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CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis
  1. Yoku Hayakawa1,
  2. Guangchun Jin1,
  3. Hongshan Wang1,
  4. Xiaowei Chen1,
  5. Christoph B Westphalen1,2,
  6. Samuel Asfaha1,
  7. Bernhard W Renz1,
  8. Hiroshi Ariyama1,
  9. Zinaida A Dubeykovskaya1,
  10. Yoshihiro Takemoto1,
  11. Yoomi Lee1,
  12. Ashlesha Muley1,
  13. Yagnesh Tailor1,
  14. Duan Chen3,
  15. Sureshkumar Muthupalani4,
  16. James G Fox4,
  17. Arthur Shulkes5,
  18. Daniel L Worthley1,
  19. Shigeo Takaishi1,6,
  20. Timothy C Wang1
  1. 1Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA
  2. 2Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany
  3. 3Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway
  4. 4Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA
  5. 5Department of Surgery, University of Melbourne, Austin Health, Melbourne, Australia
  6. 6Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan
  1. Correspondence to Dr Timothy C Wang, Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, 1130 St. Nicholas Avenue, ICRC 923, New York, NY 07024, USA; tcw21{at}columbia.edu

Abstract

Objective Progastrin is the incompletely cleaved precursor of gastrin that is secreted by G-cells in the gastric antrum. Both gastrin and progastrin bind to the CCK2 receptor (Cckbr or CCK2R) expressed on a subset of gastric epithelial cells. Little is known about how gastrin peptides and CCK2R regulate gastric stem cells and carcinogenesis. Interconversion among progenitors in the intestine is documented, but the mechanisms by which this occurs are poorly defined.

Design We generated CCK2R-CreERT mice and performed inducible lineage tracing experiments. CCK2R+ antral cells and Lgr5+ antral stem cells were cultured in a three-dimensional in vitro system. We crossed progastrin-overexpressing mice with Lgr5-GFP-CreERT mice and examined the role of progastrin and CCK2R in Lgr5+ stem cells during MNU-induced carcinogenesis.

Results Through lineage tracing experiments, we found that CCK2R defines antral stem cells at position +4, which overlapped with an Lgr5neg or low cell population but was distinct from typical antral Lgr5high stem cells. Treatment with progastrin interconverts Lgr5neg or low CCK2R+ cells into Lgr5high cells, increases CCK2R+ 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 expansion and carcinogenesis.

Conclusions 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.

  • GASTRIC CANCER
  • GASTRIN RECEPTORS
  • INTESTINAL STEM CELL
  • GASTRIN

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