Journal
CANCER CELL
Volume 21, Issue 1, Pages 36-51Publisher
CELL PRESS
DOI: 10.1016/j.ccr.2011.12.004
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Funding
- NIH [RO1DK060758, 1U54CA126513, R01CA120979, 5U01 CA143056, P01-CA098101, P30-DK050306]
- Mildred-Scheel-Stiftung, Deutsche Krebshilfe, Germany
- NCI [K07 CA132892]
- Louis V. Gerstner, Jr. Scholars Award
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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-1 beta 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-1 beta-IL-6 signaling cascade and DII1-dependent Notch signaling.
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