tazawa, Nishizaki Masahiko, Yuuri Hashimoto, Naoto Hori, Ryoichi Katsube, Shinji Kuroda, Kazuhiro Noma, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-2368

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  • Preclinical study of telomerase-specific p53 tumor suppressor gene overexpression in human scirrhous gastric cancer cells with different p53 status

    Naoto Hori, Hiroshi Tazawa, Masahiko Nishizaki, Satoru Kikuchi, Shuya Yano, Michihiro Ishida, Megumi Watanabe, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-5338

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  • Companion diagnostics-based telomerase-specific oncolytic virotherapy: preclinical evaluation in human colorectal cancer cell lines differentially affected in the RAS/RAF/MEK signaling pathway

    Shuta Tamura, Hiroshi Tazawa, Naoto Hori, Takeshi Koujima, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Takeshi Nagasaka, Masahiko Nishizaki, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   75   2015年8月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2015-3531

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  • Color-coding cancer and stromal cells with genetic reporters in a patient-derived orthotopic xenograft (PDOX) model of pancreatic cancer enhances fluorescence-guided surgery

    S. Yano, Y. Hiroshima, A. Maawy, H. Kishimoto, A. Suetsugu, S. Miwa, M. Toneri, M. Yamamoto, M. H. G. Katz, J. B. Fleming, Y. Urata, H. Tazawa, S. Kagawa, M. Bouvet, T. Fujiwara, R. M. Hoffman

    CANCER GENE THERAPY   22 ( 7 )   344 - 350   2015年7月

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    記述言語:英語   出版者・発行元:NATURE PUBLISHING GROUP  

    Precise fluorescence-guided surgery (FGS) for pancreatic canter has the potential to greatly improve the outcome in this recalcitrant disease. To achieve this goal, we have used genetic reporters to-color code cancer and stroma cells in a patient-derived orthotopic xenograft (PDOX) model. The telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 was used to label the cancer cells of a pancreatic cancer PDOX. The PDOX was previously grown in a red fluorescent protein (RFP) transgenic Mouse that stably labeled the PDOX stroma cells bright red. The color-coded PDOX Model enabled FGS to to completely resect the pancreatic tumors including stroma. Dual-colored FGS significantly prevented local recurrence; which bright-light surgery or single-color FGS could not. FGS, with color-coded canter and stroma cells has important potential for improving the outcome of recalcitrant-cancer surgery.

    DOI: 10.1038/cgt.2015.26

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  • 上部消化管 超高齢者食道癌手術への取り組みと放射線併用ウイルス療法の可能性 査読

    田辺 俊介, 白川 靖博, 賀島 肇, 国府島 健, 前田 直見, 大原 利章, 黒田 新士, 櫻間 教文, 野間 和広, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   115回   OP - 2   2015年4月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • その他 鉄コントロールによるがん幹細胞に対する新規治療 査読

    二宮 卓之, 大原 利章, 浦野 真一, 勝部 亮一, 野間 和広, 田澤 大, 白川 靖博, 香川 俊輔, 藤原 俊義

    日本外科学会定期学術集会抄録集   115回   OP - 7   2015年4月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • Cancer cells mimic in vivo spatial-temporal cell-cycle phase distribution and chemosensitivity in 3-dimensional Gelfoam (R) histoculture but not 2-dimensional culture as visualized with real-time FUCCI imaging (vol 14, pg 808, 2015)

    Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminaru Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    CELL CYCLE   14 ( 8 )   1338 - 1338   2015年4月

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    記述言語:英語   出版者・発行元:TAYLOR & FRANCIS INC  

    DOI: 10.1080/15384101.2015.1035048

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  • 食道癌におけるFAP(fibroblast activation protein)陽性癌関連線維芽細胞の発現と癌転移の関係

    賀島肇, 野間和広, 加藤卓也, 勝部亮一, 二宮卓之, 大原利章, 田澤大, 白川靖博, 香川俊輔, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   26th   2015年

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  • 癌関連線維芽細胞を標的とした新規食道癌治療法の開発

    勝部亮一, 野間和広, 賀島肇, 加藤卓也, 二宮卓之, 大原利章, 田澤大, 白川靖博, 香川俊輔, 小林久隆, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   26th   2015年

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  • Salmonella typhimurium A1-R decoys quiescent cancer cells to cycle rendering them chemosensitive

    S. Yano, Y. Zhang, M. Zhao, Y. Hiroshima, S. Miwa, F. Uehara, H. Kishimoto, H. Tazawa, T. Fujiwara, R. M. Hoffman

    EUROPEAN JOURNAL OF CANCER   50   96 - 96   2014年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:ELSEVIER SCI LTD  

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  • Invading cancer cells are mostly in G0/G1 and resist chemotherapy demonstrated by real-time FUCCI imaging of cell-cycle kinetics in Gelfoam (R) histoculture

    Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-1982

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  • Virus-guided fluorescence imaging of intraperitoneal free gastric cancer cells as a potential clinical biomarker

