Hypoxia inducible factors in cancer stem cells.
Hypoxia inducible factors in cancer stem cells.
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DOI：
10.1038/sj.bjc.6605551
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发表时间：
2010-03-02
影响因子：
8.8
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中科院分区：
文献类型：
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氧是细胞代谢、生存和增殖的重要调节剂。细胞对氧水平的反应部分是通过缺氧诱导因子（HIF）的转录活性来监测的。在缺氧条件下，HIF 调节多种促血管生成和促糖酵解途径。在实体癌中，由于血管结构混乱和坏死区域，缺氧区域通常存在于整个组织中。在这些区域中，缺氧状态以空间和时间的方式波动。短暂的缺氧循环导致 HIF 蛋白的活性增加，高于非病理组织的典型活性。缺氧的程度与患者生存率低、治疗耐药和侵袭性肿瘤表型密切相关，但缺氧和 HIF 对肿瘤生物学的全面贡献是一个积极研究的领域。最近的报告将传统疗法的耐药性与干细胞样肿瘤群体（称为癌症干细胞（CSC））的转移潜力联系起来。我们和其他人已经证明，在脑肿瘤内，CSC 存在于两个生态位中：血管周围位置和周围的坏死组织。受限的氧气条件增加了 CSC 分数并促进获得茎状状态。癌症干细胞的生存、自我更新和肿瘤生长严重依赖 HIF。这些观察结果和正常干细胞生物学的观察结果为缺氧对恶性肿瘤的影响提供了新的机制解释。此外，肿瘤中缺氧的存在可能会给治疗带来挑战，因为即使成功杀死 CSC，也会促进 CSC 表型。目前的实验证据表明，CSC 是受缺氧等微环境条件控制的可塑细胞状态，这对于开发旨在破坏微环境的新疗法可能至关重要。
Oxygen is an essential regulator of cellular metabolism, survival, and proliferation. Cellular responses to oxygen levels are monitored, in part, by the transcriptional activity of the hypoxia inducible factors (HIFs). Under hypoxia, HIFs regulate a variety of pro-angiogenic and pro-glycolysis pathways. In solid cancers, regions of hypoxia are commonly present throughout the tissue because of the chaotic vascular architecture and regions of necrosis. In these regions, the hypoxic state fluctuates in a spatial and temporal manner. Transient hypoxic cycling causes an increase in the activity of the HIF proteins above what is typical for non-pathologic tissue. The extent of hypoxia strongly correlates to poor patient survival, therapeutic resistance and an aggressive tumour phenotype, but the full contribution of hypoxia and the HIFs to tumour biology is an area of active investigation. Recent reports link resistance to conventional therapies and the metastatic potential to a stem-like tumour population, termed cancer stem cells (CSCs). We and others have shown that within brain tumours CSCs reside in two niches, a perivascular location and the surrounding necrotic tissue. Restricted oxygen conditions increase the CSC fraction and promote acquisition of a stem-like state. Cancer stem cells are critically dependant on the HIFs for survival, self-renewal, and tumour growth. These observations and those from normal stem cell biology provide a new mechanistic explanation for the contribution of hypoxia to malignancy. Further, the presence of hypoxia in tumours may present challenges for therapy because of the promotion of CSC phenotypes even upon successful killing of CSCs. The current experimental evidence suggests that CSCs are plastic cell states governed by microenvironmental conditions, such as hypoxia, that may be critical for the development of new therapies targeted to disrupt the microenvironment.