Eales K L, Hollinshead K E R, Tennant D A
Institute of Metabolism and Systems Research, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK.
Department of Life, Health and Environmental Sciences, University ofL'Aquila, L'Aquila, Italy.
Oncogenesis. 2016 Jan 25;5(1):e190. doi: 10.1038/oncsis.2015.50.
Low oxygen tension (hypoxia) is a pervasive physiological and pathophysiological stimulus that metazoan organisms have contended with since they evolved from their single-celled ancestors. The effect of hypoxia on a tissue can be either positive or negative, depending on the severity, duration and context. Over the long-term, hypoxia is not usually consistent with normal function and so multicellular organisms have had to evolve both systemic and cellular responses to hypoxia. Our reliance on oxygen for efficient adenosine triphosphate (ATP) generation has meant that the cellular metabolic network is particularly sensitive to alterations in oxygen tension. Metabolic changes in response to hypoxia are elicited through both direct mechanisms, such as the reduction in ATP generation by oxidative phosphorylation or inhibition of fatty-acid desaturation, and indirect mechanisms including changes in isozyme expression through hypoxia-responsive transcription factor activity. Significant regions of cancers often grow in hypoxic conditions owing to the lack of a functional vasculature. As hypoxic tumour areas contain some of the most malignant cells, it is important that we understand the role metabolism has in keeping these cells alive. This review will outline our current understanding of many of the hypoxia-induced changes in cancer cell metabolism, how they are affected by other genetic defects often present in cancers, and how these metabolic alterations support the malignant hypoxic phenotype.
低氧张力（缺氧）是一种普遍存在的生理和病理生理刺激，后生动物自从单细胞祖先进化而来后就一直在应对这种刺激。缺氧对组织的影响可能是正面的，也可能是负面的，这取决于严重程度、持续时间和具体情况。从长期来看，缺氧通常与正常功能不相容，因此多细胞生物必须进化出对缺氧的全身和细胞反应。我们对氧气以高效生成三磷酸腺苷（ATP）的依赖意味着细胞代谢网络对氧张力的变化特别敏感。对缺氧的代谢变化是通过直接机制引发的，如氧化磷酸化生成ATP减少或脂肪酸去饱和作用受到抑制，以及间接机制，包括通过缺氧反应转录因子活性改变同工酶表达。由于缺乏功能性脉管系统，癌症的重要区域通常在缺氧条件下生长。由于缺氧的肿瘤区域含有一些最恶性的细胞，因此了解代谢在维持这些细胞存活中所起的作用非常重要。本综述将概述我们目前对癌细胞代谢中许多缺氧诱导变化的理解，它们如何受到癌症中经常出现的其他遗传缺陷的影响，以及这些代谢改变如何支持恶性缺氧表型。
