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Cancer Cell. 2015 Dec 14;28(6):800-814. doi: 10.1016/j.ccell.2015.10.003. Epub 2015 Nov 12.

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

Author information

1
Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
2
Department of Cell and Developmental Biology, Institute of Molecular Genetics, Academy of Sciences of the Czech Republic, Prague 14220, Czech Republic.
3
Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA; Department of General, Visceral, Transplantation, Vascular, and Thoracic Surgery, Hospital of the University of Munich, Munich 81377, Germany.
4
Department of Tumor Pathology, Gifu University Graduate School of Medicine, Gifu 501-1194, Japan.
5
Division of Clinical Pathology and Cell Biology, Department of Pathology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
6
Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
7
Department of Radiation Oncology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
8
Departments of Rehabilitation and Regenerative Medicine and Microbiology and Immunology, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
9
Division of Comparative Medicine, Massachusetts Institute of Technology, Cambridge, MA 02139, USA.
10
Herbert Irving Comprehensive Cancer Center Biomedical Informatics Shared Resource and Department of Biomedical Informatics, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA.
11
Department of Biological Sciences and the Purdue Center for Cancer Research, Purdue University, West Lafayette, IN 47907, USA.
12
Division of Digestive and Liver Disease, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, NY 10032, USA. Electronic address: tcw21@columbia.edu.

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.

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PMID:
26585400
PMCID:
PMC4684751
DOI:
10.1016/j.ccell.2015.10.003
[Indexed for MEDLINE]
Free PMC Article

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