To verify the molecular mechanism of pancreatic cancer progression related with chronic inflammation via cancer stem cell expansion.

• Project/Area Number: 17K16570
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Kumamoto University
• Principal Investigator: ARIMA Kouta 熊本大学, 医学部附属病院, 非常勤診療医師 (10792616)
• Project Period (FY): 2017-04-01 – 2019-03-31
• Project Status: Completed (Fiscal Year 2018)
• Budget Amount: ¥4,160,000 (Direct Cost: ¥3,200,000、Indirect Cost: ¥960,000); Fiscal Year 2018: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000); Fiscal Year 2017: ¥2,080,000 (Direct Cost: ¥1,600,000、Indirect Cost: ¥480,000)
• Keywords: 慢性炎症 / 癌幹細胞 / 全トランスレチノイン酸 / 膵臓癌 / 膵癌 / プロスタグランジンE2 / ALDH1 / PGE2

Outline of Final Research Achievements

Chronic inflammation which has affected a lot of cells, such as immune cell and cancer stem cell (CSC), is a risk factor of many cancers, however, they have not been applied clinical application yet due to complicated interactions. The current study showed to identify the critical CSC marker in pancreatic cancer and new tumor -progressing mechanism via expanding CSC fraction. In addition, we found that ATRA (all-trans retinoic acid) could be a therapeutic reagent for the patients whose tumor is accumulated prostaglandin E2 due to chronic inflammation.

Academic Significance and Societal Importance of the Research Achievements

膵癌は最も難治性の消化器癌の1つであり、有効な抗がん剤治療は数少なく効果も乏しいのが現状である。本研究では、慢性炎症に起因したATRAの枯渇を介した膵癌増殖の新規メカニズムを明らかにした。ATRAが白血病治療薬として使用されるようになってから白血病治療は劇的に進化したが、固形癌においては未だ有効な効果が得られた癌腫はない。本研究で明らかにしたようなメカニズムの影響が強い膵癌症例に限定することで、ATRAが膵癌に対して有効な新規治療薬なり得る。

Research Products

• [Journal Article] Impact of Repeated Hepatectomy on Liver Regeneration in Hepatocellular Carcinoma: A Propensity Score-based Analysis (2019)
  • Author(s): ARIMA KOTA、NITTA HIDETOSHI、BEPPU TORU、NAKAGAWA SHIGEKI、OKABE HIROHISA、IMAI KATSUNORI、CHIKAMOTO AKIRA、YAMASHITA YO-ICHI、YAMASHITA YASUYUKI、BABA HIDEO
  • Journal Title: Anticancer Research Volume: 39 Issue: 2 Pages: 965-970
  • DOI: 10.21873/anticanres.13200
  • Peer Reviewed
• [Journal Article] Inhibition of 15-PGDH causes Kras-driven tumor expansion through prostaglandin E2-ALDH1 signaling in the pancreas (2018)
  • Author(s): Arima Kota、Ohmuraya Masaki、Miyake Keisuke、Koiwa Mayu、Uchihara Tomoyuki、Izumi Daisuke、Gao Feng、Yonemura Atsuko、Bu Luke、Okabe Hirohisa、Imai Katsunori、Hashimoto Daisuke、Baba Yoshifumi、Chikamoto Akira、Yamashita Yo-ichi、Furukawa Toru、Araki Kimi、Baba Hideo、Ishimoto Takatsugu
  • Journal Title: Oncogene Volume: 38 Issue: 8 Pages: 1211-1224
  • DOI: 10.1038/s41388-018-0510-y
  • Peer Reviewed
• [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] Impact of loss-of-function mutations at the RNF43 locus on colorectal cancer development and progression (2018)
  • Author(s): Eto T, Miyake K, Nosho K, Ohmuraya M, Imamura Y, Arima K, Kanno S, Fu L, Kiyozumi Y, Izumi D, Sugihara H, Hiyoshi Y, Miyamoto Y, Sawayama H, Iwatsuki M, Baba Y, Yoshida N, Furukawa T, Araki K, Baba H, Ishimoto T
  • Journal Title: The Journal of Pathology Volume: 245 Issue: 4 Pages: 445-455
  • DOI: 10.1002/path.5098
  • Peer Reviewed
• [Journal Article] Tumor-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. (2018)
  • Author(s): Kitano Y, Okabe H, Yamashita YI, Nakagawa S, Saito Y, Umezaki N, Tsukamoto M, Yamao T, Yamamura K, Arima K, Kaida T, Miyata T, Mima K, Imai K, Hashimoto D, Komohara Y, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Br J Cancer Volume: 118(2) Issue: 2 Pages: 171-180
  • DOI: 10.1038/bjc.2017.401
  • Peer Reviewed / Open Access
• [Journal Article] Tumor-infiltrating inflammatory and immune cells in patients with extrahepatic cholangiocarcinoma. (2018)
  • Author(s): Kitano Y, Okabe H, Yamashita YI, Nakagawa S, Saito Y, Umezaki N, Tsukamoto M, Yamao T, Yamamura K, Arima K, Kaida T, Miyata T, Mima K, Imai K, Hashimoto D, Komohara Y, Chikamoto A, Ishiko T, Baba H
  • Journal Title: Br J Cancer. Volume: 118(2) Pages: 171-180
  • Peer Reviewed
• [Journal Article] Clinical significance of half-lives of tumor markers α-fetoprotein and des-γ-carboxy prothrombin after hepatectomy for hepatocellular carcinoma. (2018)
  • Author(s): Tsukamoto M, Nitta H, Imai K, Higashi T, Nakagawa S, Okabe H, Arima K, Kaida T, Taki K, Hashimoto D, Chikamoto A, Ishiko T, Beppu T, Baba H
  • Journal Title: Hepatol Res. Volume: 48 Issue: 3
  • DOI: 10.1111/hepr.12942
  • Peer Reviewed
• [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] 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
  • Peer Reviewed
• [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] 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, Lin SJ, 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: 153(1) Pages: 191-204
  • Peer Reviewed
• [Presentation] Verification of mechanism that the activated inflammatory signaling enhances pancreatic cancer progression. (2018)
  • Author(s): Arima K, Itoyama R, Ishimoto T, Miyake K, Uchihara T, Nakagawa S, Okabe H, Hayashi H, Imai K, Chikamoto A, Yamashita YI, Baba H.
  • Organizer: 第29回日本消化器癌発生学会
• [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
• [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): 3.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