Harnessing the hypoxia-inducible factor in cancer and ischemic disease
Harnessing the hypoxia-inducible factor in cancer and ischemic disease
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DOI：
10.1016/j.bcp.2006.10.013
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发表时间：
2007-02-01
影响因子：
5.8
通讯作者：
Pouyssegur, Jacques
中科院分区：
文献类型：
--
作者：
Brahimi-Horn, M. Christiane;Pouyssegur, Jacques
当组织中的氧水平低时，即当组织微环境变得缺氧时，α/β-异二聚体转录因子缺氧诱导因子（HIF）发挥作用，而当氧水平高时则不起作用。某些病理生理状况，例如缺血性疾病和癌症，由于脉管系统有缺陷或不足而导致局部组织氧合水平低。高度增殖的肿瘤细胞迅速形成团块，距离脉管系统太远而无法获得营养和氧合。在这种情况下，HIT 会激活或抑制大量基因，特别是启动新血管的形成并改变新陈代谢。通过这种方式，肿瘤块重新建立了有利于进一步增殖的条件。人们对直接抑制或刺激 HIF 活性分别在癌症和缺血性疾病的治疗中表现出兴趣。其他涉及肿瘤代谢和细胞内 pH 控制的 HIF 靶基因的调节也可能被证明在癌症治疗中有用。然而，在进一步深入之前，必须更好地了解 HIF 信号通路的基础知识。这篇综述将向读者介绍调节 HIF 的分子机制及其作用的一些生物学后果，特别是在肿瘤代谢、生长和侵袭方面。还将讨论通过靶向 HIF 或其下游效应器来强制肿瘤消退或增加血管形成的方法。 (c) 2006 Elsevier Inc. 保留所有权利。
The alpha/beta-heterodimeric transcription factor hypoxia-inducible factor (HIF) functions when the oxygen level in tissues is low, i.e. when the tissue microenvironment becomes hypoxic, and is non-functional when the level of oxygen is high. Certain pathophysiological conditions such as ischemic disorders and cancer encounter low levels of local tissue oxygenation due to a defective or insufficient vasculature. Highly proliferating tumour cells rapidly form into a mass that becomes located too far from the vasculature to be nourished and oxygenated. Under such conditions HIT activates or represses a vast array of genes that in particular, initiate the formation of new blood vessels and modify metabolism. In this way the tumour mass re-establishes conditions favourable for further proliferation. Interest is being expressed in the direct repression or stimulation of HIF activity, respectively, in the treatment of cancer and of ischemic disorders. The modulation of other HIF-target genes implicated, in particular, in tumour metabolism and intracellular pH control may also prove to be useful in cancer therapy. However, before going further a better understanding of the basics of the HIF signalling pathway is essential. This review will introduce the reader to the molecular mechanisms that regulate HIF and some of the biological consequences of its action, in particular in tumour metabolism, growth and invasion. Approaches to either enforce tumour regression or increase blood vessel formation through the targeting of HIF or its downstream effectors will also be discussed. (c) 2006 Elsevier Inc. All rights reserved.