Identification of the molecular mechanism underlying cancer stem cell regulation via arachidonic cascade

• Project/Area Number: 16K15595
• Research Category: Grant-in-Aid for Challenging Exploratory Research
• Allocation Type: Multi-year Fund
• Research Field: General surgery
• Research Institution: Kumamoto University
• Principal Investigator: ISHIMOTO Takatsugu 熊本大学, 大学院生命科学研究部(医), 特任講師 (00594889)
• Co-Investigator(Kenkyū-buntansha): 馬場 秀夫 熊本大学, 大学院生命科学研究部(医), 教授 (20240905) ; 岩槻 政晃 熊本大学, 大学院生命科学研究部(医), 助教 (50452777)
• Co-Investigator(Renkei-kenkyūsha): OOMURAYA Masaki 兵庫医科大学, 医学部, 教授 (60398229)
• Project Period (FY): 2016-04-01 – 2018-03-31
• Project Status: Completed (Fiscal Year 2017)
• Budget Amount: ¥3,510,000 (Direct Cost: ¥2,700,000、Indirect Cost: ¥810,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2016: ¥1,690,000 (Direct Cost: ¥1,300,000、Indirect Cost: ¥390,000)
• Keywords: 癌幹細胞 / 慢性炎症 / アラキドン酸 / アラキドン酸カスケード

Outline of Final Research Achievements

Based on cancer stem cell (CSC) theory, tumors consist of a hierarchical organization of cellular subpopulations that have stem cell-like properties, and these tumor cells have been implicated in chemoresistance and tumor relapse. However, the most important CSC marker harboring a clinical impact in pancreatic cancer has not yet been determined. The purpose of current study was to identify the critical CSC marker in pancreatic cancer and to examine the molecular mechanism of pancreatic cancer progression via CSC expansion. Further analysis on pancreatic tumors in gene engineering mice leads to the identification of new pancreatic cancer biomarker.

