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

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

Author information

1
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Alvord Brain Tumor Center, University of Washington, Seattle, WA 98104, USA; Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA; Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
2
Cancer Biology and Genetics Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA; Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
3
Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
4
Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
5
Brain Tumor Center, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA; Human Oncology and Pathogenesis Program and Department of Pathology, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
6
Human Biology Division, Fred Hutchinson Cancer Research Center, Seattle, WA 98109, USA; Alvord Brain Tumor Center, University of Washington, Seattle, WA 98104, USA. Electronic address: eholland@fhcrc.org.

Abstract

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.

PMID:
24607407
PMCID:
PMC3999042
DOI:
10.1016/j.stem.2014.01.005
[Indexed for MEDLINE]
Free PMC Article

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