Analysic of the gastric stem cell carcinognic mechanism and application of stem cell marker for gasgtric cancer prevention and therapy

• Project/Area Number: 17K09346
• Research Category: Grant-in-Aid for Scientific Research (C)
• Allocation Type: Multi-year Fund
• Section: 一般
• Research Field: Gastroenterology
• Research Institution: The University of Tokyo
• Principal Investigator: Hirata Yoshihiro 東京大学, 医科学研究所, 准教授 (10529192)
• Co-Investigator(Kenkyū-buntansha): 山田 篤生 東京大学, 医学部附属病院, 助教 (80534932)
• Project Period (FY): 2017-04-01 – 2020-03-31
• Project Status: Completed (Fiscal Year 2019)
• Budget Amount: ¥4,550,000 (Direct Cost: ¥3,500,000、Indirect Cost: ¥1,050,000); Fiscal Year 2019: ¥910,000 (Direct Cost: ¥700,000、Indirect Cost: ¥210,000); Fiscal Year 2018: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000); Fiscal Year 2017: ¥1,820,000 (Direct Cost: ¥1,400,000、Indirect Cost: ¥420,000)
• Keywords: 胃癌 / 幹細胞 / オルガノイド / 化生 / ヘリコバクター / 肝細胞 / 分化

Outline of Final Research Achievements

Role of gastric epithelial stem cell and its intracellular signaling in gastric carcinogenesis and metaplasia development were assessed using mouse and organoid model. Either infection with Helicobacter pylori or MAPK activation by Kras mutation in epithelial cells induced mouse gastric metaplasia and cell proliferation of organoid. Neither Lgr5+ gastric cells nor TGFb signaling affected gastric metaplastic process. Kras induced metaplasia was associated with overexpression of stem cell markers, such as CD44 and Sox9 in gastric epithelial cells. Stomach specific marker knockout mice also showed epithelial proliferation and tumorigenesis with CD44 upregulation, suggesting the importance of CD44 in gastric carcinogenesis and metaplasia development.

Academic Significance and Societal Importance of the Research Achievements

本研究で着目した胃粘膜の化生は胃癌の前癌病変もしくは傍癌病変としてしられ、我々の既報においても胃癌高危険群の層別化に有用な病理学的変化である。胃癌幹細胞マーカーの一つとして知られているCD44の発現が化生発生に重要な役割を果たすことを解明した本研究から、胃炎患者をCD44の発現によってあらたな層別化を行うことによりさらに効率的な胃癌スクリーニング法を確立することができる。胃癌および胃粘膜の幹細胞マーカー分子は多数報告されているが、幹細胞を標的とした胃癌治療はいまだ実用化されていない。本結果からはCD44発現細胞を標的とすることが胃癌の有効な新規治療となる可能性がある。

Research Products

• [Int'l Joint Research] コロンビア大学(米国)
• [Journal Article] Three types of metaplasia model through Kras activation, Pten deletion, or Cdh1 deletion in the gastric epithelium. (2019)
  • Author(s): Kinoshita H, Hayakawa Y, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Ikenoue T, Ushiku T, Fukayama M, Hirata Y, Koike K.
  • Journal Title: Journal of Pathology Volume: 247 Issue: 1 Pages: 35-47
  • DOI: 10.1002/path.5163
  • Peer Reviewed / Open Access
• [Journal Article] Characteristics and predictors of gastric cancer after Helicobacter pylori eradication. (2018)
  • Author(s): Shichijo S, Hirata Y.
  • Journal Title: World J Gastroenterol. Volume: 24 Issue: 20 Pages: 2163-2172
  • DOI: 10.3748/wjg.v24.i20.2163
  • Peer Reviewed / Open Access
• [Journal Article] Mature gastric chief cells are not required for the development of metaplasia. (2018)
  • Author(s): Kinoshita H, Hayakawa Y, Niu Z, Konishi M, Hata M, Tsuboi M, Hayata Y, Hikiba Y, Ihara S, Nakagawa H, Hirata Y, Wang TC, Koike K.
  • Journal Title: Am J Physiol Gastrointest Liver Physiol. Volume: - Issue: 5 Pages: G583-G596
  • DOI: 10.1152/ajpgi.00351.2017
  • Peer Reviewed / Int'l Joint Research
• [Presentation] MODELING SIGNET RING CELL CANCER BY USING MOUSE MODELS AND ORGANOIDS (2018)
  • Author(s): Masahiro Hata, Yoku Hayakawa, Hiroto Kinoshita, Hayato Nakagawa, Yoshihiro Hirata, Timothy C. Wang, Kazuhiko Koike
  • Organizer: 米国消化器病学会
  • Int'l Joint Research
• [Presentation] 除菌前・後の組織学的腸上皮化生と内視鏡的萎縮による除菌後胃癌のリスクの相違 (2018)
  • Author(s): 新倉量太 平田喜裕 小池和彦
  • Organizer: 第１０４回日本消化器病学会総会