Research Products

• [Journal Article] Downregulation of 15-hydroxyprostaglandin dehydrogenase by interleukin-1β from activated macrophages leads to poor prognosis in pancreatic cancer. (2018)
  • Author(s): Arima K, Komohara Y, Bu L, Tsukamoto M, Itoyama R, Miyake K, Uchihara T, Ogata Y, Nakagawa S, Okabe H, Imai K, Hashimoto D, Chikamoto A, Yamashita YI, Baba H, Ishimoto T
  • Journal Title: Cancer Sci Volume: 109(2) Issue: 2 Pages: 462-470
  • DOI: 10.1111/cas.13467
  • Peer Reviewed / Open Access
• [Journal Article] Activation of Transforming Growth Factor Beta 1 Signaling in Gastric Cancer-associated Fibroblasts Increases Their Motility, via Expression of Rhomboid 5 Homolog 2, and Ability to Induce Invasiveness of Gastric Cancer Cells. (2017)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Onishi N, Huang KK, Joyce LN, Kalpana R, Tay ST, Suzuki Y, Cho BC, Kuroda D, Arima K, Izumi D, Iwatsuki M, Baba Y, Oki E, Watanabe M, Saya H, Hirakawa K, Baba H, Tan P.
  • Journal Title: Gastroenterology Volume: in press Issue: 1 Pages: 191-204
  • DOI: 10.1053/j.gastro.2017.03.046
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Colorectal Cancer Stem Cells Acquire Chemoresistance Through the Upregulation of F-Box/WD Repeat-Containing Protein 7 and the Consequent Degradation of c-Myc. (2017)
  • Author(s): Izumi D, Ishimoto T, Miyake K, Eto T, Arima K, Kiyozumi Y, Uchihara T, Kurashige J, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Yoshida N, Watanabe M, Goel A, Tan P, Baba H.
  • Journal Title: Stem Cells. Volume: 35(9) Issue: 9 Pages: 2027-2036
  • DOI: 10.1002/stem.2668
  • Peer Reviewed
• [Journal Article] PD-L1 Expression, Tumor-infiltrating Lymphocytes, and Clinical Outcome in Patients With Surgically Resected Esophageal Cancer. (2017)
  • Author(s): Yagi T, Baba Y, Ishimoto T, Iwatsuki M, Miyamoto Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Ann Surg. Volume: Dec 4 Issue: 3 Pages: 471-478
  • DOI: 10.1097/sla.0000000000002616
  • Peer Reviewed / Open Access
• [Journal Article] Clinical usefulness of postoperative C-reactive protein/albumin ratio in pancreatic ductal adenocarcinoma. (2017)
  • Author(s): Arima K, Yamashita YI, Hashimoto D, Nakagawa S, Umezaki N, Yamao T, Tsukamoto M, Kitano Y, Yamamura K, Miyata T, Okabe H, Ishimoto T, Imai K, Chikamoto A, Baba H.
  • Journal Title: Am J Surg. Volume: Aug 26 Issue: 1 Pages: 111-115
  • DOI: 10.1016/j.amjsurg.2017.08.016
  • Peer Reviewed
• [Journal Article] Fibroblast growth factor receptor 2 expression, but not its genetic amplification, is associated with tumor growth and worse survival in esophagogastric junction adenocarcinoma. (2016)
  • Author(s): Tokunaga R, Imamura Y, Nakamura K, Ishimoto T, Nakagawa S, Miyake K, Nakaji Y, Tsuda Y, Iwatsuki M, Baba Y, Sakamoto Y, Miyamoto Y, Saeki H, Yoshida N, Oki E, Watanabe M, Oda Y, Bass AJ, Maehara Y, Baba H.
  • Journal Title: Oncotarget Volume: in press Issue: 15 Pages: 19748-61
  • DOI: 10.18632/oncotarget.7782
  • Peer Reviewed / Open Access / Int'l Joint Research
• [Journal Article] Human Microbiome Fusobacterium Nucleatum in Esophageal Cancer Tissue Is Associated with Prognosis (2016)
  • Author(s): Yamamura K, Baba Y, Nakagawa S, Mima K, Miyake K, Nakamura K, Sawayama H, Kinoshita K, Ishimoto T, Iwatsuki M, Sakamoto Y, Yamashita Y, Yoshida N, Watanabe M, Baba H.
  • Journal Title: Clin Cancer Res Volume: 22(22) Issue: 22 Pages: 5574-5581
  • DOI: 10.1158/1078-0432.ccr-16-1786
  • Peer Reviewed
• [Presentation] Inhibition of 15-PGDH causes Kras-driven tumor expansion through all-trans retinoic acid metabolism in the pancreas. (2018)
  • Author(s): Ishimoto T, Arima K, Baba Y, Yamashita Y, Baba H.
  • Organizer: American Association for Cancer Research Annual Meeting 2018
  • Int'l Joint Research
• [Presentation] Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive tumor cells and Kras-driven tumorigenesis in pancreas. (2017)
  • Author(s): Arima K, Ishimoto T, Ohmuraya M, Miyake K, Eto T, Okabe H, Kitano Y, Yamamura K, Kaida T, Imai K, Hashimoto D, Chikamoto A, Yamashita YI, Baba H.
  • Organizer: American Association for Cancer Research Annual Meeting 2017
  • Int'l Joint Research
• [Presentation] 15-PGDH inhibition enhances KRAS-driven tumor cell expansion via all-trans retinoic acid depletion in pancreas (2017)
  • Author(s): Arima K, Ishimoto T, Ohmuraya M, Miyake K, Uchihara T, Eto T, Nakagawa S, Imai K, Hashimoto D, Chikamoto A, Yamashita YI, Baba H.
  • Organizer: The 76th Annual Meeting of the Japan Cancer Association.
• [Presentation] 慢性炎症関連シグナルの活性化に伴う膵癌進展メカニズムの解明 (2017)
  • Author(s): 有馬浩太、石本崇胤、大村谷昌樹、三宅慧輔、内原智幸、塚本雅代、梅崎直紀、江藤二男、北野雄希、宮田辰徳、中川茂樹、岡部弘尚、今井克憲、馬場祥史、橋本大輔、近本亮、山下洋市、古川徹、荒木喜美、馬場秀夫
  • Organizer: 第28回日本消化器癌発生学会
• [Presentation] Prostaglandin E2 accumulation enhances the expansion of ALDH1-positive cells and Kras-driven tumorigenesis in the pancreas. (2017)
  • Author(s): Arima K、Ishimoto T, Ohmuraya M, Miyake K, Eto T, Okabe H, Kitano Y, Yamamura K, Kaida T, Imai K, Hashimoto D, Chikamoto A, Baba H
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: ワシントン（米国）
  • Int'l Joint Research
• [Presentation] RHBDF2 in stromal fibroblasts mediates TGF-β signaling and enhances gastric cancer cell invasion via intercellular crosstalk. (2017)
  • Author(s): Ishimoto T, Miyake K, Yashiro M, Eto T, Izumi D, Arima K, Baba Y, Watanabe M, Hirakawa K, Baba H
  • Organizer: AACR Annual Meeting 2017
  • Place of Presentation: ワシントン（米国）
  • Int'l Joint Research
• [Presentation] 腫瘍間質ゲノム解析に基づいた胃癌浸潤を制御する新規分子機構の解明 (2017)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、江藤二男、有馬浩太、泉大輔、岩槻政晃、馬場祥史、渡邊雅之、平川弘聖、Patrick Tan、馬場秀夫
  • Organizer: 第89回日本胃癌学会総会
  • Place of Presentation: 広島国際会議場（広島県）
• [Presentation] Identification of the novel molecules mediating gastric cancer invasion based on genomic analysis of cancer-associated fibroblasts. (2016)
  • Author(s): Ishimoto T, Miyake K, Nandi T, Yashiro M, Huang K, Arima K, Izumi D, Baba Y, Baba H, Tan P
  • Organizer: ESMO-ASIA 2016
  • Place of Presentation: シンガポール
  • Int'l Joint Research
• [Presentation] Verification of mechanism that CSC markers are implicated in poor prognosis for pancreatic ductal adenocarcinoma. (2016)
  • Author(s): Arima K, Ishimoto T, Ohmuraya M, Okabe H, Kitano Y, Yamamura K, Kaida T, Nakagawa S, Imai K, Hashimoto D, Chikamoto A, Yamashita Y, Baba H
  • Organizer: ESMO-ASIA 2016
  • Place of Presentation: シンガポール
  • Int'l Joint Research
• [Presentation] Cancer Associated Fibroblasts (CAFs)ゲノム解析に基づいた胃癌浸潤を制御する新規遺伝子の同定 (2016)
  • Author(s): 石本崇胤、三宅慧輔、八代正和、有馬浩太、泉大輔、澤山浩、岩槻政晃、馬場祥史、坂本快郎、吉田直矢、平川弘聖、馬場秀夫、Patrick Tan
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）
• [Presentation] がん幹細胞マーカーが膵癌進展を引き起こすメカニズムの解明 (2016)
  • Author(s): 有馬浩太、石本崇胤、大村谷昌樹、三宅慧輔、江藤二男、甲斐田剛圭、東孝暁、岡部弘尚、新田英利、橋本大輔、近本 亮、山下洋市、馬場秀夫
  • Organizer: 第75回日本癌学会学術総会
  • Place of Presentation: パシフィコ横浜（神奈川県）