Faculty Profiles - FUJIWARA Toshiyoshi

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Improved Resection and Outcome of Colon-Cancer Liver Metastasis with Fluorescence-Guided Surgery Using In Situ GFP Labeling with a Telomerase-Dependent Adenovirus in an Orthotopic Mouse Model

Shuya Yano, Kiyoto Takehara, Shinji Miwa, Hiroyuki Kishimoto, Yukihiko Hiroshima, Takashi Murakami, Yasuo Urata, Shunsuke Kagawa, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

PLOS ONE 11 ( 2 ) 2016.2

Language：English Publisher：PUBLIC LIBRARY SCIENCE

Fluorescence-guided surgery (FGS) of cancer is an area of intense development. In the present report, we demonstrate that the telomerase-dependent green fluorescent protein (GFP)-containing adenovirus OBP-401 could label colon-cancer liver metastasis in situ in an orthotopic mouse model enabling successful FGS. OBP-401-GFP-labeled liver metastasis resulted in complete resection with FGS, in contrast, conventional bright-light surgery (BLS) did not result in complete resection of the metastasis. OBP-401-FGS reduced the recurrence rate and prolonged over-all survival compared with BLS. In conclusion, adenovirus OBP-401 is a powerful tool to label liver metastasis in situ with GFP which enables its complete resection, not possible with conventional BLS.

DOI： 10.1371/journal.pone.0148760

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Targeted Photodynamic Virotherapy Armed with a Genetically Encoded Photosensitizer

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 2016.1

Language：English Publisher：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.

DOI： 10.1158/1535-7163.MCT-15-0344

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

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 2016.1

Language：English Publisher：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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Anti-high mobility group box 1 monoclonal antibody improves ischemia/reperfusion injury and mode of liver regeneration after partial hepatectomy

AMERICAN JOURNAL OF SURGERY 211 ( 1 ) 179 - 188 2016.1

Language：English Publisher：EXCERPTA MEDICA INC-ELSEVIER SCIENCE INC

DOI： 10.1016/j.amjsurg.2015.06.025

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Cell-cycle-dependent drug-resistant quiescent cancer cells induce tumor angiogenesis after chemotherapy as visualized by real-time FUCCI imaging

Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

Cell Cycle DOI: 10.1080/15384101.2016.1220461 2016

Adenoviral targeting of malignant melanoma for fluorescenceguided surgery prevents recurrence in orthotopic nude-mouse models

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

Oncotarget 7 ( 14 ) 18558 - 18572 2016

Language：English Publisher：Impact Journals LLC

Malignant melanoma requires precise resection in order to avoid metastatic recurrence. We report here that the telomerase-dependent, green fluorescent protein (GFP)-containing adenovirus OBP-401 could label malignant melanoma with GFP in situ in orthotopic mouse models. OBP-401-based fluorescence-guided surgery (FGS) resulted in the complete resection of malignant melanoma in the orthotopic models, where conventional bright-light surgery (BLS) could not. High-dose administration of OBP-401 enabled FGS without residual cancer cells or recurrence, due to its dual effect of cancer-cell labeling with GFP and killing.

DOI： 10.18632/oncotarget.6670

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PubMed

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Expansion of epigenetic alterations in EFEMP1 promoter predicts malignant formation in pancreatobiliary intraductal papillary mucinous neoplasms

Kazuhiro Yoshida, Takeshi Nagasaka, Yuzo Umeda, Takehiro Tanaka, Keisuke Kimura, Fumitaka Taniguchi, Tomokazu Fuji, Kunitoshi Shigeyasu, Yoshiko Mori, Hiroyuki Yanai, Takahito Yagi, Ajay Goel, Toshiyoshi Fujiwara

Journal of Cancer Research and Clinical Oncology, Zeitschrift fur Krebsforschung und Klinische Onkologie, Zeitschrift fur Krebsforschung 1 - 13 2016

Surgical outcome of patients undergoing pancreaticoduodenectomy

Kosei Takagi, Takahito Yagi, Ryuichi Yoshida, Susumu Shinoura, Yuzo Umeda, Daisuke Nobuoka, Takashi Kuise, Nobuyuki Watanabe, Kenta Sui, Tomokazu Fuji, Toshiyoshi Fujiwara

