title: Gastrin stimulates a cholecystokinin-2-receptor-expressing cardia progenitor cell and promotes progression of Barrett's-like esophagus.
abstract: OBJECTIVE
  The incidence of esophageal adenocarcinoma (EAC) is increasing, but factors contributing to malignant progression of its precursor lesion, Barrett's esophagus (BE), have not been defined. Hypergastrinemia caused by long-term use of proton pump inhibitors (PPIs), has been suggested as one possible risk factor. The gastrin receptor, CCK2R, is expressed in the cardia and upregulated in BE, suggesting the involvement of the gastrin-CCK2R pathway in progression. In the L2-IL-1β mouse model, Barrett's-like esophagus arises from the gastric cardia. Therefore, we aimed to analyze the effect of hypergastrinemia on CCK2R+ progenitor cells in L2-IL-1β mice.
  
  
  METHODS
  L2-IL-1β mice were mated with hypergastrinemic (INS-GAS) mice or treated with PPIs to examine the effect of hypergastrinemia in BE progression. CCK2R-CreERT crossed with L2-IL-1β mice were used to analyze the lineage progenitor potential of CCK2R+ cells. Cardia glands were cultured in vitro, and the effect of gastrin treatment analyzed. L2-IL-1β mice were treated with a CCK2R antagonist YF476 as a potential chemopreventive drug.
  
  
  RESULTS
  Hypergastrinemia resulted in increased proliferation and expansion of Barrett's-like esophagus. Lineage tracing experiments revealed that CCK2R+ cells are long-lived progenitors that can give rise to such lesions under chronic inflammation. Gastrin stimulated organoid growth in cardia culture, while CCK2R inhibition prevented Barrett's-like esophagus and dysplasia.
  
  
  CONCLUSIONS
  Our data suggest a progression model for BE to EAC in which CCK2R+ progenitor cells, stimulated by hypergastrinemia, proliferate to give rise to metaplasia and dysplasia. Hypergastrinemia can result from PPI use, and the effects of hypergastrinemia in human BE should be studied further.
authors.affiliation: Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Yoomi
authors.initials: Y
authors.lastname: Lee
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Aleksandra M
authors.initials: AM
authors.lastname: Urbanska
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Yoku
authors.initials: Y
authors.lastname: Hayakawa
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.|Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Hongshan
authors.initials: H
authors.lastname: Wang
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Andrew S
authors.initials: AS
authors.lastname: Au
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Aesis M
authors.initials: AM
authors.lastname: Luna
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.|Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China.
authors.forename: Wenju
authors.initials: W
authors.lastname: Chang
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Guangchun
authors.initials: G
authors.lastname: Jin
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Julian A
authors.initials: JA
authors.lastname: Abrams
authors.affiliation: Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, NY, USA.|Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA.
authors.forename: Richard A
authors.initials: RA
authors.lastname: Friedman
authors.affiliation: Department of Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, England.
authors.forename: Andrea
authors.initials: A
authors.lastname: Varro
authors.affiliation: Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA.
authors.forename: Kenneth K
authors.initials: KK
authors.lastname: Wang
authors.affiliation: Hammersmith Medicines Research, Central Middlesex Hospital, London, UK.
authors.forename: Malcolm
authors.initials: M
authors.lastname: Boyce
authors.affiliation: Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.affiliation: Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA.
authors.forename: Antonia R
authors.initials: AR
authors.lastname: Sepulveda
authors.affiliation: Medical Clinic II, Clinic of the Right Bank, Technical University of Munich, Munich, Germany.
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA.
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000818:Animals; D001471:Barrett Esophagus / Q000209:etiology* / Q000378:metabolism* / Q000473:pathology; D015415:Biomarkers; D004195:Disease Models, Animal; D018450:Disease Progression; D005755:Gastrins / Q000378:metabolism* / Q000494:pharmacology; D005786:Gene Expression Regulation; D006943:Hyperglycemia; D007150:Immunohistochemistry; D008679:Metaplasia; D051379:Mice; D008822:Mice, Transgenic; D032386:Myoblasts, Cardiac / Q000187:drug effects / Q000378:metabolism*; D010641:Phenotype; D043887:Receptor, Cholecystokinin B / Q000235:genetics* / Q000378:metabolism
chemical_list: D015415:Biomarkers; D005755:Gastrins; D043887:Receptor, Cholecystokinin B
keywords: Barrett’s esophagus; esophageal cancer; gastrin; gastrin receptors; stem cells