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.

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

Substances

  • Antineoplastic Agents
  • Basic Helix-Loop-Helix Transcription Factors
  • Bhlha15 protein, mouse
  • CXCR4 protein, mouse
  • Cadherins
  • Chemokine CXCL12
  • Cxcl12 protein, mouse
  • MIST1 protein, human
  • Receptors, CXCR4
  • Wnt Proteins
  • Wnt-5a Protein
  • Wnt5a protein, mouse
  • RhoA protein, mouse
  • rho GTP-Binding Proteins