Acta Medica Okayama, Acta. Medica Okayama, Acta medicinae Okayama, Acta medica Okayama 70 ( 3 ) 197 - 204 2016

A case of right-sided Bochdalek hernia incidentally diagnosed in a gastric cancer patient

Kikuchi S, Nishizaki M, Kuroda S, Kagawa S, Fujiwara T

BMC Surg 16 ( 34 ) doi: 10.1186/s12893-016-0145-2 2016

Iron depletion enhances the effect of sorafenib in hepatocarcinoma

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

Language：English Publisher：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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Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Shuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert, M. Hoffman

Cell Cycle 1 - 9 2016

Efficient detection of human circulating tumor cells without significant production of false-positive cells by a novel conditionally replicating adenovirus

Sakurai F, Narii N, Tomita K, Togo S, Takahashi K, Machitani M, Tachibana M, Ouchi M, Katagiri N, Urata Y, Fujiwara T, Mizuguchi H

Mol. Ther. Methods Clin. Dev 3 ( 16001 ) 2016

肝移植医療を地域と大学が一体としてまとめ上げた実績とさらなる発展

八木孝仁, 篠浦先, 楳田祐三, 吉田龍一, 信岡大輔, 杭瀬崇, 渡辺信之, 高木弘誠, 須井健太, 藤原俊義, 高木章乃夫, 吉田真理, 保田裕子, 森松博史

肝胆膵 72 ( 3 ) 481 - 487 2016

Behçet's disease complicated by ileocecal and esophageal perforation

Tsukumo Yuta, Kawamoto Kazuyuki, Takagi Kosei, Chin Kai, Matsuba Yuri, Nagahisa Yoshio, Okabe Michio, Shirakawa Yasuhiro, Itoh Tadashi, Fujiwara Toshiyoshi

Okayama Igakkai Zasshi (Journal of Okayama Medical Association) 128 ( 1 ) 27 - 32 2016

Language：Japanese Publisher：Okayama Medical Association

A 36-year-old Japanese man known to have incomplete Behçet's disease (oral aphthous ulcers, genital ulcers, skin lesions, and esophageal and ileocecal ulcers) was admitted to our hospital in January 2011 for abdominal pain. We administered corticosteroids and immunosuppressants. Two months later, we performed an ileocecal resection to control gastrointestinal bleeding from the ileocecal ulcers. High fever persisted after this surgery, and upper gastrointestinal endoscopy demonstrated ulcer penetration between the lower and abdominal esophagus. Eighteen days after the initial ileocecal resection, we performed a lower esophagus resection, gastric tube reconstruction and enterostomy, during which we confirmed a 5-mm-dia. perforated site at the posterior wall of the abdominal esophagus. Postoperative anastomotic leakage and empyema occurred, but they were relieved by thoracic drainage and empyema dissection.

DOI： 10.4044/joma.128.27

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Other Link： http://ousar.lib.okayama-u.ac.jp/metadata/54077

Therapeutic efficacy in vivo of a telomerase-dependent adenovirus in an orthotopic model of chemotherapy-resistant human stomach carcinomatosis peritonitis visualized with cell cycle color coding FUCCI imaging

Yano S, Takehara K, Tazawa H, Kishimoto H, Urata Y, Kagawa S, Fujiwara T, Hoffman RM

Journal of Cellular Biochemistry doi: 10.1002/jcb.25593 2016

Pretreatment of donor islets with papain improves allograft survival without systemic immunosuppression in mice

Kenjiro Kumano, Hitomi Nishinakamura, Toshiyuki Mera, Takeshi Itoh, Hiroyuki Takahashi, Toshiyoshi Fujiwara, Shohta Kodama

