Abstract
Glioblastomas are lethal cancers characterized by florid angiogenesis promoted in part by glioma stem cells (GSCs). Because hypoxia regulates angiogenesis, we examined hypoxic responses in GSCs. We now demonstrate that hypoxia-inducible factor HIF2alpha and multiple HIF-regulated genes are preferentially expressed in GSCs in comparison to non-stem tumor cells and normal neural progenitors. In tumor specimens, HIF2alpha colocalizes with cancer stem cell markers. Targeting HIFs in GSCs inhibits self-renewal, proliferation, and survival in vitro, and attenuates tumor initiation potential of GSCs in vivo. Analysis of a molecular database reveals that HIF2A expression correlates with poor glioma patient survival. Our results demonstrate that GSCs differentially respond to hypoxia with distinct HIF induction patterns, and HIF2alpha might represent a promising target for antiglioblastoma therapies.
Publication types
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Research Support, N.I.H., Extramural
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Research Support, Non-U.S. Gov't
MeSH terms
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Animals
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Basic Helix-Loop-Helix Transcription Factors / physiology*
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Biomarkers, Tumor / metabolism
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Brain Neoplasms / blood supply
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Brain Neoplasms / metabolism*
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Brain Neoplasms / pathology
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Cell Hypoxia
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Cell Proliferation
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Cell Survival
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Cells, Cultured
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Glioblastoma / blood supply
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Glioblastoma / metabolism*
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Glioblastoma / pathology
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Humans
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Hypoxia-Inducible Factor 1, alpha Subunit / physiology*
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Mice
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Mice, Inbred BALB C
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Mice, Nude
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Neoplasm Transplantation
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Neoplastic Stem Cells / physiology*
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Neovascularization, Pathologic / metabolism
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Neovascularization, Pathologic / pathology
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Stem Cells / physiology
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Vascular Endothelial Growth Factor A / metabolism
Substances
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Basic Helix-Loop-Helix Transcription Factors
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Biomarkers, Tumor
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HIF1A protein, human
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Hypoxia-Inducible Factor 1, alpha Subunit
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Vascular Endothelial Growth Factor A
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endothelial PAS domain-containing protein 1