CXCR4-expressing Mist1⁺ progenitors in the gastric antrum contribute to gastric cancer development

Authors

Kosuke Sakitani, Vagelos College of Physicians and Surgeons
Yoku Hayakawa, Vagelos College of Physicians and Surgeons
Huan Deng, Vagelos College of Physicians and Surgeons
Hiroshi Ariyama, Vagelos College of Physicians and Surgeons
Hiroto Kinoshita, Graduate School of Medicine
Mitsuru Konishi, Graduate School of Medicine
Satoshi Ono, Graduate School of Medicine
Nobumi Suzuki, The Institute for Adult Diseases, Asahi Life Foundation
Sozaburo Ihara, The Institute for Adult Diseases, Asahi Life Foundation
Zhengchuan Niu, Vagelos College of Physicians and Surgeons
Woosook Kim, Vagelos College of Physicians and Surgeons
Takayuki Tanaka, Vagelos College of Physicians and Surgeons
Haibo Liu, Vagelos College of Physicians and Surgeons
Xiaowei Chen, Vagelos College of Physicians and Surgeons
Yagnesh Tailor, Vagelos College of Physicians and Surgeons
James G. Fox, Massachusetts Institute of Technology
Stephen F. Konieczny, College of Science
Hiroshi Onodera, The University of Tokyo
Antonia R. Sepulveda, Vagelos College of Physicians and Surgeons
Samuel Asfaha, Vagelos College of Physicians and SurgeonsFollow
Yoshihiro Hirata, Graduate School of Medicine
Daniel L. Worthley, The University of Adelaide
Kazuhiko Koike, Graduate School of Medicine
Timothy C. Wang, Vagelos College of Physicians and Surgeons

Document Type

Article

Publication Date

1-1-2017

Journal

Oncotarget

Volume

8

Issue

67

First Page

111012

Last Page

111025

URL with Digital Object Identifier

10.18632/oncotarget.22451

Abstract

Mist1 was recently shown to identify a discrete population of stem cells within the isthmus of the oxyntic gland within the gastric corpus. Chief cells at the base of the gastric corpus also express Mist1. The relevance of Mist1 expression as a marker of specific cell populations within the antral glands of the distal stomach, however, is unknown. Using Mist1-CreERT mice, we revealed that Mist1+ antral cells, distinct from the Mist1+ population in the corpus, comprise long-lived progenitors that reside within the antral isthmus above Lgr5+ or CCK2R+ cells. Mist1+ antral progenitors can serve as an origin of antral tumors induced by loss of Apc or MNU treatment. Mist1+ antral progenitors, as well as other antral stem/progenitor population, express Cxcr4, and are located in close proximity to Cxcl12 (the Cxcr4 ligand)-expressing endothelium. During antral carcinogenesis, there is an expansion of Cxcr4+ epithelial cells as well as the Cxcl12+ perivascular niche. Deletion of Cxcl12 in endothelial cells or pharmacological blockade of Cxcr4 inhibits antral tumor growth. Cxcl12/Cxcr4 signaling may be a potential therapeutic target.