Hypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.
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.
Li
Zhizhong
Z
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Bao
Shideng
S
Wu
Qiulian
Q
Wang
Hui
H
Eyler
Christine
C
Sathornsumetee
Sith
S
Shi
Qing
Q
Cao
Yiting
Y
Lathia
Justin
J
McLendon
Roger E
RE
Hjelmeland
Anita B
AB
Rich
Jeremy N
JN
D000818:Animals; D051792:Basic Helix-Loop-Helix Proteins / Q000502:physiology*; D014408:Biomarkers, Tumor / Q000378:metabolism; D001932:Brain Neoplasms / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D015687:Cell Hypoxia; D049109:Cell Proliferation; D002470:Cell Survival; D002478:Cells, Cultured; D005909:Glioblastoma / Q000098:blood supply / Q000378:metabolism* / Q000473:pathology; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000502:physiology*; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D014411:Neoplastic Stem Cells / Q000502:physiology*; D009389:Neovascularization, Pathologic / Q000378:metabolism / Q000473:pathology; D013234:Stem Cells / Q000502:physiology; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099162:Endothelial PAS Domain-Containing Protein 1
D051792:Basic Helix-Loop-Helix Proteins; D014408:Biomarkers, Tumor; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D042461:Vascular Endothelial Growth Factor A; D000099162:Endothelial PAS Domain-Containing Protein 1; C497442:HIF1A protein, human