The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype.
The hypoxic microenvironment maintains glioblastoma stem cells and promotes reprogramming towards a cancer stem cell phenotype.
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DOI：
10.4161/cc.8.20.9701
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发表时间：
2009-10-15
期刊：
影响因子：
--
通讯作者：
Rich JN
中科院分区：
文献类型：
--
作者：
Heddleston JM;Li Z;McLendon RE;Hjelmeland AB;Rich JN
胶质母细胞瘤是高度致命的癌症，其包含具有自我更新癌症干细胞的细胞层级，所述癌症干细胞可以在二次移植试验中增殖肿瘤。研究表明癌症干细胞在癌症生物学中的潜在重要性对治疗耐药性、血管生成和肿瘤扩散有贡献。我们最近报道了生理氧水平差异诱导肿瘤干细胞中缺氧诱导因子-2 α（HIF 2 α）水平。HIF 1 α在所有癌细胞的增殖和存活中发挥作用，但也在正常神经祖细胞中被激活，这表明治疗指数可能受到限制，而HIF 2 α仅在癌症干细胞中是必需的，并且正常神经祖细胞不表达，这表明HIF 2 α是癌症干细胞的特异性靶点。我们现在将这些研究扩展到研究缺氧在调节肿瘤细胞可塑性中的作用。我们发现，缺氧促进干细胞和非干细胞群体的自我更新能力，并促进非干细胞群体中更像干细胞的表型，增加神经球形成以及上调重要的干细胞因子，如OCT 4，NANOG和c-MYC。HIF 2 α的重要性得到进一步支持，因为强制表达不可降解的HIF 2 α可诱导癌症干细胞标志物并增强非干细胞群体的致瘤潜力。这一新的发现可能表明HIF 2 α在促进胶质瘤肿瘤发生中的特定作用。非干细胞胶质瘤群体和干细胞样表型的意想不到的可塑性强调了除了癌症干细胞之外，开发靶向微环境对肿瘤影响的治疗策略的重要性。
Glioblastomas are highly lethal cancers that contain cellular hierarchies with self-renewing cancer stem cells that can propagate tumors in secondary transplant assays. The potential significance of cancer stem cells in cancer biology has been demonstrated by studies showing contributions to therapeutic resistance, angiogenesis, and tumor dispersal. We recently reported that physiologic oxygen levels differentially induce hypoxia inducible factor-2α (HIF2α) levels in cancer stem cells. HIF1α functioned in proliferation and survival of all cancer cells but also was activated in normal neural progenitors suggesting a potentially restricted therapeutic index while HIF2α was essential in only in cancer stem cells and was not expressed by normal neural progenitors demonstrating HIF2α is a cancer stem cell specific target. We now extend these studies to examine the role of hypoxia in regulating tumor cell plasticity. We find that hypoxia promotes the self-renewal capability of the stem and non-stem population as well as promoting a more stem-like phenotype in the non-stem population with increased neurosphere formation as well as upregulation of important stem cell factors, such as OCT4, NANOG, and c-MYC. The importance of HIF2α was further supported as forced expression of non-degradable HIF2α induced a cancer stem cell marker and augmented the tumorigenic potential of the non-stem population. This novel finding may indicate a specific role of HIF2α in promoting glioma tumorigenesis. The unexpected plasticity of the non-stem glioma population and the stem-like phenotype emphasizes the importance of developing therapeutic strategies targeting the microenvironmental influence on the tumor in addition to cancer stem cells.
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