ISLETS 8 ( 5 ) 145 - 155 2016

Language：English Publisher：TAYLOR & FRANCIS INC

Although current immunosuppression protocols improve the efficacy of clinical allogenic islet transplantation, T cell-mediated allorejection remains unresolved, and major histocompatibility complexes (MHCs) play a crucial role in this process. Papain, a cysteine protease, has the unique ability to cleave the extracellular domain of the MHC class I structure. We hypothesized that pretreatment of donor islets with papain would diminish the expression of MHC class I on islets, reducing allograft immunogenicity and contributing to prolongation of islet allograft survival. BALB/c islets pretreated with papain were transplanted into C57BL/6J mice as an acute allorejection model. Treatment with 1mg/mL papain significantly prolonged islet allograft survival. In vitro, to determine the inhibitory effect on T cell-mediated alloreactions, we performed lymphocyte proliferation assays and mixed lymphocyte reactions. Host T cell activation against allogenic islet cells was remarkably suppressed by pretreatment of donor islet cells with 10mg/mL papain. Flow cytometric analysis was also performed to investigate the effect of papain treatment on the expression of MHC class I on islets. One or 10mg/mL papain treatment reduced MHC class I expression on the islet cell surface. Pretreatment of donor islets with papain suppresses MHC class I-mediated allograft rejection in mice and contributes to prolongation of islet allograft survival without administration of systemic immunosuppressants. These results suggest that pretreatment of human donor islets with papain may reduce the immunogenicity of the donor islets and minimize the dosage of systemic immunosuppressants required in a clinical setting.

DOI： 10.1080/19382014.2016.1223579

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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

Yano S, Takehara K, Tazawa H, Kishimoto H, Kagawa S, Bouvet M, Fujiwara T, Hoffman RM

Journal of Cellular Biochemistry doi: 10.1002/jcb.25735 2016

胃癌術後肝転移再発に対してThird-LineのCPT-11が奏効し長期生存を得た1 例

菊地覚次, 西﨑正彦, 黒田新士, 香川俊輔, 藤原俊義

癌と化学療法 43 ( 12 ) 2219 - 2221 2016

Language：Japanese Publisher：(株)癌と化学療法社

症例は63歳、男性。早期胃癌(pT1bN0M0、pStage IA)術後20ヵ月のCTにて多発肝転移再発を認め、first-lineとしてS-1+CDDP療法2コース施行後、腫瘍は増大し、second-lineとしてnab-PTX6コース施行するも腫瘍増大、肝酵素上昇、体重減少と全身状態の悪化を認めた。しかし、third-lineのCPT-11が奏効し、肝酵素も正常化、体重も増加し全身状態、ADLの改善も認め、8ヵ月PRを維持した。CPT-11合計17コース施行後に腫瘍が増大し、その後S-1+oxaliplatin療法、DTX、再度CPT-11、ramucirumab投与を行い、再発後31ヵ月原病死された。胃癌肝転移に対してCPT-11はkey drugになる可能性があり、また予後延長には胃癌に有効なkey drugをすべて使い切るマネージメントが重要と考えられた。(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2016&ichushi_jid=J00296&link_issn=&doc_id=20161222480266&doc_link_id=%2Fab8gtkrc%2F2016%2F004312%2F266%2F2219-2221%26dl%3D0&url=https%3A%2F%2Fwww.medicalonline.jp%2Fjamas.php%3FGoodsID%3D%2Fab8gtkrc%2F2016%2F004312%2F266%2F2219-2221%26dl%3D0&type=MedicalOnline&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00004_2.gif

Tumor-specific cell-cycle decoy by Salmonella typhimurium A1-R combined with tumor-selective cell-cycle trap by methioninase overcome tumor intrinsic chemoresistance as visualized by FUCCI imaging

Shuya Yano, Kiyoto Takehara, Ming Zhao, Yuying Tan, Qinghong Han, Shukuan Li, Michael Bouvet, Toshiyoshi Fujiwara, Robert M. Hoffman

