title: Bile acid and inflammation activate gastric cardia stem cells in a mouse model of Barrett-like metaplasia.
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.
authors.affiliation: Division of Digestive and Liver Diseases, Department of Medicine, Columbia University Medical Center, New York, NY 10032, USA. michael.quante@lrz.tum.de
authors.forename: Michael
authors.initials: M
authors.lastname: Quante
authors.forename: Govind
authors.initials: G
authors.lastname: Bhagat
authors.forename: Julian A
authors.initials: JA
authors.lastname: Abrams
authors.forename: Frederic
authors.initials: F
authors.lastname: Marache
authors.forename: Pamela
authors.initials: P
authors.lastname: Good
authors.forename: Michele D
authors.initials: MD
authors.lastname: Lee
authors.forename: Yoomi
authors.initials: Y
authors.lastname: Lee
authors.forename: Richard
authors.initials: R
authors.lastname: Friedman
authors.forename: Samuel
authors.initials: S
authors.lastname: Asfaha
authors.forename: Zinaida
authors.initials: Z
authors.lastname: Dubeykovskaya
authors.forename: Umar
authors.initials: U
authors.lastname: Mahmood
authors.forename: Jose-Luiz
authors.initials: JL
authors.lastname: Figueiredo
authors.forename: Jan
authors.initials: J
authors.lastname: Kitajewski
authors.forename: Carrie
authors.initials: C
authors.lastname: Shawber
authors.forename: Charles J
authors.initials: CJ
authors.lastname: Lightdale
authors.forename: Anil K
authors.initials: AK
authors.lastname: Rustgi
authors.forename: Timothy C
authors.initials: TC
authors.lastname: Wang
mesh_terms: D000230:Adenocarcinoma / Q000473:pathology; D000818:Animals; D001471:Barrett Esophagus / Q000209:etiology / Q000473:pathology*; D001647:Bile Acids and Salts / Q000494:pharmacology*; D055415:Bone Morphogenetic Protein 4 / Q000235:genetics / Q000378:metabolism; D000071616:CDX2 Transcription Factor; D002299:Cardia / Q000473:pathology*; D004938:Esophageal Neoplasms / Q000473:pathology; D004941:Esophagitis / Q000473:pathology*; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D053583:Interleukin-1beta / Q000235:genetics / Q000378:metabolism; D015850:Interleukin-6 / Q000235:genetics / Q000378:metabolism; D008679:Metaplasia / Q000473:pathology; D051379:Mice; D008822:Mice, Transgenic; D009077:Mucins / Q000235:genetics / Q000378:metabolism; D009124:Muscle Proteins / Q000235:genetics / Q000378:metabolism; D010455:Peptides / Q000235:genetics / Q000378:metabolism; D051881:Receptor, Notch1 / Q000235:genetics / Q000378:metabolism; D015398:Signal Transduction; D013234:Stem Cells / Q000473:pathology*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism; D000071164:Trefoil Factor-2; D015854:Up-Regulation
chemical_list: D001647:Bile Acids and Salts; C525810:Bmp4 protein, mouse; D055415:Bone Morphogenetic Protein 4; D000071616:CDX2 Transcription Factor; C487514:Cdx2 protein, mouse; D018398:Homeodomain Proteins; D053583:Interleukin-1beta; D015850:Interleukin-6; D009077:Mucins; D009124:Muscle Proteins; C497762:Notch1 protein, mouse; D010455:Peptides; D051881:Receptor, Notch1; C000604007:TFF2 protein, human; C481546:TFF2 protein, mouse; D014157:Transcription Factors; D000071164:Trefoil Factor-2