    Megumi Watanabe, Shunsuke Kagawa, Michihiro Ishida, Naoto Hori, Satoru Kikuchi, Shinji Kuroda, Hiroyuki Kishimoto, Masahiko Nishizaki, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-4726

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  • REAL TIME COLOR CODED IMAGING OF CELL CYCLE PHASE DEMONSTRATES WHY INVASIVE METASTATIC CANCER CELLS ARE DRUG RESISTANT

    Robert M. Hoffman, Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Mako Yamamoto, Hiroyuki Kishimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

    ANNALS OF ONCOLOGY   25   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:OXFORD UNIV PRESS  

    DOI: 10.1093/annonc/mdu435.28

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  • Three-dimensional Gelfoam (R) histoculture enables cancer cells to mimic in vivo cancer cell cycling as visualized with FUCCI imaging

    Shuya Yano, Shinji Miwa, Sumiyuki Mii, Yukihiko Hiroshima, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Toshiyoshi Fujiwara, Robert M. Hoffman

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-1979

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  • Combination strategy of endoscopic resection and telomerase-targeting oncolytic virus for eradicating lymph node metastasis of submucosal invasive colorectal cancer

    Naoto Hori, Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-4025

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  • Salmonella typhimurium A1-R induces quiescent FUCCI-expressing cancer cells to cycle and become chemosensitive

    Shuya Yano, Yong Zhang, Ming Zhao, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Hiroyuki Kishimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara, Robert M. Hoffman

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-711

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  • Development of systemically-deliverable telomerase-specific oncolytic adenovirus

    Katsuyuki Aoyama, Shinji Kuroda, Hiroshi Tazawa, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-719

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  • Real-time FUCCI imaging demonstrates targeting dormant cancer cells

    Shuya Yano, Ming Zhao, Hiroshi Tazawa, Robert M. Hoffman, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-1975

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  • Iron chelation therapy increased the anticancer effect of sorafenib in hepatocarcinoma

    Shinichi Urano, Toshiaki Ohara, Ryoichi Katsube, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Kazuhiro Nouso, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-1681

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  • A novel photodynamic therapy with virus-mediated delivery of photosensitive cytotoxic fluorescent protein KillerRed for human cancers

    Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Hiroyuki Kishimoto, Toshiyoshi Fujiwara, Nobuhiro Narii, Hiroyuki Mizuguchi

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-706

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  • Real-time FUCCI imaging of cell cycle phase in tumors demonstrates why cancer chemotherapy is not effective in solid cancers

    Shuya Yano, Yasunori Tome, Yong Zhang, Yukihiko Hiroshima, Shinji Miwa, Fuminari Uehara, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Ming Zhao, Toshiyoshi Fujiwara, Robert M. Hoffman

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-5095

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  • Combination therapy of telomerase-specific oncolytic adenovirus and zoledronic acid in human osteosarcoma cells

    Yasuaki Yamakawa, Joe Hasei, Hiroshi Tazawa, Toshinori Omori, Shuhei Osaki, Tsuyoshi Sasaki, Aki Yoshida, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-725

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  • Telomerase-dependent oncolytic adenovirus sensitizes human osteosarcoma cells to chemotherapy through Mcl-1 downregulation

    Shuhei Osaki, Toshinori Omori, Hiroshi Tazawa, Joe Hasei, Yasuaki Yamakawa, Tsuyoshi Sasaki, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-342

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  • Novel combination therapy of adenoviral gene transfer of HER2-extracellular domain and trastuzumab-based photoimmunotherapy for HER2 negative cancer cells

    Michihiro Ishida, Shunsuke Kagawa, Kyoko Shimoyama, Kiyoto Takehara, Kazuhiro Noma, Shunsuke Tanabe, Hiroshi Tazawa, Junji Matsuoka, Hisataka Kobayashi, Toshiyoshi Fujiwara

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-2615

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  • Telomerase-specific GFP-expressing adenovirus enables fluorescence-guided surgery (FGS) for patient-derived orthotopic xenograft (PDOX) in nude mice

    Shuya Yano, Yukihiko Hiroshima, Ali Maawy, Matthew H. G. Katz, Jason B. Fleming, Hiroyuki Kishimoto, Atsushi Suetsugu, Fuminari Uehara, Shinji Miwa, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    CANCER RESEARCH   74 ( 19 )   2014年10月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2014-1218

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  • 鉄コントロールによるがん幹細胞の新規治療法(Iron control is a potent novel therapeutic for cancer stem cells) 査読

    二宮 卓之, 大原 利章, 浦野 真一, 勝部 亮一, 野間 和広, 田澤 大, 香川 俊輔, 水谷 昭文, 笠井 智成, 妹尾 昌治, 藤原 俊義

    日本癌学会総会記事   73回   P - 1187   2014年9月

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  • ヒト大腸腺腫細胞の大腸癌細胞への進展における慢性炎症由来一酸化窒素の証明とfascinの同定(Nitric oxide from chronic inflammation and fascin in conversion of human colonic adenoma cells into adenocarcinoma cells)

