The role of bone marrow-derived cells and interleukin-17 in the mouse model of Helicobacter-infected gastric cancer

• Project/Area Number: 23590919
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: Kyushu University
• Principal Investigator: TAKAISHI Shigeo 九州大学, 学内共同利用施設等, 准教授 (20596829)
• Research Collaborator: WANG Timothy C. コロンビア大学, 医学部消化器内科, 教授 ; HAYAKAWA Yoku コロンビア大学, 医学部消化器内科, 主任研究員
• Project Period (FY): 2011-04-28 – 2015-03-31
• Project Status: Completed (Fiscal Year 2014)
• Budget Amount: ¥5,200,000 (Direct Cost: ¥4,000,000、Indirect Cost: ¥1,200,000); Fiscal Year 2013: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2012: ¥1,430,000 (Direct Cost: ¥1,100,000、Indirect Cost: ¥330,000); Fiscal Year 2011: ¥2,340,000 (Direct Cost: ¥1,800,000、Indirect Cost: ¥540,000)
• Keywords: 胃発癌マウス / 胃前庭部上皮幹細胞 / Lgr5陽性細胞 / ガストリン/CCK２受容体 / プロガストリン / ヘリコバクター菌感染 / 発癌物質メチルニトロソウレア / CCK２受容体阻害薬YF476 / ガストリン/CCK2受容体 / 国際情報交換（アメリカ合衆国） / 国際情報交換、アメリカ合衆国 / 「国際情報交流、アメリカ合衆国」 / 国際情報交流、アメリカ合衆国

Outline of Final Research Achievements

We found that gastrin/CCK2-receptor (CCK2R) defines antral stem cells at position +4, which overlapped with an Lgr5 negative or low cell population but was distinct from typical antral Lgr5 high stem cells. Treatment with progastrin interconverts Lgr5 negative or low, CCK2R positive cells into Lgr5 high cells, increases CCK2R positive cell numbers and promotes gland fission and carcinogenesis in response to the chemical carcinogen MNU. Pharmacological inhibition or genetic ablation of CCK2R attenuated progastrin-dependent stem cell expansionand carcinogenesis.
In summary, CCK2R labels +4 antral stem cells that can be activated and expanded by progastrin, thus identifying one hormonal trigger for gastric stem cell interconversion and a potential target for gastric cancer chemoprevention and therapy.

