Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth

Cell Stem Cell. 2014 Mar 6;14(3):357-69. doi: 10.1016/j.stem.2014.01.005.


Stem-like glioma cells reside within a perivascular niche and display hallmark radiation resistance. An understanding of the mechanisms underlying these properties will be vital for the development of effective therapies. Here, we show that the stem cell marker CD44 promotes cancer stem cell phenotypes and radiation resistance. In a mouse model of glioma, Cd44(-/-) and Cd44(+/-) animals showed improved survival compared to controls. The CD44 ligand osteopontin shared a perivascular expression pattern with CD44 and promoted glioma stem cell-like phenotypes. These effects were mediated via the γ-secretase-regulated intracellular domain of CD44, which promoted aggressive glioma growth in vivo and stem cell-like phenotypes via CBP/p300-dependent enhancement of HIF-2α activity. In human glioblastoma multiforme, expression of CD44 correlated with hypoxia-induced gene signatures and poor survival. Altogether, these data suggest that in the glioma perivascular niche, osteopontin promotes stem cell-like properties and radiation resistance in adjacent tumor cells via activation of CD44 signaling.

Publication types

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

MeSH terms

  • Animals
  • Basic Helix-Loop-Helix Transcription Factors / metabolism
  • Brain Neoplasms / metabolism
  • Brain Neoplasms / pathology*
  • Cell Line, Tumor
  • Cell Proliferation / drug effects
  • Disease Models, Animal
  • E1A-Associated p300 Protein / metabolism
  • Glioblastoma / metabolism
  • Glioblastoma / pathology*
  • Humans
  • Hyaluronan Receptors / chemistry
  • Hyaluronan Receptors / metabolism*
  • Ligands
  • Mice
  • Neoplasm Invasiveness
  • Neoplastic Stem Cells / drug effects
  • Neoplastic Stem Cells / metabolism
  • Neoplastic Stem Cells / pathology*
  • Osteopontin / metabolism*
  • Phenotype
  • Platelet-Derived Growth Factor / pharmacology
  • Protein Structure, Tertiary
  • Signal Transduction* / drug effects
  • Stem Cell Niche* / drug effects
  • Survival Analysis


  • Basic Helix-Loop-Helix Transcription Factors
  • Hyaluronan Receptors
  • Ligands
  • Platelet-Derived Growth Factor
  • Osteopontin
  • endothelial PAS domain-containing protein 1
  • E1A-Associated p300 Protein
  • EP300 protein, human