    神田 裕介, 河口 徳一, 田澤 大, 平畑 美緒, 小沼 邦重, 北川 知行, 尾崎 充彦, 岡田 太

    日本癌学会総会記事   73回   P - 1025   2014年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 食道癌の悪性化に対するCAF標的光免疫療法の開発(Development of novel strategy of targeting cancer associated fibroblast (CAFs) for resistant esophageal cancer) 査読

    勝部 亮一, 野間 和広, 渡邉 伸一郎, 浦野 真一, 二宮 卓之, 大原 利章, 白川 靖博, 田澤 大, 香川 俊輔, 小林 久隆, 藤原 俊義

    日本癌学会総会記事   73回   P - 3157   2014年9月

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  • 鉄キレート療法は肝癌におけるソラフェニブの抗腫瘍効果を増強する(Iron chelation therapy enhances the anticancer effect of sorafenib in hepatocarcinoma) 査読

    浦野 真一, 大原 利章, 勝部 亮一, 野間 和広, 友野 靖子, 田澤 大, 能祖 一裕, 白川 靖博, 藤原 俊義

    日本癌学会総会記事   73回   P - 2328   2014年9月

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  • ONCOLYTIC ADENOVIRUS INHIBITS TRANSFORMING GROWTH FACTOR-beta-INDUCED EPITHELIAL-MESENCHYMAL TRANSITION IN HUMAN CANCER CELLS

    Yuuri Hashimoto, Hiroshi Tazawa, Ryosuke Yoshida, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   244 - 245   2014年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

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  • MiCRORNA-7 INHIBITS THE STEM-LIKE PROPERTIES OF CD133(+) HUMAN GASTRIC CANCER CELLS

    Teppei Onishi, Hiroshi Tazawa, Shuya Yano, Yuuri Hashimoto, Ryosuke Yoshida, Shunsuke Kagawa, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   266 - 266   2014年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

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  • MECHANISM OF RESISTANCE TO TRASTUZUMAB AND MOLECULAR SENSITIZATION VIA ADCC ACTIVATION BY EXOGENOUS EXPRESSION OF HER2 EXTRACELLULAR DOMAIN

    Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   16 ( 7-8 )   277 - 278   2014年7月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:WILEY-BLACKWELL  

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  • 慢性炎症に伴う一酸化窒素生成はヒト大腸腺腫細胞から大腸癌細胞を誘導する

    田澤大, 河口徳一, 蔵満保宏, 神田裕介, 尾崎充彦, 藤原俊義, 北川知行, 岡田太

    日本NO学会学術集会プログラム抄録集   14th   60   2014年5月

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    記述言語:日本語  

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  • Molecular surgery using a novel biological agent, OBP-301, for lymph node micrometastasis in human colorectal cancer.

    Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

    JOURNAL OF CLINICAL ONCOLOGY   32 ( 15 )   2014年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER SOC CLINICAL ONCOLOGY  

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  • PS-052-4 がん関連線維芽細胞(Cancer Associated Fibroblasts)を標的とした新規癌治療法の開発(PS-052 食道 基礎-2,ポスターセッション,第114回日本外科学会定期学術集会)

    野間 和広, 白川 靖博, 二宮 卓之, 勝部 亮一, 前田 直見, 田辺 俊介, 大原 利章, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会雑誌   115 ( 2 )   678 - 678   2014年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • PS-113-5 大腸癌におけるproenostic factorとしてのmiRNA(PS-113 大腸 基礎-1,ポスターセッション,第114回日本外科学会定期学術集会)

    久保田 暢人, 永坂 岳司, 母里 淑子, 森川 達也, 吉田 一博, 横道 直佑, 稲田 涼, 竹原 裕子, 竹原 清人, 河合 毅, 藤 智和, 楳田 祐三, 田澤 大, 藤原 俊義

    日本外科学会雑誌   115 ( 2 )   801 - 801   2014年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • OP-048-7 テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌に対する低侵襲治療の開発(OP-048 大腸 その他,一般演題,第114回日本外科学会定期学術集会)

    菊地 覚次, 岸本 浩行, 田澤 大, 西崎 正彦, 香川 俊輔, 浦田 泰生, Hoffman Robert, 藤原 俊義

    日本外科学会雑誌   115 ( 2 )   401 - 401   2014年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • OP-001-6 温阻血再灌流+肝切除モデルにおけるHMGB1制御による再灌流障害および肝再生への影響解析(OP-001 肝 基礎-1,一般演題,第114回日本外科学会定期学術集会)

    杉原 正大, 貞森 裕, 西堀 正洋, 佐藤 康晴, 田澤 大, 吉田 龍一, 楳田 祐三, 篠浦 先, 永坂 岳司, 八木 孝仁, 藤原 俊義

    日本外科学会雑誌   115 ( 2 )   313 - 313   2014年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • 大腸癌におけるprognostic factorとしてのmiRNA

    久保田 暢人, 永坂 岳司, 母里 淑子, 森川 達也, 吉田 一博, 横道 直佑, 稲田 涼, 竹原 裕子, 竹原 清人, 河合 毅, 藤 智和, 楳田 祐三, 田澤 大, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   801 - 801   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • がん関連線維芽細胞(Cancer Associated Fibroblasts)を標的とした新規癌治療法の開発 査読

