文章：

循环缺氧和自由基调节血管生成和放疗反应

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response

原文发布日期：2008-06-01

DOI: 10.1038/nrc2397

类型: Review Article

开放获取: 否

要点：

1. This Review discusses four important and interrelated features of tumour hypoxia: the hypoxic response, the factors that influence tumour hypoxia, the role of hypoxia in the initiation of angiogenesis (angiogenic switch) and how hypoxia influences treatment responses.
2. The hypoxia response, driven primarily by the heterodimeric transcription factor hypoxia-inducible factor 1 (HIF1) influences cell survival, behaviour and angiogenesis.
3. Several pathophysiological factors contribute to the development of tumour hypoxia, which is typified by heterogeneity in oxygenation in space and in time.
4. Conflicting theories exist with respect to whether hypoxic stabilization of HIF1 is the primary feature of the angiogenic switch. There is clear evidence that HIF1 upregulation is associated with angiogenesis acceleration as opposed to angiogenesis initiation.
5. The appearance of perivascular (oxygenated regions) HIF1 expression during angiogenesis acceleration might be the result of increased levels of reactive oxygen species, associated with proliferation and/or instability in flow and hypoxia–reoxygenation injury.
6. Cytotoxic therapies, such as radiation therapy, improve tumour oxygenation but also increase HIF1 levels and transactivation of target genes through mechanisms associated with stress granule depolymerization and the production of free radicals. The upregulation of HIF1 in these circumstances protects tumour and endothelial cells from damage by the cytotoxic therapy.

要点翻译：

1. 本综述探讨肿瘤缺氧四个重要且相互关联的特征：缺氧反应、影响肿瘤缺氧的因素、缺氧在血管生成启动（血管生成开关）中的作用，以及缺氧如何影响治疗反应。
2. 主要由异源二聚体转录因子缺氧诱导因子1（HIF1）驱动的缺氧反应，影响细胞存活、行为及血管生成。
3. 多种病理生理因素导致肿瘤缺氧的形成，其典型特征是氧合在空间和时间上的异质性。
4. 关于HIF1的缺氧稳定性是否为血管生成开关的主要特征，目前存在争议。有明确证据表明HIF1上调与血管生成加速相关，而非血管生成启动。
5. 血管生成加速期间出现血管周（氧合区）HIF1表达，可能是活性氧水平升高的结果，这与增殖和/或血流不稳定及缺氧-复氧损伤相关。
6. 放射治疗等细胞毒性疗法可改善肿瘤氧合，但也会通过应激颗粒解聚和自由基产生等机制，增加HIF1水平及其靶基因的转录激活。此种情况下HIF1的上调可保护肿瘤细胞和内皮细胞免受细胞毒性疗法损伤。

英文摘要：

Hypoxia and free radicals, such as reactive oxygen and nitrogen species, can alter the function and/or activity of the transcription factor hypoxia-inducible factor 1 (HIF1). Interplay between free radicals, hypoxia and HIF1 activity is complex and can influence the earliest stages of tumour development. The hypoxic environment of tumours is heterogeneous, both spatially and temporally, and can change in response to cytotoxic therapy. Free radicals created by hypoxia, hypoxia–reoxygenation cycling and immune cell infiltration after cytotoxic therapy strongly influence HIF1 activity. HIF1 can then promote endothelial and tumour cell survival. As discussed here, a constant theme emerges: inhibition of HIF1 activity will have therapeutic benefit.

摘要翻译： 

缺氧和自由基（如活性氧和氮物种）可改变转录因子缺氧诱导因子1（HIF1）的功能和/或活性。自由基、缺氧与HIF1活性之间的相互作用非常复杂，并可影响肿瘤发展的最早阶段。肿瘤的缺氧环境在空间和时间上均呈异质性，且可因细胞毒性治疗而发生变化。由缺氧、缺氧-再氧合循环以及细胞毒性治疗后免疫细胞浸润产生的自由基，可强烈影响HIF1活性。HIF1进而可促进内皮细胞和肿瘤细胞的存活。正如本文所讨论，一个持续的主题浮现：抑制HIF1活性将带来治疗获益。

原文链接：

Cycling hypoxia and free radicals regulate angiogenesis and radiotherapy response