Research Papers:
Gastrin stimulates a cholecystokinin2receptorexpressing cardia progenitor cell and promotes progression of Barrett’slike esophagus
PDF | Full Text | Supplementary Files | How to cite
Yoomi Lee1,*, Aleksandra M. Urbanska2,*, Yoku Hayakawa2, Hongshan Wang2,3, Andrew S. Au2, Aesis M. Luna4, Wenju Chang2,3, Guangchun Jin2, Govind Bhagat4, Julian A. Abrams2, Richard A. Friedman5,6, Andrea Varro7, Kenneth K. Wang8, Malcolm Boyce9, Anil K. Rustgi10, Antonia R. Sepulveda4, Michael Quante11, Timothy C. Wang2
1Division of Hematology and Oncology, Department of Medicine, Columbia University Medical Center, New York, NY, USA
2Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY, USA
3Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
4Department of Pathology and Cell Biology, Columbia University Medical Center, New York, NY, USA
5Biomedical Informatics Shared Resource, Herbert Irving Comprehensive Cancer Center, New York, NY, USA
6Department of Biomedical Informatics, Columbia University Medical Center, New York, NY, USA
7Department of Physiology, Institute of Translational Medicine, University of Liverpool, Liverpool, England
8Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, MN, USA
9Hammersmith Medicines Research, Central Middlesex Hospital, London, UK
10Division of Gastroenterology, Departments of Medicine and Genetics, Abramson Cancer Center, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
11Medical Clinic II, Clinic of the Right Bank, Technical University of Munich, Munich, Germany
*These authors contributed equally to this work
Correspondence to:
Timothy C. Wang, email: [email protected]
Keywords: Barrett’s esophagus, esophageal cancer, gastrin, gastrin receptors, stem cells
Received: March 15, 2016 Accepted: June 13, 2016 Published: July 18, 2016
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.
Design: 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.