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

Yoku Hayakawa; Hiroshi Ariyama; Jitka Stancikova; Kosuke Sakitani; Samuel Asfaha; Bernhard W Renz; Zinaida A Dubeykovskaya; Wataru Shibata; Hongshan Wang; Christoph B Westphalen; Xiaowei Chen; Yoshihiro Takemoto; Woosook Kim; Shradha S Khurana; Yagnesh Tailor; Karan Nagar; Hiroyuki Tomita; Akira Hara; Antonia R Sepulveda; Wanda Setlik; Michael D Gershon; Subhrajit Saha; Lei Ding; Zeli Shen; James G Fox; Richard A Friedman; Stephen F Konieczny; Daniel L Worthley; Vladimir Korinek; Timothy C Wang

doi:10.1016/j.ccell.2015.10.003

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

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

Authors

Yoku Hayakawa¹, Hiroshi Ariyama¹, Jitka Stancikova², Kosuke Sakitani¹, Samuel Asfaha¹, Bernhard W Renz³, Zinaida A Dubeykovskaya¹, Wataru Shibata¹, Hongshan Wang¹, Christoph B Westphalen¹, Xiaowei Chen¹, Yoshihiro Takemoto¹, Woosook Kim¹, Shradha S Khurana¹, Yagnesh Tailor¹, Karan Nagar¹, Hiroyuki Tomita⁴, Akira Hara⁴, Antonia R Sepulveda⁵, Wanda Setlik⁶, Michael D Gershon⁶, Subhrajit Saha⁷, Lei Ding⁸, Zeli Shen⁹, James G Fox⁹, Richard A Friedman¹⁰, Stephen F Konieczny¹¹, Daniel L Worthley¹, Vladimir Korinek², Timothy C Wang¹²

Affiliations

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.

Publication types

Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't

MeSH terms

Animals
Anoikis
Antineoplastic Agents / pharmacology
Basic Helix-Loop-Helix Transcription Factors / genetics
Basic Helix-Loop-Helix Transcription Factors / metabolism*
Bone Marrow Transplantation
Cadherins / metabolism
Cell Communication
Cell Line, Tumor
Cell Lineage
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology
Cellular Senescence
Chemokine CXCL12 / metabolism
Endothelial Cells / metabolism
Endothelial Cells / pathology
Epithelial Cells / drug effects
Epithelial Cells / metabolism*
Epithelial Cells / pathology
Gastric Mucosa / drug effects
Gastric Mucosa / metabolism*
Gastric Mucosa / pathology
Humans
Lymphocytes / metabolism
Lymphocytes / pathology
Male
Mice
Mice, Transgenic
Neoplastic Stem Cells / drug effects
Neoplastic Stem Cells / metabolism*
Neoplastic Stem Cells / pathology
Receptors, CXCR4 / metabolism
Signal Transduction
Stem Cell Niche*
Stomach Neoplasms / drug therapy
Stomach Neoplasms / genetics
Stomach Neoplasms / metabolism*
Stomach Neoplasms / pathology
Time Factors
Tumor Microenvironment*
Wnt Proteins / metabolism
Wnt Signaling Pathway
Wnt-5a Protein
rho GTP-Binding Proteins / metabolism
rhoA GTP-Binding Protein

Substances

Antineoplastic Agents
BHLHA15 protein, human
Basic Helix-Loop-Helix Transcription Factors
Bhlha15 protein, mouse
CXCR4 protein, mouse
Cadherins
Chemokine CXCL12
Cxcl12 protein, mouse
Receptors, CXCR4
Wnt Proteins
Wnt-5a Protein
Wnt5a protein, mouse
RhoA protein, mouse
rho GTP-Binding Proteins
rhoA GTP-Binding Protein

Abstract

Publication types

MeSH terms

Substances

Grants and funding