Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.
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.
Pubmed ID: 22264787 RIS Download
Adenocarcinoma | Animals | Barrett Esophagus | Bile Acids and Salts | Bone Morphogenetic Protein 4 | Cardia | Esophageal Neoplasms | Esophagitis | Homeodomain Proteins | Interleukin-1beta | Interleukin-6 | Metaplasia | Mice | Mice, Transgenic | Mucins | Muscle Proteins | Peptides | Receptor, Notch1 | Signal Transduction | Stem Cells | Transcription Factors | Up-Regulation