    野間 和広, 白川 靖博, 二宮 卓之, 勝部 亮一, 前田 直見, 田辺 俊介, 大原 利章, 田澤 大, 香川 俊輔, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   678 - 678   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 温阻血再灌流+肝切除モデルにおけるHMGB1制御による再灌流障害および肝再生への影響解析

    杉原 正大, 貞森 裕, 西堀 正洋, 佐藤 康晴, 田澤 大, 吉田 龍一, 楳田 祐三, 篠浦 先, 永坂 岳司, 八木 孝仁, 藤原 俊義

    日本外科学会雑誌   115 ( 臨増2 )   313 - 313   2014年3月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 慢性炎症に伴うNO生成はアノイキス抵抗性を介し大腸腺腫細胞から大腸癌細胞を誘導する

    田澤大, 河口徳一, 蔵満保宏, 神田裕介, 尾崎充彦, 藤原俊義, 北川知行, 岡田太

    日本消化器癌発生学会総会プログラム・抄録集   25th   102   2014年

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    記述言語:日本語  

    J-GLOBAL

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  • Telomerase-targeting oncolytic adenovirus as a thetherapeutic and diagnostic agent

    S. Kagawa, H. Tazawa, K. Shigeyasu, H. Kishimoto, S. Kuroda, T. Fujiwara

    HUMAN GENE THERAPY   24 ( 12 )   A13 - A13   2013年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:MARY ANN LIEBERT, INC  

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  • FUCCI cell cycle imaging identifies drug-resistant quiescent cancer cells within tumors

    Shuya Yano, Yasunori Tome, Yong Zhang, Shinji Miwa, Atsushi Suetsugu, Hiroyuki Kishimoto, Hiroshi Tazawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

    MOLECULAR CANCER THERAPEUTICS   12 ( 11 )   2013年11月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1535-7163.TARG-13-B60

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  • がん関連線維芽細胞を標的とした新たな癌治療法の可能性 光線免疫療法を用いて(Novel cancer therapy targeting cancer-associated fibroblasts(CAFs) by targeted infrared photoimmunotherapy(PIT)) 査読

    勝部 亮一, 野間 和広, 渡邉 伸一郎, 浦野 真一, 大原 利章, 白川 靖博, 田澤 大, 香川 俊輔, 小林 久隆, 藤原 俊義

    日本癌学会総会記事   72回   349 - 350   2013年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 鉄欠乏状態は肝細胞癌におけるソラフェニブの感受性を改善しうる(Iron depletion status has a possibility to improve the sensitivity of sorafenib in HCC) 査読

    浦野 真一, 大原 利章, 勝部 亮一, 渡邉 伸一郎, 野間 和広, 友野 靖子, 田澤 大, 能祖 一裕, 白川 靖博, 貞森 裕, 藤原 俊義

    日本癌学会総会記事   72回   345 - 345   2013年10月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 蛍光標識による血中遊離癌細胞のLiquid Biopsy技術のバイオマーカー解析への応用 査読

    重安 邦俊, 橋本 悠里, 竹原 清人, 宇野 太, 永坂 岳司, 田澤 大, 香川 俊輔, 浦田 泰生, 藤原 俊義

    日本癌治療学会誌   48 ( 3 )   2759 - 2759   2013年9月

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    記述言語:日本語   出版者・発行元:(一社)日本癌治療学会  

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  • 温阻血再灌流+70%肝切除におけるHMGB1の動態解析と制御

    杉原 正大, 貞森 裕, 佐藤 太祐, 吉田 龍一, 楳田 祐三, 篠浦 先, 田澤 大, 永坂 岳司, 八木 孝仁, 藤原 俊義

    日本消化器外科学会総会   68回   RS - 54   2013年7月

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    記述言語:日本語   出版者・発行元:(一社)日本消化器外科学会  

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  • 癌特異的蛍光発現ウイルスによる胃癌症例腹腔洗浄液中での癌細胞検出法とその意義 査読

    香川 俊輔, 重安 邦俊, 田澤 大, 宇野 太, 岸本 浩行, 黒田 新士, 石田 道拡, 渡邉 めぐみ, 西崎 正彦, 藤原 俊義

    日本消化器外科学会総会   68回   O - 6   2013年7月

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    記述言語:日本語   出版者・発行元:(一社)日本消化器外科学会  

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  • StageIII大腸癌根治術後の再発予測におけるMGMTプロモーター領域のメチル化解析の有用性

    母里 淑子, 永坂 岳司, 竹原 裕子, 吉田 一博, 重安 邦俊, 楳田 祐三, 田澤 大, 貞森 裕, 藤原 俊義

    日本消化器外科学会総会   68回   O - 2   2013年7月

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    記述言語:日本語   出版者・発行元:(一社)日本消化器外科学会  

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  • MGMT Methylation As a Novel Biomarker for the Identification of Stage III Colorectal Cancers At High-Risk of Disease Recurrence Following Curative Surgery 査読

    Yoshiko Mori, Takeshi Nagasaka, Hiroshi Tazawa, Yuzo Umeda, Tatsuya Morikawa, Nobuhito Kubota, Kazuhiro Yoshida, Yuko Takehara, Naosuke Yokomichi, Kiyoto Takehara, Kunitoshi Shigeyasu, Akihiro Nyuya, Rikiya Shiwaku, Manabu Suno, Naoshi Nishida, Toshiyoshi Fujiwara, Ajay Goel

    GASTROENTEROLOGY   144 ( 5 )   S85 - S85   2013年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:W B SAUNDERS CO-ELSEVIER INC  

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  • Novel photoimmunotherapy (PIT) targeting cancer-associated fibroblasts (CAFs) for esophageal cancer.

