Faculty Profiles - KAGAWA Shunsuke

Papers - KAGAWA Shunsuke

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Double-Flap Technique as an Antireflux Procedure in Esophagogastrostomy after Proximal Gastrectomy

Shinji Kuroda, Masahiko Nishizaki, Satoru Kikuchi, Kazuhiro Noma, Shunsuke Tanabe, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

JOURNAL OF THE AMERICAN COLLEGE OF SURGEONS 223 ( 2 ) E7 - E13 2016.8

In Vivo Isolation of a Highly-aggressive Variant of Triple-negative Human Breast Cancer MDA-MB-231 Using Serial Orthotopic Transplantation

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 2016.8

Language：English Publishing type：Research paper (scientific journal) Publisher：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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A case of right-sided Bochdalek hernia incidentally diagnosed in a gastric cancer patient

Satoru Kikuchi, Masahiko Nishizaki, Shinji Kuroda, Shunsuke Kagawa, Toshiyoshi Fujiwara

BMC SURGERY 16 ( 34 ) doi: 10.1186/s12893-016-0145-2 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：BIOMED CENTRAL LTD

Background: Bochdalek hernia (BH) is generally congenital, presenting with respiratory distress. However, this pathology is rarely detected in adults. Some adult cases of BH present with symptoms attributed to the hernia, but incidental detection of BH is increasing among asymptomatic adults due to advances in imaging modalities. This report presents the management of incidental BH patients detected in the preoperative period of gastric cancer.
Case presentation: An asymptomatic 76-year-old woman was diagnosed with advanced gastric cancer during follow-up after radiotherapy for uterine cervical cancer. Computed tomography (CT) was performed to exclude metastatic gastric cancer, incidentally detecting right-sided BH. We planned distal gastrectomy with lymph node dissection for gastric cancer and simultaneous repair of BH using a laparoscopic approach. We performed laparoscopic gastrectomy for gastric cancer and investigated the right-sided BH to assess whether repair during surgery was warranted. Herniation of the liver into the right hemithorax was observed, but was followed-up without surgical repair because the right hepatic lobe was adherent to the remnant right anterior hemidiaphragm and covered the huge defect in the right hemidiaphragm. No intra-or postoperative pneumothorax was observed during pneumoperitoneum.
Conclusion: Regardless of symptoms, repair of adult BH is generally recommended to prevent visceral incarceration. However, BH in asymptomatic adults appears to be more common than previously reported in the literature. Surgeons need to consider the management of incidental BH encountered during thoracic or abdominal surgery.

DOI： 10.1186/s12893-016-0145-2

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Recurrence after Endoscopic Curative Resection of Mucosal Gastric Cancer Associated with an Adjacent Neoplastic Precursor Lesion

Satoru Kikuchi, Shunsuke Kagawa, Toshiaki Ohara, Tetsushi Kubota, Kazuya Kuwada, Tetsuya Kagawa, Shinji Kuroda, Yasuhiro Shirakawa, Masahiko Nishizaki, Toshiyoshi Fujiwara

ACTA MEDICA OKAYAMA 70 ( 3 ) 213 - 216 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：OKAYAMA UNIV MED SCHOOL

A 69-year-old man underwent endoscopic submucosal dissection (ESD) for early gastric cancer (EGC) at the lesser curvature in the angle of stomach. Histological examination revealed tub1, pM, ly0, v0, pLM(-), pVM(-), and the resection was considered curative. The scar after ESD was followed by esophagogastroduodenoscopy (EGD) and biopsy. Twenty months later, EGD showed an ulcerative lesion in the vicinity of the ESD scar, and histological examination of the biopsy specimen showed adenocarcinoma. A distal gastrectomy with lymph node dissection was then performed. Postoperative pathology showed tub1, pM, pN0, ly0, v0, and Stage 1A. Skip lesions were seen in the specimen resected by ESD, and the histological review confirmed so-called "dysplasia-like atypia" (DLA) between the lesions. It has been reported recently that in DLA, the dysplasia-like change involves only the bases of the pits, without upper pit or surface epithelium involvement, and it is said that the rate of DLA is higher in gastric cancer patients. We speculated that a precancerous lesion close to the resected cancer developed into a local recurrence.

DOI： 10.18926/AMO/54421

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Ablation of MCL1 expression by virally induced microRNA-29 reverses chemoresistance in human osteosarcomas

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 ) doi: 10.1038/srep28953 2016.6

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

DOI： 10.1038/srep28953

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Trastuzumab-Based Photoimmunotherapy Integrated with Viral HER2 Transduction Inhibits Peritoneally Disseminated HER2-Negative Cancer

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 2016.3

Language：English Publishing type：Research paper (scientific journal) Publisher：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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【新薬認可で治療革命の幕開けがんのウイルス療法がん細胞だけを破壊する組換えウイルスその作用機序と開発動向】テロメラーゼ標的化がん治療・診断用アデノウイルス

