Li Zhizhong, Bao Shideng, Wu Qiulian, Wang Hui, Eyler Christine, Sathornsumetee Sith, Shi Qing, Cao Yiting, Lathia Justin, McLendon Roger E, Hjelmeland Anita B, Rich Jeremy N
Department of Pharmacology and Cancer Biology, Duke University Medical Center, Durham, NC 27710, USA.
Cancer Cell. 2009 Jun 2;15(6):501-13. doi: 10.1016/j.ccr.2009.03.018.
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.
胶质母细胞瘤是一种致死性癌症，其特征在于由胶质瘤干细胞（GSCs）部分促进的活跃血管生成。由于缺氧调节血管生成，我们研究了GSCs中的缺氧反应。我们现在证明，与非干细胞肿瘤细胞和正常神经祖细胞相比，缺氧诱导因子HIF2α和多个HIF调节基因在GSCs中优先表达。在肿瘤标本中，HIF2α与癌症干细胞标志物共定位。靶向GSCs中的HIF可抑制体外自我更新、增殖和存活，并减弱GSCs在体内的肿瘤起始潜能。对分子数据库的分析表明，HIF2A表达与胶质瘤患者的不良生存相关。我们的结果表明，GSCs对缺氧有不同的反应，具有独特的HIF诱导模式，并且HIF2α可能是抗胶质母细胞瘤治疗的一个有前景的靶点。
