Mist1 Expressing Gastric Stem Cells Maintain the Normal and Neoplastic Gastric Epithelium and Are Supported by a Perivascular Stem Cell Niche

Authors

Yoku Hayakawa, Vagelos College of Physicians and Surgeons
Hiroshi Ariyama, Vagelos College of Physicians and Surgeons
Jitka Stancikova, Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic
Kosuke Sakitani, Vagelos College of Physicians and Surgeons
Samuel Asfaha, Vagelos College of Physicians and Surgeons
Bernhard W. Renz, Vagelos College of Physicians and Surgeons
Zinaida A. Dubeykovskaya, Vagelos College of Physicians and Surgeons
Wataru Shibata, Vagelos College of Physicians and Surgeons
Hongshan Wang, Vagelos College of Physicians and Surgeons
Christoph B. Westphalen, Vagelos College of Physicians and Surgeons
Xiaowei Chen, Vagelos College of Physicians and Surgeons
Yoshihiro Takemoto, Vagelos College of Physicians and Surgeons
Woosook Kim, Vagelos College of Physicians and Surgeons
Shradha S. Khurana, Vagelos College of Physicians and Surgeons
Yagnesh Tailor, Vagelos College of Physicians and Surgeons
Karan Nagar, Vagelos College of Physicians and Surgeons
Hiroyuki Tomita, Graduate School of Medicine
Akira Hara, Graduate School of Medicine
Antonia R. Sepulveda, Vagelos College of Physicians and Surgeons
Wanda Setlik, Vagelos College of Physicians and Surgeons
Michael D. Gershon, Vagelos College of Physicians and Surgeons
Subhrajit Saha, Albert Einstein College of Medicine of Yeshiva University
Lei Ding, Vagelos College of Physicians and Surgeons
Zeli Shen, Massachusetts Institute of Technology
James G. Fox, Massachusetts Institute of Technology
Richard A. Friedman, Vagelos College of Physicians and Surgeons
Stephen F. Konieczny, Purdue Center for Cancer Research
Daniel L. Worthley, Vagelos College of Physicians and Surgeons
Vladimir Korinek, Institute of Molecular Genetics of the Academy of Sciences of the Czech Republic

Document Type

Article

Publication Date

12-14-2015

Journal

Cancer Cell

Volume

28

Issue

6

First Page

800

Last Page

814

URL with Digital Object Identifier

10.1016/j.ccell.2015.10.003

Abstract

The regulation and stem cell origin of normal and neoplastic gastric glands are uncertain. Here, we show that Mist1 expression marks quiescent stem cells in the gastric corpus isthmus. Mist1+ stem cells serve as a cell-of-origin for intestinal-type cancer with the combination of Kras and Apc mutation and for diffuse-type cancer with the loss of E-cadherin. Diffuse-type cancer development is dependent on inflammation mediated by Cxcl12+ endothelial cells and Cxcr4+ gastric innate lymphoid cells (ILCs). These cells form the perivascular gastric stem cell niche, and Wnt5a produced from ILCs activates RhoA to inhibit anoikis in the E-cadherin-depleted cells. Targeting Cxcr4, ILCs, or Wnt5a inhibits diffuse-type gastric carcinogenesis, providing targets within the neoplastic gastric stem cell niche.