MET signaling regulates glioblastoma stem cells

Cancer Res. 2012 Aug 1;72(15):3828-38. doi: 10.1158/0008-5472.CAN-11-3760. Epub 2012 May 22.

Abstract

Glioblastomas multiforme (GBM) contain highly tumorigenic, self-renewing populations of stem/initiating cells [glioblastoma stem cells (GSC)] that contribute to tumor propagation and treatment resistance. However, our knowledge of the specific signaling pathways that regulate GSCs is limited. The MET tyrosine kinase is known to stimulate the survival, proliferation, and invasion of various cancers including GBM. Here, we identified a distinct fraction of cells expressing a high level of MET in human primary GBM specimens that were preferentially localized in perivascular regions of human GBM biopsy tissues and were found to be highly clonogenic, tumorigenic, and resistant to radiation. Inhibition of MET signaling in GSCs disrupted tumor growth and invasiveness both in vitro and in vivo, suggesting that MET activation is required for GSCs. Together, our findings indicate that MET activation in GBM is a functional requisite for the cancer stem cell phenotype and a promising therapeutic target.

Publication types

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

MeSH terms

  • Animals
  • Brain Neoplasms / genetics
  • Brain Neoplasms / pathology*
  • Gene Expression Regulation, Neoplastic / drug effects
  • Glioblastoma / genetics
  • Glioblastoma / pathology*
  • Humans
  • Interleukin Receptor Common gamma Subunit / genetics
  • Mice
  • Mice, Inbred NOD
  • Mice, Knockout
  • Mice, SCID
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Neoplastic Stem Cells / physiology
  • Proto-Oncogene Proteins c-met / antagonists & inhibitors
  • Proto-Oncogene Proteins c-met / genetics
  • Proto-Oncogene Proteins c-met / metabolism
  • Proto-Oncogene Proteins c-met / physiology*
  • RNA, Small Interfering / pharmacology
  • Signal Transduction / drug effects
  • Signal Transduction / genetics
  • Signal Transduction / physiology
  • Tumor Burden / drug effects
  • Tumor Burden / genetics
  • Tumor Cells, Cultured

Substances

  • Il2rg protein, mouse
  • Interleukin Receptor Common gamma Subunit
  • RNA, Small Interfering
  • MET protein, human
  • Proto-Oncogene Proteins c-met