田澤大, 香川俊輔, 重安邦俊, 藤原俊義

実験医学 34 ( 1 ) 13 - 18 2016.1

Language：Japanese Publisher：(株)羊土社

アデノウイルスは本来ヒトの細胞に感染・増殖し、最終的に感染した細胞をさまざまな機序により破壊する。近年の遺伝子工学技術の進歩により、アデノウイルスの増殖能にがん選択性をもたせることで新たながん治療薬としての臨床開発が進められている。本稿では、われわれが独自に開発したテロメラーゼ活性選択的に制限増殖するアデノウイルス製剤を用いたがん治療法・診断法に関する研究成果や臨床応用について概説する。がん細胞の無制限な増殖能に関連するテロメラーゼを標的とすることで多くのがん患者に対する治療・診断技術の開発が期待される。(著者抄録)

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p53 Replacement Therapy for Cancer. Reviewed

Tazawa H, Kagawa S, Fujiwara T

Recent results in cancer research. Fortschritte der Krebsforschung. Progres dans les recherches sur le cancer 209 1 - 15 2016

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

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 Publishing type：Research paper (scientific journal) 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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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 Publishing type：Research paper (scientific journal) 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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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

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

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. International journal

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 ) e0148760 2016

Language：English Publishing type：Research paper (scientific journal)

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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[Therapeutic Potential of Targeting Cancer-Associated Fibroblasts in Esophageal Cancer]. Reviewed

Kazuhiro Noma, Hajime Kashima, Takayuki Ninomiya, Ryoichi Katsube, Shinichiro Watanabe, Toshiaki Ohara, Hiroshi Tazawa, Shunsuke Kagawa, Yasuhiro Shirakawa, Toshiyoshi Fujiwara

Gan to kagaku ryoho. Cancer & chemotherapy 42 ( 10 ) 1228 - 30 2015.10

Language：Japanese Publishing type：Research paper (scientific journal)

Advances in molecular and cellular biochemistry, such as the development of targeted cancer therapy, have dramatically improved the prognosis of cancer patients. Emerging data have suggested that bevacizumab treatment may act by controlling the cancer microenvironment. Many reports have examined the interaction of cancer cells with the tumor microenvironment, and cancer-associated fibroblasts (CAFs) are thought to play a central role in this process. We speculated that the cancer microenvironment and in particular, CAFs, strongly influence the development of esophageal cancer. We have analyzed the signaling pathways of molecular targets. However, inhibition of a single signaling pathway is insufficient to treat cancer effectively. Photoimmunotherapy is a molecular-targeted specific cancer therapy using near-infrared radiation, which was introduced by Mitsunaga et al. in 2011. We are using its specific method of killing cells to target CAFs. We will report the results of its effect on cancer cells in the future.

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胃疾患に対する内視鏡外科手術手技腹腔鏡下噴門側胃切除術におけるリンパ節郭清手技の定型化

西崎正彦, 黒田新士, 菊地覚次, 坂本修一, 田邊俊介, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

日本臨床外科学会雑誌 76 ( 増刊 ) 389 - 389 2015.10

手術手技腹腔鏡下噴門側胃切除後の「観音開き法」による完全体腔内食道残胃吻合

黒田新士, 西崎正彦, 野間和広, 香川俊輔, 白川靖博, 藤原俊義

手術 69 ( 10 ) 1487 - 1492 2015.9

胃癌合併Bochdalek孔ヘルニアに対する用手補助腹腔鏡下手術による一期的根治手術の1例

堀直人, 香川俊輔, 黒田新士, 岸本浩行, 西崎正彦, 藤原俊義

日本内視鏡外科学会雑誌 20 ( 5 ) 473 - 479 2015.9

Language：Japanese Publisher：(一社)日本内視鏡外科学会

患者は65歳,男性.腹痛・嘔吐を主訴に前医を受診し,上部消化管内視鏡検査で早期胃癌を,CTで左横隔膜にBochdalek孔ヘルニアを指摘された.胃癌に対する内視鏡的切除が非治癒切除となり,追加切除目的に当院紹介となった.胃癌のリンパ節郭清と今後のヘルニア嵌頓のリスクを考慮し,同時手術にて腹腔鏡補助下に胃切除およびヘルニア修復術を行った.気腹による胸腔内圧上昇に胸腔トロッカーを要し,ヘルニア門修復での視野確保には用手補助を追加したが,腹腔鏡下に幽門側胃切除とヘルニア根治術を完遂した.これまでに横隔膜ヘルニアと悪性腫瘍とを同時に手術した報告はなく,若干の文献的考察を加えて報告する.(著者抄録)

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Other Link： https://search.jamas.or.jp/index.php?module=Default&action=Link&pub_year=2015&ichushi_jid=J03270&link_issn=&doc_id=20150925140005&doc_link_id=10.11477%2Fmf.4426200166&url=https%3A%2F%2Fdoi.org%2F10.11477%2Fmf.4426200166&type=%88%E3%8F%91.jp_%83I%81%5B%83%8B%83A%83N%83Z%83X&icon=https%3A%2F%2Fjk04.jamas.or.jp%2Ficon%2F00024_2.gif

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 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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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Genetic and epigenetic alterations of netrin-1 receptors in gastric cancer with chromosomal instability

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 doi:10.1186/s13148-015-0096-y 2015.7

Language：English Publishing type：Research paper (scientific journal) Publisher：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.

DOI： 10.1186/s13148-015-0096-y

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