    Shinichiro Watanabe, Kazuhiro Noma, Shinichi Urano, Toshiaki Ohara, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   73 ( 8 )   2013年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2013-4946

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  • Combined effect of zoledronic acid and telomerase-specific oncolytic virotherapy for human osteosarcoma cells.

    Yasuaki Yamakawa, Joe Hasei, Hiroshi Tazawa, Shuhei Osaki, Tsuyoshi Sasaki, Toshiyuki Kunisada, Aki Yoshida, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   73 ( 8 )   2013年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2013-3320

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  • Iron depletion by deferasirox have a synergistic effect on sorafenib in hepatocellular carcinoma.

    Shinichi Urano, Toshiaki Ohara, Shinichiro Watanabe, Kazuhiro Noma, Yasuko Tomono, Hiroshi Tazawa, Masafumi Kataoka, Nouso Kazuhiro, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   73 ( 8 )   2013年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2013-5608

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  • Cytotoxic effect of photosensitive fluorescent protein KillerRed-expressing adenovirus against human cancer cells

    Kiyoto Takehara, Hiroshi Tazawa, Yuuri Hashimoto, Hiroyuki Kishimoto, Nobuhiro Narii, Hiroyuki Mizuguchi, Toshiyoshi Fujiwara

    CANCER RESEARCH   73 ( 8 )   2013年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2013-3318

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  • Oncolytic adenovirus-armed p53 induces apoptosis significantly through upregulating miR-93 and 106b in human osteosarcoma cells

    Joe Hasei, Tsuyoshi Sasaki, Hiroshi Tazawa, Yuuri Hashimoto, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   73 ( 8 )   2013年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2013-3316

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  • WS-17-7 テロメラーゼ活性を指標とする血中遊離癌細胞の高感度検出法の開発と遺伝子解析技術への応用(WS ワークショップ,第113回日本外科学会定期学術集会)

    重安 邦俊, 橋本 悠里, 宇野 太, 永坂 岳司, 田澤 大2), 香川 俊輔, 水口 裕之, 浦田 泰生, 藤原 俊義

    日本外科学会雑誌   114 ( 2 )   338 - 338   2013年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • PS-067-5 テロメラーゼ依存性増殖型アデノウイルス製剤を用いた早期大腸癌の低侵襲治療の開発(PS ポスターセッション,第113回日本外科学会定期学術集会)

    菊地 覚次, 岸本 浩行, 田澤 大, 橋本 悠里, 宇野 太, 西崎 正彦, 香川 俊輔, 浦田 泰生, Hoffman Robert, 藤原 俊義

    日本外科学会雑誌   114 ( 2 )   612 - 612   2013年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • PS-084-5 温阻血再灌流+肝切除モデルにおけるHMGBIの動態解析および肝再生機序の解明(PS ポスターセッション,第113回日本外科学会定期学術集会)

    杉原 正大, 貞森 裕, 西堀 正洋, 佐藤 康晴, 田澤 大, 吉田 龍一, 楳田 祐三, 篠浦 先, 永坂 岳司, 八木 孝仁, 藤原 俊義

    日本外科学会雑誌   114 ( 2 )   637 - 637   2013年3月

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    記述言語:日本語   出版者・発行元:一般社団法人日本外科学会  

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  • 消化器癌における血中遊離癌細胞の検出と臨床応用 テロメラーゼ活性を指標とする血中遊離癌細胞の高感度検出法の開発と遺伝子解析技術への応用 査読

    重安 邦俊, 橋本 悠里, 宇野 太, 永坂 岳司, 田澤 大, 香川 俊輔, 水口 裕之, 浦田 泰生, 藤原 俊義

    日本外科学会雑誌   114 ( 臨増2 )   338 - 338   2013年3月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 温阻血再灌流+肝切除モデルにおけるHMGB1の動態解析および肝再生機序の解明

    杉原 正大, 貞森 裕, 西堀 正洋, 佐藤 康晴, 田澤 大, 吉田 龍一, 楳田 祐三, 篠浦 先, 永坂 岳司, 八木 孝仁, 藤原 俊義

    日本外科学会雑誌   114 ( 臨増2 )   637 - 637   2013年3月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • 癌微小リンパ節転移を標的とするテロメラーゼ特異的制限増殖型ウイルス製剤の開発.

