title: CCK2R identifies and regulates gastric antral stem cell states and carcinogenesis.
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.
  
  
  METHODS
  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 Lgr5(neg or low) cell population but was distinct from typical antral Lgr5(high) stem cells. Treatment with progastrin interconverts Lgr5(neg or low) CCK2R+ cells into Lgr5(high) 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.
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Guangchun
authors.initials: G
authors.lastname: Jin
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Xiaowei
authors.initials: X
authors.lastname: Chen
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA Department of Internal Medicine III, Klinikum der Universität München, Munich, Germany.
authors.forename: Christoph B
authors.initials: CB
authors.lastname: Westphalen
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Bernhard W
authors.initials: BW
authors.lastname: Renz
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Ariyama
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Zinaida A
authors.initials: ZA
authors.lastname: Dubeykovskaya
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Yoshihiro
authors.initials: Y
authors.lastname: Takemoto
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Yoomi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Ashlesha
authors.initials: A
authors.lastname: Muley
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Yagnesh
authors.initials: Y
authors.lastname: Tailor
authors.affiliation: Department of Cancer Research and Molecular Medicine, Norwegian University of Science and Technology, Trondheim, Norway.
authors.forename: Duan
authors.initials: D
authors.lastname: Chen
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: Sureshkumar
authors.initials: S
authors.lastname: Muthupalani
authors.affiliation: Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, Massachusetts, USA.
authors.forename: James G
authors.initials: JG
authors.lastname: Fox
authors.affiliation: Department of Surgery, University of Melbourne, Austin Health, Melbourne, Australia.
authors.forename: Arthur
authors.initials: A
authors.lastname: Shulkes
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Daniel L
authors.initials: DL
authors.lastname: Worthley
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA Center for Advanced Medical Innovation, Kyushu University, Fukuoka, Japan.
authors.forename: Shigeo
authors.initials: S
authors.lastname: Takaishi
authors.affiliation: Division of Digestive and Liver Disease, Department of Medicine, Columbia University Medical Center, New York, New York, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D063646:Carcinogenesis; D002478:Cells, Cultured; D005755:Gastrins / Q000502:physiology; D051379:Mice; D011498:Protein Precursors / Q000502:physiology; D011706:Pyloric Antrum / Q000166:cytology*; D043887:Receptor, Cholecystokinin B / Q000502:physiology*; D013234:Stem Cells / Q000502:physiology*
chemical_list: D005755:Gastrins; D011498:Protein Precursors; D043887:Receptor, Cholecystokinin B; C013706:big gastrin
keywords: GASTRIC CANCER; GASTRIN; GASTRIN RECEPTORS; INTESTINAL STEM CELL