title: Osteopontin-CD44 signaling in the glioma perivascular niche enhances cancer stem cell phenotypes and promotes aggressive tumor growth.
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.
authors.affiliation: 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.
authors.forename: Alexander
authors.initials: A
authors.lastname: Pietras
authors.affiliation: 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.
authors.forename: Amanda M
authors.initials: AM
authors.lastname: Katz
authors.affiliation: Cell Biology Program, Memorial Sloan-Kettering Cancer Center, New York, NY 10021, USA.
authors.forename: Elin J
authors.initials: EJ
authors.lastname: Ekström
authors.affiliation: 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.
authors.forename: Boyoung
authors.initials: B
authors.lastname: Wee
authors.affiliation: 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.
authors.forename: John J
authors.initials: JJ
authors.lastname: Halliday
authors.affiliation: 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.
authors.forename: Kenneth L
authors.initials: KL
authors.lastname: Pitter
authors.affiliation: 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.
authors.forename: Jillian L
authors.initials: JL
authors.lastname: Werbeck
authors.affiliation: Department of Neurological Surgery, University of Pittsburgh, Pittsburgh, PA 15213, USA.
authors.forename: Nduka M
authors.initials: NM
authors.lastname: Amankulor
authors.affiliation: 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.
authors.forename: Jason T
authors.initials: JT
authors.lastname: Huse
authors.affiliation: 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.
authors.forename: Eric C
authors.initials: EC
authors.lastname: Holland
mesh_terms: D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000378:metabolism; D001932:Brain Neoplasms / Q000378:metabolism / Q000473:pathology*; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D004195:Disease Models, Animal; D050881:E1A-Associated p300 Protein / Q000378:metabolism; D005909:Glioblastoma / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D018960:Hyaluronan Receptors / Q000737:chemistry / Q000378:metabolism*; D008024:Ligands; D051379:Mice; D009361:Neoplasm Invasiveness; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D053495:Osteopontin / Q000378:metabolism*; D010641:Phenotype; D010982:Platelet-Derived Growth Factor / Q000494:pharmacology; D017434:Protein Structure, Tertiary; D015398:Signal Transduction / Q000187:drug effects; D055153:Stem Cell Niche / Q000187:drug effects; D016019:Survival Analysis; D000099162:Endothelial PAS Domain-Containing Protein 1
chemical_list: D051792:Basic Helix-Loop-Helix Proteins; D050881:E1A-Associated p300 Protein; D018960:Hyaluronan Receptors; D008024:Ligands; D053495:Osteopontin; D010982:Platelet-Derived Growth Factor; D000099162:Endothelial PAS Domain-Containing Protein 1; C494360:EP300 protein, human