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Cancer Cell. 2012 Jan 17;21(1):36-51. doi: 10.1016/j.ccr.2011.12.004.

Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.

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1
Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. michael.quante@lrz.tum.de

Abstract

Esophageal adenocarcinoma (EAC) arises from Barrett esophagus (BE), intestinal-like columnar metaplasia linked to reflux esophagitis. In a transgenic mouse model of BE, esophageal overexpression of interleukin-1β phenocopies human pathology with evolution of esophagitis, Barrett-like metaplasia and EAC. Histopathology and gene signatures closely resembled human BE, with upregulation of TFF2, Bmp4, Cdx2, Notch1, and IL-6. The development of BE and EAC was accelerated by exposure to bile acids and/or nitrosamines, and inhibited by IL-6 deficiency. Lgr5(+) gastric cardia stem cells present in BE were able to lineage trace the early BE lesion. Our data suggest that BE and EAC arise from gastric progenitors due to a tumor-promoting IL-1β-IL-6 signaling cascade and Dll1-dependent Notch signaling.

PMID:
22264787
PMCID:
PMC3266546
DOI:
10.1016/j.ccr.2011.12.004
[Indexed for MEDLINE]
Free PMC Article

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