Deveropment of novel treatment and analysis in molecular mechanism of cell-cell interaction for Hepatobliriary pancreato carcimona

• Project/Area Number: 15K19875
• Research Category: Grant-in-Aid for Young Scientists (B)
• Allocation Type: Multi-year Fund
• Research Field: Digestive surgery
• Research Institution: Tokyo Medical and Dental University
• Principal Investigator: Aihara Arihiro 東京医科歯科大学, 医学部附属病院, 非常勤講師 (90451939)
• Project Period (FY): 2015-04-01 – 2017-03-31
• Project Status: Completed (Fiscal Year 2016)
• Budget Amount: ¥3,900,000 (Direct Cost: ¥3,000,000、Indirect Cost: ¥900,000); Fiscal Year 2016: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000); Fiscal Year 2015: ¥1,950,000 (Direct Cost: ¥1,500,000、Indirect Cost: ¥450,000)
• Keywords: 細胞間相互作用 / ASPH / 膵癌 / 肝細胞癌 / Notch signaling / 胆管癌 / Notch / 肝内胆管癌

Outline of Final Research Achievements

Hepatobiliary pancreatic cancer is well known as poor prognostic cancers. Our purpose is development of novel treatment and investigation of cell-cell interaction in hepatobiliary pancreatic cancer. Overexpresion of aspartate beta-hydroxylase (ASPH) is frequently obeserved not only in hepatocellular carcinoma but also in pancreatic and biliary cancer, which positively regulates Notch signaling pathway. The biological effects of ASPH inhibitors on the Notch signaling cascade were evaluated. The ASPH inhibitor reduced suppressed cell migration, invasion in pancreatic and biliary cancer. Furthermore, substantial inhibition of tumor growth and progression was observed in animal models. ASPH is promising for treatment of hepatobiliary pancreatic cancer. Additionally experiments to investigate cell-cell interaction in Neuroendocrine tumor were established and novel animal model was developed to analyze molecular mechanisms acquiring resistance for anti-cancer treatment.

