Abstract

Oxygen deficiency is one of the key pathogenetic factors determining development and severity of many diseases, including inflammatory, infectious diseases, and cancer. Lack of oxygen activates the signaling pathway of the hypoxia-inducible transcription factor HIF in cells that has three isoforms, HIF-1, HIF-2, HIF-3, regulating expression of several thousand genes. Throughout tumor progression, HIF activation stimulates angiogenesis, promotes changes in cell metabolism, adhesion, invasiveness, and ability to metastasize. HIF isoforms can play opposite roles in the development of inflammatory and neoplastic processes. Humans and laboratory animals differ both in tolerance to hypoxia and in the levels of expression of HIF and HIF-dependent genes, which may lead to predisposition to the development of certain oncological disorders. In particular, the ratio of different histogenetic types of tumors may vary among people living in the mountains and at the sea level. However, despite the key role of hypoxia at almost all stages of tumor development, basal tolerance to oxygen deficiency is not considered as a factor of predisposition to the tumor growth initiation. In literature, there are many works characterizing the level of local hypoxia in various tumors, and suggesting fundamental approaches to its mitigation by HIF inhibition. HIF inhibitors, as a rule, have a systemic effect on the organism, however, basal tolerance of an organism to hypoxia as well as the level of HIF expression are not taken into account in the process of their use. The review summarizes the literature data on different HIF isoforms and their role in tumor progression, with extrapolation to organisms with high and low tolerance to hypoxia, as well as on the prevalence of various types of tumors in the populations living at high altitudes.

中文翻译：

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缺氧耐受性与肿瘤发展关系的 HIF 依赖性机制

摘要

缺氧是决定许多疾病发展和严重程度的关键致病因素之一，包括炎症、传染病和癌症。缺氧会激活细胞中缺氧诱导转录因子 HIF 的信号通路，该转录因子具有 HIF-1、HIF-2、HIF-3 三种亚型，调节数千个基因的表达。在整个肿瘤进展过程中，HIF 激活会刺激血管生成，促进细胞代谢、粘附、侵袭性和转移能力的变化。HIF 亚型在炎症和肿瘤过程的发展中可以发挥相反的作用。人类和实验动物在对缺氧的耐受性以及 HIF 和 HIF 依赖性基因的表达水平方面存在差异，这可能导致某些肿瘤疾病的发展。特别是，不同组织遗传学类型肿瘤的比例可能因生活在山区和海平面上的人而异。然而，尽管缺氧在肿瘤发展的几乎所有阶段都起着关键作用，但对缺氧的基础耐受性并不被认为是肿瘤开始生长的易感因素。在文献中，有许多作品描述了各种肿瘤的局部缺氧水平，并提出了通过抑制 HIF 来缓解缺氧的基本方法。HIF 抑制剂通常对生物体具有全身作用，但是在其使用过程中不考虑生物体对缺氧的基础耐受性以及 HIF 表达水平。该综述总结了关于不同 HIF 亚型及其在肿瘤进展中的作用的文献数据，