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1: Oncogene. 2009 Aug 31. [Epub ahead of print] LinkOut
- E1 [& j9 H# _Hypoxia promotes expansion of the CD133-positive glioma stem cells through activation of HIF-1alpha. d( ^7 y8 k! J- R' {7 V4 j( r
Soeda A, Park M, Lee D, Mintz A, Androutsellis-Theotokis A, McKay RD, Engh J, Iwama T, Kunisada T, Kassam AB, Pollack IF, Park DM.
3 L- b8 F$ L+ v# A& H& ~+ d; YBrain Tumor Program, University of Pittsburgh Cancer Institute, Pittsburgh, PA, USA." Q5 A% {# ]) o6 g7 r7 i
( \' s! c' c) O: ~6 [0 g& XHypoxia contributes to the progression of a variety of cancers by activating adaptive transcriptional programs that promote cell survival, motility and tumor angiogenesis. Although the importance of hypoxia and subsequent hypoxia-inducible factor-1alpha (HIF-1alpha) activation in tumor angiogenesis is well known, their role in the regulation of glioma-derived stem cells is unclear. In this study, we show that hypoxia (1% oxygen) promotes the self-renewal capacity of CD133-positive human glioma-derived cancer stem cells (CSCs). Propagation of the glioma-derived CSCs in a hypoxic environment also led to the expansion of cells bearing CXCR4 (CD184), CD44(low) and A2B5 surface markers. The enhanced self-renewal activity of the CD133-positive CSCs in hypoxia was preceded by upregulation of HIF-1alpha. Knockdown of HIF-1alpha abrogated the hypoxia-mediated CD133-positive CSC expansion. Inhibition of the phosphatidylinositol 3-kinase(PI3K)-Akt or ERK1/2 pathway reduced the hypoxia-driven CD133 expansion, suggesting that these signaling cascades may modulate the hypoxic response. Finally, CSCs propagated at hypoxia robustly retained the undifferentiated phenotype, whereas CSCs cultured at normoxia did not. These results suggest that response to hypoxia by CSCs involves the activation of HIF-1alpha to enhance the self-renewal activity of CD133-positive cells and to inhibit the induction of CSC differentiation. This study illustrates the importance of the tumor microenvironment in determining cellular behavior.Oncogene advance online publication, 31 August 2009; doi:10.1038/onc.2009.252.+ k% A7 Z; ?5 H; j9 V) M) e; y
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PMID: 19718046 [PubMed - as supplied by publisher]* h+ ]. n$ U. f" T- h/ e3 v
* U) C& r' I9 M" f7 Y) U2: Cancer Cell. 2009 Jun 2;15(6):501-13. Gene, Gene (GeneRIF), HomoloGene, Nucleotide, Nucleotide (RefSeq), Nucleotide (Weighted), Protein (RefSeq), Protein (Weighted), Substance (MeSH Keyword), Taxonomy via GenBank, UniGene, Protein, GEO Profiles, LinkOut
, q) x: r1 c! u- s7 Q- t3 X( EHypoxia-inducible factors regulate tumorigenic capacity of glioma stem cells.
/ d- Y6 m+ F& {4 q) Y5 ~) ELi Z, Bao S, Wu Q, Wang H, Eyler C, Sathornsumetee S, Shi Q, Cao Y, Lathia J, McLendon RE, Hjelmeland AB, Rich JN.6 Y* f0 M3 K& l X5 z
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
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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.. h6 ?; v" ~" i$ s7 v" x% y+ h
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PMID: 19477429 [PubMed - indexed for MEDLINE]
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V1 {2 r1 h! l* s, ]PMCID: PMC2693960 [Available on 2010/06/02] |
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发表于 2009-9-26 11:09
