Bile Acid and Inflammation Activate Gastric Cardia Stem Cells in a Mouse Model of Barrett-Like Metaplasia

• Published in: Cancer cell Vol. 21; no. 1; pp. 36 - 51
• Main Authors: Quante, Michael, Bhagat, Govind, Abrams, Julian A., Marache, Frederic, Good, Pamela, Lee, Michele D., Lee, Yoomi, Friedman, Richard, Asfaha, Samuel, Dubeykovskaya, Zinaida, Mahmood, Umar, Figueiredo, Jose-Luiz, Kitajewski, Jan, Shawber, Carrie, Lightdale, Charles J., Rustgi, Anil K., Wang, Timothy C.
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 17.01.2012
• Subjects: Adenocarcinoma - pathology; Animals; Barrett Esophagus - etiology; Barrett Esophagus - pathology; Bile Acids and Salts - pharmacology; Bone Morphogenetic Protein 4 - genetics; Bone Morphogenetic Protein 4 - metabolism; Cardia - pathology; CDX2 Transcription Factor; Esophageal Neoplasms - pathology; Esophagitis - pathology; Homeodomain Proteins - genetics; Homeodomain Proteins - metabolism; Interleukin-1beta - genetics; Interleukin-1beta - metabolism; Interleukin-6 - genetics; Interleukin-6 - metabolism; Metaplasia - pathology; Mice; Mice, Transgenic; Mucins - genetics; Mucins - metabolism; Muscle Proteins - genetics; Muscle Proteins - metabolism; Peptides - genetics; Peptides - metabolism; Receptor, Notch1 - genetics; Receptor, Notch1 - metabolism; Signal Transduction; Stem Cells - pathology; Transcription Factors - genetics; Transcription Factors - metabolism; Trefoil Factor-2; Up-Regulation
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2011.12.004

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. ► IL-1β overexpression in the mouse esophagus induces IL-6 dependent BE and EAC ► Bile acids accelerate intestinal metaplasia and dysplasia in this mouse model of BE ► Notch signaling in columnar cells, not goblet cells is associated with carcinogenesis ► BE and EAC likely arise from gastric cardia progenitor cells