CELL CYCLE 15 ( 13 ) 1715 - 1723 2016

Language：English Publisher：TAYLOR & FRANCIS INC

We previously reported real-time monitoring of cell cycle dynamics of cancer cells throughout a live tumor intravitally using a fluorescence ubiquitination 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 FUCCI imaging demonstrated that cytotoxic agents killed only proliferating cancer cells at the surface and, in contrast, and had little effect on the quiescent cancer cells. Resistant quiescent cancer cells restarted cycling after the cessation of chemotherapy. Thus cytotoxic chemotherapy which targets cells in S/G(2)/M, is mostly ineffective on solid tumors, but causes toxic side effects on tissues with high fractions of cycling cells, such as hair follicles, bone marrow and the intestinal lining. We have termed this phenomenon tumor intrinsic chemoresistance (TIC). We previously demonstrated that tumor-targeting Salmonella typhimurium A1-R (S. typhimurium A1-R) decoyed quiescent cancer cells in tumors to cycle from G(0)/G(1) to S/G(2)/M demonstrated by FUCCI imaging. We have also previously shown that when cancer cells were treated with recombinant methioninase (rMETase), the cancer cells were selectively trapped in S/G(2), shown by cell sorting as well as by FUCCI. In the present study, we show that sequential treatment of FUCCI-expressing stomach cancer MKN45 in vivo with S. typhimurium A1-R to decoy quiescent cancer cells to cycle, with subsequent rMETase to selectively trap the decoyed cancer cells in S/G(2) phase, followed by cisplatinum (CDDP) or paclitaxel (PTX) chemotherapy to kill the decoyed and trapped cancer cells completely prevented or regressed tumor growth. These results demonstrate the effectiveness of the praradigm of decoy, trap and shoot chemotherapy.

DOI： 10.1080/15384101.2016.1181240

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Oxidative stress balance is dysregulated and represents an additional target for treating cholangiocarcinoma

Daisuke Uchida, Akinobu Takaki, Hisashi Ishikawa, Yasuko Tomono, Hironari Kato, Koichiro Tsutsumi, Naofumi Tamaki, Takayuki Maruyama, Takaaki Tomofuji, Ryuichiro Tsuzaki, Tetsuya Yasunaka, Kazuko Koike, Hiroshi Matsushita, Fusao Ikeda, Yasuhiro Miyake, Hidenori Shiraha, Kazuhiro Nouso, Ryuichi Yoshida, Yuzo Umeda, Susumu Shinoura, Takahito Yagi, Toshiyoshi Fujiwara, Manabu Morita, Masaki Fukushima, Kazuhide Yamamoto, Hiroyuki Okada

FREE RADICAL RESEARCH 50 ( 7 ) 732 - 743 2016

Language：English Publisher：TAYLOR & FRANCIS LTD

Background: Pancreatico-biliary malignancies exhibit similar characteristics, including obesity-related features and poor prognosis, and require new treatment strategies. Oxidative stress is known to induce DNA damage and carcinogenesis, and its reduction is viewed as being favorable. However, it also has anti-infection and anti-cancer functions that need to be maintained. To reveal the effect of oxidative stress on cancer progression, we evaluated oxidative stress and anti-oxidative balance in pancreatic cancer (PC) and cholangiocarcinoma (CC) patients, as well as the effect of add-on antioxidant treatment to chemotherapy in a mouse cholangiocarcinoma model.
Methods: We recruited 84 CC and 80 PC patients who were admitted to our hospital. Serum levels of reactive oxygen metabolites (ROM) and the anti-oxidative OXY-adsorbent test were determined and the balance of these tests was defined as an oxidative index. A diabetic mouse-based cholangiocarcinoma model was utilized to evaluate the effects of add-on antioxidant therapy on cholangiocarcinoma chemotherapy.
Results: Serum ROM was higher and anti-oxidant OXY was lower in CC patients with poor outcomes. These parameters were not significantly different in PC patients. In mice, vitamin E administration induced antioxidant hemeoxygenase (HO)-1 protein expression in cancer tissue, while the number of stem-like cells increased. L-carnitine administration improved intestinal microbiome and biliary acid balance, upregulated the hepatic mitochondrial membrane uptake related gene Cpt1 in non-cancerous tissue, and did not alter stem-like cell numbers.
Conclusion: Oxidative stress balance was dysregulated in cholangiocarcinoma with poor outcome. The mitochondrial function-supporting agent L-carnitine is a good candidate to control oxidative stress conditions.

DOI： 10.3109/10715762.2016.1172071

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