    児島 亨, 渡邉雄一, 橋本悠里, 黒田新士, 山崎泰源, 矢野修也, 田澤 大, 宇野 太, 香川俊輔, 田中紀章, 浦田泰生, 藤原俊義

    岡山医学会雑誌   2013年

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  • 腫瘍融解アデノウイルスによるE2F1-マイクロRNA-7-EGFR経路を介したオートファジー細胞死の誘導分子機構.

    田澤 大, 矢野修也, 吉田亮介, 山崎泰源, 佐々木剛, 橋本悠里, 黒田新士, 大内正明, 大西哲平, 宇野 太, 香川俊輔, 浦田泰生, 藤原俊義

    岡山医学会雑誌   2013年

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  • 鉄代謝を利用した新規分子標的薬併用療法

    浦野真一, 大原利章, 白川靖博, 野間和広, 前田直見, 田辺俊介, 櫻間教文, 田澤大, 藤原俊儀

    日本消化器癌発生学会総会プログラム・抄録集   24th   2013年

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  • 予後および病態評価が可能な新規食道癌同所移植性モデル

    大原利章, 白川靖博, 野間和広, 浦野真一, 前田直見, 田辺俊介, 櫻間教文, 田澤大, 藤原俊義

    日本消化器癌発生学会総会プログラム・抄録集   24th   2013年

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  • 腫瘍特異的制限増殖型アデノウイルスを用いた血液循環腫瘍細胞の遺伝子解析技術の開発(Development of genetic analysis of circulating tumor cells using a telomerase-specific replication-competent adenovirus) 査読

    重安 邦俊, 橋本 悠里, 宇野 太, 永坂 岳司, 田澤 大, 香川 俊輔, 水口 裕之, 浦田 泰生, 藤原 俊義

    日本癌学会総会記事   71回   50 - 50   2012年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 癌関連線維芽細胞が食道癌の増殖に寄与する(Cancer-associated fibroblasts contribute to progression of esophageal cancer) 査読

    渡邉 伸一郎, 野間 和広, 浦野 真一, 大原 利章, 橋本 悠里, 田澤 大, 藤原 俊義

    日本癌学会総会記事   71回   143 - 143   2012年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • Preclinical evaluation of cytotoxic effect of photosensitive fluorescent protein in human cancer cells

    Hiroshi Tazawa, Tsuyoshi Sasaki, Yuuri Hashimoto, Satoru Kikuchi, Hiroyuki Kishimoto, Hiroyuki Mizuguchi, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-5656

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  • Inhibitory effect of oncolytic adenovirus on transforming growth factor-beta-induced epithelial-mesenchymal transition in human cancer cells

    Yuuri Hashimoto, Hiroshi Tazawa, Yasuo Urata, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-343

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  • A precise orthotopic rectal tumor model for evaluating therapeutic response of cancer treatment

    Satoru Kikuchi, Hiroyuki Kishimoto, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Masahiko Nishizaki, Shunsuke Kagawa, Yasuo Urata, Robert M. Hoffman, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-2442

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  • Iron deficiency suppresses EMT through down-regulation of N-cadherin in esophageal cancer.

    Shinichiro Watanabe, Seishi Nishitani, Kazuhiro Noma, Toshiaki Ohara, Yasuko Tomono, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-2421

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  • A highly sensitive detection system of genetic alterations in circulating tumor cells using a telomerase-specific replication-competent adenovirus

    Kunitoshi Shigeyasu, Yuuri Hashimoto, Tatsuya Morikawa, Yoshiko Mori, Dong-Sheng Sun, Shunsuke Kagawa, Futoshi Uno, Hiroshi Tazawa, Takeshi Nagasaka, Satoru Kyo, Hiroyuki Mizuguchi, Yasuo Urata, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-2385

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  • p53-mediated apoptotic signaling overcomes the resistance to oncolytic adenovirus in human osteosarcoma cells

    Joe Hasel, Tsuyoshi Sasaki, Hiroshi Tazawa, Yuuri Hashimoto, Toshiyuki Kunisada, Yasuo Urata, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-5651

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  • Iron chelator contributes to anti-angiogenic therapy via selective induction of VEGF-A

    Toshiaki Ohara, Kazuhiro Noma, Seishi Nishitani, Shinichiro Watanabe, Yasuko Tomono, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   72   2012年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2012-2323

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  • テロメラーゼ依存性腫瘍融解ウイルス療法の骨・軟部肉腫に対する前臨床的検討.

