TY - JOUR
T1 - Bile acid and inflammation activate gastric cardia stem cells in a mouse model of barrett-like metaplasia
AU - Quante, Michael
AU - Bhagat, Govind
AU - Abrams, Julian A.
AU - Marache, Frederic
AU - Good, Pamela
AU - Lee, Michele D.
AU - Lee, Yoomi
AU - Friedman, Richard
AU - Asfaha, Samuel
AU - Dubeykovskaya, Zinaida
AU - Mahmood, Umar
AU - Figueiredo, Jose Luiz
AU - Kitajewski, Jan
AU - Shawber, Carrie
AU - Lightdale, Charles J.
AU - Rustgi, Anil K.
AU - Wang, Timothy C.
N1 - Funding Information:
These studies are supported by NIH (RO1DK060758, 1U54CA126513, and R01CA120979 to T.C.W; 5U01 CA143056 to A.K.R., T.C.W., U.M.). A.K.R. was further supported by NIH P01-CA098101 and P30-DK050306 grants. M.Q. was supported by a grant from the Mildred-Scheel-Stiftung, Deutsche Krebshilfe, Germany. J.A. is supported by a Career Development Award from the NCI (K07 CA132892) and by a Louis V. Gerstner, Jr. Scholars Award. We acknowledge the assistance of the Transgenic Mouse and Genomics Core of the Irving Cancer Research Center at Columbia University, and the Electronic Microscopy Core Facility at the University of Pennsylvania. We thank all members of the Wang lab for fruitful discussions.
PY - 2012/1/17
Y1 - 2012/1/17
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=84862909168&partnerID=8YFLogxK
U2 - 10.1016/j.ccr.2011.12.004
DO - 10.1016/j.ccr.2011.12.004
M3 - Article
C2 - 22264787
AN - SCOPUS:84862909168
SN - 1535-6108
VL - 21
SP - 36
EP - 51
JO - Cancer Cell
JF - Cancer Cell
IS - 1
ER -