Research Products

• [Journal Article] CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis. (2015)
  • Author(s): Hayakawa Y, Jin G, Wang H, Chen X, Westphalen CB, Asfaha S, Renz BW, Ariyama H, Dubeykovskaya ZA, Takemoto Y, Lee Y, Muley A, Tailor Y, Chen D, Muthupalani S, Fox JG, Shulkes A, Worthley DL, Takaishi S, Wang TC.
  • Journal Title: Gut Volume: 64(4) Issue: 4 Pages: 544-553
  • DOI: 10.1136/gutjnl-2014-307190
  • Peer Reviewed
• [Journal Article] Progastrin Promotes Antral Carcinogenesis and Gastric Stem Cell Function (2013)
  • Author(s): Yoku Hayakawa, Shigeo Takaishi, Guangchun Jin, Hiroshi Ariyama, Christoph B. Westphalen, Samuel Asfaha, Yagnesh H. Tailor, Wataru Shibata, Xiangdong Yang, Duan Chen, Mark T. Whary, Sureshkumar Muthupalani, James G. Fox, Arthur Shulkes, Timothy C. Wang
  • Journal Title: Gastroenterology Volume: Vol. 144, Issue 5, Suppl. 1
  • Peer Reviewed
• [Journal Article] The unfolded protein response is activated in Helicobacter-induced gastric carcinogenesis in a non-cell autonomous manner (2013)
  • Author(s): Baird M, Woon Ang P, Clark I, Bishop D, Oshima M, Cook MC, Hemmings C, Takaishi S, Worthley D, Boussioutas A, Wang TC, Taupin D.
  • Journal Title: Laboratory Investigation Volume: 93(1) Issue: 1 Pages: 112-122
  • DOI: 10.1038/labinvest.2012.131
  • Peer Reviewed
• [Journal Article] P53 gene mutation increases progastrin dependent colonic proliferation and colon cancer formation in mice (2012)
  • Author(s): Ramanathan V, Jin G, Westphalen CB, Whelan A, Dubeykovskiy A, Takaishi S, Wang TC.
  • Journal Title: Cancer Investigation Volume: 30(4) Issue: 4 Pages: 275-286
  • DOI: 10.3109/07357907.2012.657814
  • Peer Reviewed
• [Journal Article] In vivo analysis of mouse gastrin gene regulation in enhanced GFP-BAC transgenic mice. (2011)
  • Author(s): Takaishi S, Shibata W, Tomita H, Jin G, Yang X, Ericksen R, Dubeykovskaya Z, Asfaha S, Quante M, Betz KS, Shulkes A, Wang TC.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol Volume: 300(2) Issue: 2 Pages: G334-G344
  • DOI: 10.1152/ajpgi.00134.2010
  • Peer Reviewed
• [Journal Article] Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche and promote tumor growth. (2011)
  • Author(s): Quante M, Tu SP, Tomita H, Gonda T, Wang SS, Takaishi S, Baik GH, Shibata W, Diprete B, Betz KS, Friedman R, Varro A, Tycko B, Wang TC.
  • Journal Title: Cancer Cell Volume: 19(2) Issue: 2 Pages: 257-272
  • DOI: 10.1016/j.ccr.2011.01.020
  • Peer Reviewed
• [Journal Article] Inhibition of gastric carcinogenesis by the hormone, gastrin, is mediated by suppression of TFF1 epigenetic silencing. (2011)
  • Author(s): Tomita H, Kawakami K, Minamoto T, et al
  • Journal Title: Gastroenterology Volume: 140 (3) Issue: 3 Pages: 879-91
  • DOI: 10.1053/j.gastro.2010.11.037
  • Peer Reviewed
• [Journal Article] IFN-γ inhibits gastric carcinogenesis by inducing epithelial cell autophagy and T-cell apoptosis. (2011)
  • Author(s): Tu SP, Quante M, Bhagat G, Takaishi S, Cui G, Yang XD, Muthuplani S, Shibata W, Fox JG, Pritchard DM, Wang TC.
  • Journal Title: Cancer Research Volume: 71(12) Issue: 12 Pages: 4247-4259
  • DOI: 10.1158/0008-5472.can-10-4009
  • Peer Reviewed
• [Presentation] Progastrin Promotes Antral Carcinogenesis and Gastric Stem Cell Function (2013)
  • Author(s): Hayakawa Y, Takaishi S, Jin G, Ariyama H, Westphalen CB, Asfaha S, Tailor Y, Shibata W, Yang X, Chen D, Whary MT, Muthupalani S, Fox JG, Shulkes A, Wang TC
  • Organizer: Digestive Disease Week 2013
  • Place of Presentation: アメリカ合衆国、フロリダ
• [Presentation] Bone marrow-derived myofibroblasts contribute to the mesenchymal stem cell niche (2011)
  • Author(s): Takaishi S
  • Organizer: 第70回日本癌学会学術総会
  • Place of Presentation: 名古屋国際会議場
• [Presentation] Progastrin Promotes Antral Carcinogenesis and Gastric Stem Cell Function
  • Author(s): Yoku Hayakawa, Shigeo Takaishi, Guangchun Jin, Hiroshi Ariyama, Christoph B. Westphalen, Samuel Asfaha, Yagnesh H. Tailor, Wataru Shibata, Xiangdong Yang, Duan Chen, Mark T. Whary, Sureshkumar Muthupalani, James G. Fox, Arthur Shulkes, Timothy C. Wang
  • Organizer: Digestive Disease Week,
  • Place of Presentation: Orange County Convention Center, FL, USA
• [Book] G.I. Research 第20巻1号 総説「胃癌・大腸癌幹細胞」 (2012)
  • Author(s): 高石繁生
  • Total Pages: 6
  • Publisher: 先端医学社
• [Book] 最新内科学、６章 内科疾患と腫瘍学、２ 癌幹細胞 (2012)
  • Author(s): 高石繁生、赤司浩一
  • Publisher: 西村書店