    佐々木剛, 田澤 大, 長谷井嬢, 国定俊之, 吉田 晶, 橋本悠里, 矢野修也, 吉田亮介, 宇野 太, 香川俊輔, 森本裕樹, 浦田泰生, 藤原俊義, 尾﨑敏文

    岡山医学会雑誌   124 ( 2 )   105 - 110   2012年

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  • 鉄欠乏状態は食道がんにおいてNカドヘリンを低下させることでEMTを抑制する(Iron deficiency suppress EMT through downregulation of N-cadherin in esophageal cancer) 査読

    西谷 正史, 野間 和広, 大原 利章, 長谷井 嬢, 佐々木 剛, 渡邊 伸一郎, 大西 哲平, 吉田 亮介, 橋本 悠里, 田澤 大, 宇野 太, 香川 俊輔, 藤原 俊義

    日本癌学会総会記事   70回   467 - 468   2011年9月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • IS-9-3 乳癌のトラスツズマブ耐性機構の解析とHER2細胞外ドメイン発現によるADCC活性増強を介した感受性誘導(IS-9 国際シンポジウム(9)Translational research in breast cancer treatment,第111回日本外科学会定期学術集会)

    吉田 亮介, 田澤 大, 矢野 修也, 大西 哲平, 宇野 太, 香川 俊輔, 藤原 俊義

    日本外科学会雑誌   112 ( 1 )   2011年5月

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    記述言語:英語   出版者・発行元:一般社団法人日本外科学会  

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  • 体内鉄コントロールを利用したBevacizumabの新規治療法 査読

    大原 利章, 野間 和広, 友野 靖子, 西谷 正史, 田辺 俊介, 田澤 大, 白川 靖博, 藤原 俊義

    日本外科学会雑誌   112 ( 臨増1-2 )   771 - 771   2011年5月

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    記述言語:日本語   出版者・発行元:(一社)日本外科学会  

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  • Bioengineered oncolytic adenovirus induces autophagic cell death through an E2F1-microRNA-7-epidermal growth factor receptor axis

    Hiroshi Tazawa, Shuya Yano, Ryosuke Yoshida, Yasuo Urata, Toshiyoshi Fujiwara

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-2862

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  • Iron deficiency suppress EMT through downregulation of N-cadherin in esophageal cancer

    Seishi Nishitani, Kazuhiro Noma, Shinichiro Watanabe, Teppei Onishi, Toshiaki Ohara, Yasuko Tomono, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-3363

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  • Iron controlled treatment can be novel therapeutic agent and biomarker of Bevacizumab

    Toshiaki Ohara, Kazuhiro Noma, Shinichiro Watanabe, Teppei Ohnishi, Seishi Nishitani, Yasuko Tomono, Yuuri Hashimoto, Hiroshi Tazawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-4247

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  • Mechanism of resistance to trastuzumab and molecular sensitization via ADCC activation by exogenous expression of HER2 extracellular domain in human breast cancer cells

    Ryosuke Yoshida, Hiroshi Tazawa, Yuuri Hashimoto, Futoshi Uno, Shunsuke Kagawa, Toshiyoshi Fujiwara

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-720

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  • Preclinical evaluation of telomerase-specific oncolytic virotherapy for human bone and soft tissue sarcomas

    Tsuyoshi Sasaki, Hiroshi Tazawa, Jo Hasei, Toshiyuki Kunisada, Aki Yoshida, Yuki Morimoto, Yasuo Urata, Kazuhiro Nouso, Toshifumi Ozaki, Toshiyoshi Fujiwara

    CANCER RESEARCH   71   2011年4月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

    DOI: 10.1158/1538-7445.AM2011-5415

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  • テロメラーゼ依存的腫瘍融解アデノウイルス製剤による放射線感受性増強作用

    黒田 新士, 野間 和広, 浦田 泰生, 香川 俊輔, 藤原 俊義, 藤原 俊哉, 白川 靖博, 山崎 泰源, 矢野 修也, 宇野 太, 田澤 大, 橋本 悠里, 渡辺 雄一

    岡山医学会雑誌   123 ( 2 )   103 - 109   2011年

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    記述言語:日本語   出版者・発行元:岡山医学会  

    DNA修復機能阻害は放射線感受性を増強させるため,DNA修復に関与する因子の阻害剤は放射線増感剤となり得る.我々の開発したテロメラーゼ依存的腫瘍融解アデノウイルス製剤OBP-301(テロメライシン)は,アデノウイルスE1B55kDaタンパクを介して細胞のDNA修復に重要な役割を果たすMRN複合体(Mre11,Rad50,NBS1)を分解する機能を有する.このMRN複合体の分解によりATM(ataxia-telangiectasia mutated)の活性化が抑制され結果的にDNA修復機構が阻害される.我々はOBP-301と放射線との併用が強力な相乗効果を生み出すことをマウスの皮下腫瘍モデルおよび食道癌同所性モデルにおいて証明した.これらの結果はOBP-301が将来有望な放射線増感剤となり得ることだけでなく,E1B55kDaタンパクを産生する腫瘍融解アデノウイルス製剤と放射線との併用が悪性腫瘍に対する有力な治療戦略となり得ることを示す.