Research Products

• [Journal Article] Acquired Resistance with Epigenetic Alterations Under Long-Term Antiangiogenic Therapy for Hepatocellular Carcinoma (2017)
  • Author(s): Ohata Y, Akiyama Y, Shimada S, Mogushi K, Nakao K, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Tanabe M, Tanaka S.
  • Journal Title: Mol Cancer Ther. Volume: in press Pages: 1155-1165
  • DOI: 10.1158/1535-7163.mct-16-0728
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] ARID2 modulates DNA damage response in human hepatocellular carcinoma cells (2017)
  • Author(s): Oba A, Shimada S, Akiyama Y, Nishikawaji T, Mogushi K, Ito H, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Asahara H, Kaida A, Miura M, Tanabe M, Tanaka S.
  • Journal Title: J Hepatol. Volume: in press Pages: 942-951
  • DOI: 10.1016/j.jhep.2016.12.026
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Preoperative direct bilirubin to prothrombin time ratio index to prevent liver failure after minor hepatectomy (2016)
  • Author(s): Furuyama T, Kudo A, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Tanaka S, Tanabe M.
  • Journal Title: Journal of Hepato-Biliary-Pancreatic Sciences. Volume: 23 Pages: 763-770
  • DOI: 10.1002/jhbp.400
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Expression of transforming growth factor β1 promotes cholangiocarcinoma development and progression. (2016)
  • Author(s): Huang CK, Aihara A, Iwagami Y, Yu T, Carlson R, Koga H, Kim M, Zou J, Casulli S, Wands JR.
  • Journal Title: Cancer Lett. Volume: 1 Pages: 153-162
  • DOI: 10.1016/j.canlet.2016.05.038
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Proteasome activity is required for the initiation of precancerous pancreatic lesions. (2016)
  • Author(s): Furuyama T, Tanaka S, Shimada S, Akiyama Y, Matsumura S, Mitsunori Y, Aihara A, Ban D, Ochiai T, Kudo A, Fukamachi H, Arii S, Kawaguchi Y, Tanabe M.
  • Journal Title: Sci Rep Volume: 6 Pages: 27044-27044
  • DOI: 10.1038/srep27044
  • Peer Reviewed / Open Access / Int'l Joint Research / Acknowledgement Compliant
• [Journal Article] Molecular pathology of advanced hepatocellular carcinoma (2016)
  • Author(s): Aihara A, Wands JR, Tanaka S.
  • Journal Title: Nippon Shokakibyo Gakkai Zasshi Volume: 113 Issue: 5 Pages: 790-797
  • DOI: 10.11405/nisshoshi.113.790
  • NAID: 130005150376
• [Journal Article] Anti-Tumor Effects of Second Generation β-Hydroxylase Inhibitors on Cholangiocarcinoma Development and Progression. (2016)
  • Author(s): Huang CK, Iwagami Y, Aihara A, Chung W, de la Monte S, Thomas JM, Olsen M, Carlson R, Yu T, Dong X, Wands J.
  • Journal Title: PLoS One Volume: 11
  • DOI: 10.1371/journal.pone.0150336
  • Peer Reviewed / Int'l Joint Research
• [Journal Article] Macroscopic morphology for estimation of malignant potential in pancreatic neuroendocrine neoplasm. (2016)
  • Author(s): Katsuta E, Kudo A, Akashi T, Mitsunori Y, Matsumura S, Aihara A, Ban D, Ochiai T, Tanaka S, Eishi Y, Tanabe M.
  • Journal Title: Journal of Cancer Research and Clinical Oncology Volume: -
  • Peer Reviewed
• [Journal Article] Dominant expression of DCLK1 in human pancreatic cancer stem cells accelerates tumor invasion and metastasis. (2016)
  • Author(s): Ito H, Tanaka S, Akiyama Y, Shimada S, Adikrisna R, Matsumura S, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Yamaoka S, Tanabe M.
  • Journal Title: PlosOne Volume: -
  • DOI: 10.1371/journal.pone.0146564
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Expression of connective tissue growth factor in the livers of non-viral hepatocellular carcinoma patients with metabolic risk factors. (2016)
  • Author(s): Akahoshi K, Tanaka S, Mogushi K, Shimada S, Matsumura S, Akiyama Y, Aihara A, Mitsunori Y, Ban D, Ochiai T, Kudo A, Arii S, Tanabe M.
  • Journal Title: Journal of Gastroenterology Volume: -
  • Peer Reviewed
• [Journal Article] CD73 as a therapeutic target for pancreatic neuroendocrine tumor stem cells (2016)
  • Author(s): Katsuta, E., Tanaka, S., Mogushi, K., Shimada, S., Akiyama, Y., Aihara, A., Matsumura, S., Mitsunori, Y., Ban, D., Ochiai, T., Kudo, A., Fukamachi, H., Tanaka, H., Nakayama, K., Arii, S., Tanabe, M.
  • Journal Title: Int J Oncol. Volume: 48 Pages: 657-659
  • DOI: 10.3892/ijo.2015.3299
  • Peer Reviewed / Open Access / Acknowledgement Compliant
• [Journal Article] Aspartate β-Hydroxylase expression promotes a malignant pancreatic cellular phenotype. (2015)
  • Author(s): Dong X, Lin Q, Aihara A, Li Y, Huang CK, Chung W, Tang Q, Chen X, Carlson R, Nadolny C, Gabriel G, Olsen M, Wands JR.
  • Journal Title: Oncotarget Volume: 6(2) Pages: 1231-48
  • Peer Reviewed / Open Access
• [Presentation] 肝胆膵領域癌に対する治療標的としてのASPHの解析 (2015)
  • Author(s): 藍原有弘, Chiung-kuei Huang, Mark Olsen, Waihong Chung, Qi Tang, Xiaoqun Dong, 田中真二、田邉稔、Jack Wands
  • Organizer: 第５３回癌治療学会学術集会
  • Place of Presentation: 国立京都国際会館（京都府京都市）
  • Year and Date: 2015-10-29
• [Presentation] A cell surface beta-hydroxylase is a novel therapeutic target for pancreatic cancer (2015)
  • Author(s): 藍原 有弘、田中真二、松村聡、光法雄介、伴大輔、落合高徳、工藤篤、田邉稔、Jack Wands
  • Organizer: 第７０回日本消化器外科学会総会
  • Place of Presentation: アクトシティ浜松（静岡県浜松市）
  • Year and Date: 2015-07-15
• [Presentation] 肝胆膵領域癌に対する新規治療標的の探索 (2015)
  • Author(s): 藍原 有弘, 田中 真二, 田邉 稔, Wands Jack
  • Organizer: 第２７回日本肝胆膵外科学会学術集会
  • Place of Presentation: ホテルグランパシフィック台場（東京都港区）
  • Year and Date: 2015-06-11
• [Presentation] 藍原有弘、松永浩子、田中真二 (2015)
  • Author(s): 肝細胞癌に対するAurora kinase Bを標的とした治療開発
  • Organizer: 第５１回日本肝臓学会総会
  • Place of Presentation: ホテル日航熊本（熊本県熊本市）
  • Year and Date: 2015-05-21
• [Presentation] 肝細胞癌に対する新規治療標的としてのAspartyl-(Asparaginyl)-beta-hydroxylase (ASPH) (2015)
  • Author(s): 藍原 有弘、Chiung-Kuei Huang、Waihong Chung、松村 聡、伴 大輔、落合 高徳、工藤 篤、田中 真二、田邉 稔、Jack Wands
  • Organizer: 第１１５回日本外科学会定期学術集会
  • Place of Presentation: 名古屋国際会議場（愛知県名古屋市）
  • Year and Date: 2015-04-16