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  • TELOMERASE-SPECIFIC ONCOLYTIC ADENOVIRUS ARMED WITH WILD-TYPE P53 GENE (CGCT-04) EFFICIENTLY INDUCES APOPTOSIS IN HUMAN CANCER CELLS

    Yasumoto Yamasaki, Hideki Onimatsu, Yuuri Hashimoto, Toru Kojima, Hiroshi Tazawa, Shunsuke Kagawa, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   12 ( 12 )   1035 - 1035   2010年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

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  • PRECLINICAL STUDY OF TELOMERASE-SELECTIVE ONCOLYTIC ADENOVIRUS (OBP-301) IN COMBINATION WITH CHEMOTHERAPEUTIC AGENT AND RADIATION

    Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Yasuo Urata, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   12 ( 12 )   1035 - 1036   2010年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

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  • A NOVEL TELOMERASE-SPECIFIC ONCOLYTIC VIROTHERAPY TARGETING GASTRIC CANCER STEM CELLS

    Shuya Yano, Yuuri Hashimoto, Toru Kojima, Shinji Kuroda, Hiroshi Tazawa, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    JOURNAL OF GENE MEDICINE   11 ( 12 )   1154 - 1154   2009年12月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:JOHN WILEY & SONS LTD  

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  • Clinical Application of Telomerase-Specific Oncolytic Adenovirs to Ex Vivo Biological Imaging of Human Circulating Tumor Cells

    Futoshi Uno, Yuuri Hashimoto, Toru Kojima, Shunsuke Kagawa, Hiroshi Tazawa, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    MOLECULAR THERAPY   17   S237 - S237   2009年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:NATURE PUBLISHING GROUP  

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  • Telomerase-specific oncolytic adenovirus armed with wild-type p53 gene (CGCT-04) efficiently induces apoptosis in human cancer cells

    Yasumoto Yamasaki, Hideki Onimatsu, Yuuri Hashimoto, Toru Kojima, Hiroshi Tazawa, Shunsuke Kagawa, Hiroyuki Mizuguchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    CANCER RESEARCH   69   2009年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • Telomerase-specific oncolytic virotherapy purging cancer stem cells

    Shuya Yano, Yuuri Hashimoto, Shinji Kuroda, Tohru Kojima, Futoshi Uno, Hiroshi Tazawa, Shunsuke Kagawa, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    CANCER RESEARCH   69   2009年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • Preclinical study of telomerase-selective oncolytic adenovirus (OBP-301) in combination with chemotherapeutic agents

    Hiroshi Tazawa, Yuuri Hashimoto, Shinji Kuroda, Yasuo Urata, Toshiyoshi Fujiwara

    CANCER RESEARCH   69   2009年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • Telomerase-specific oncolytic adenovirus mediates molecular sensitization to ionizing radiation in human cancer cells through E1B55kDa expression

    Shinji Kuroda, Toshiya Fujiwara, Hiroshi Tazawa, Futoshi Uno, Shunsuke Kagawa, Yuuri Hashimoto, Masaaki Ouchi, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    CANCER RESEARCH   69   2009年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • Biological purging of lymph node metastasis of gastrointestinal cancer by telomerase-specific virotherapy

    Toru Kojima, Yuuri Hashimoto, Shinji Kuroda, Yasumoto Yamasaki, Shuya Yano, Hiroshi Tazawa, Futoshi Uno, Shunsuke Kagawa, Yasuo Urata, Noriaki Tanaka, Toshiyoshi Fujiwara

    CANCER RESEARCH   69   2009年5月

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    記述言語:英語   掲載種別:研究発表ペーパー・要旨(国際会議)   出版者・発行元:AMER ASSOC CANCER RESEARCH  

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  • スーパーオキシドジスムターゼの経口投与による炎症介在性腫瘍進行の予防(Prevention of inflammation-mediated tumor progression by orally available superoxide dismutase)

    小沼 邦重, 塩野谷 博, 田澤 大, 松原 範宜, 小林 正伸, 細川 眞澄男, 岡田 太

    日本癌学会総会記事   66回   295 - 295   2007年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • 良性腫瘍の炎症介在性の転移能獲得における反応性一酸化窒素の関与(Involvement of reactive nitrogen oxides for acquisition of metastatic properties of benign tumors through inflammation)

    岡田 太, 田澤 大, 小沼 邦重, 小林 正伸, 細川 眞澄男

    日本癌学会総会記事   66回   295 - 295   2007年8月

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    記述言語:英語   出版者・発行元:日本癌学会  

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  • The role of nitrative DNA damage in inflammation-associated carcinogenesis

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  • ゼラチンスポンジ同時皮下移植によるマウス線維肉腫細胞の悪性化進展における好中球の役割

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  • サイモシンβ4発現調節によるマウス線維肉腫細胞の悪性化形質の転換

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  • 家族性大腸腺腫FPCK‐1‐1細胞のプログレッションにおける活性窒素の役割

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  • 家族性大腸腺腫FPCK‐1‐1細胞の悪性化における間質反応の役割

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  • マウス線維肉腫細胞の悪性化進展におけるE1AFの発現増強とその意義

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    日本癌学会総会記事   58th   599 - 599   1999年8月

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受賞

  • がん研究奨励賞

    2013年6月   岡山医学会  

    田澤 大

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  • アンジェスMG賞

    2012年6月   日本遺伝子治療学会  

    田澤 大

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  • とやま賞(医薬部門)

    2010年5月   財団法人 富山県ひとづくり財団  

    田澤 大

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  • 優秀発表賞

    2007年9月   日本疾患モデル学会  

    田澤 大

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