Abramson Family Cancer Research Institute, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, PA, USA.
EMBO J. 2023 Mar 15;42(6):e112067. doi: 10.15252/embj.2022112067. Epub 2023 Feb 20.
A role for hypoxia-inducible factors (HIFs) in hypoxia-dependent regulation of tumor cell metabolism has been thoroughly investigated and covered in reviews. However, there is limited information available regarding HIF-dependent regulation of nutrient fates in tumor and stromal cells. Tumor and stromal cells may generate nutrients necessary for function (metabolic symbiosis) or deplete nutrients resulting in possible competition between tumor cells and immune cells, a result of altered nutrient fates. HIF and nutrients in the tumor microenvironment (TME) affect stromal and immune cell metabolism in addition to intrinsic tumor cell metabolism. HIF-dependent metabolic regulation will inevitably result in the accumulation or depletion of essential metabolites in the TME. In response, various cell types in the TME will respond to these hypoxia-dependent alterations by activating HIF-dependent transcription to alter nutrient import, export, and utilization. In recent years, the concept of metabolic competition has been proposed for critical substrates, including glucose, lactate, glutamine, arginine, and tryptophan. In this review, we discuss how HIF-mediated mechanisms control nutrient sensing and availability in the TME, the competition for nutrients, and the metabolic cross-talk between tumor and stromal cells.
缺氧诱导因子（HIFs）在缺氧依赖性肿瘤细胞代谢调节中的作用已经得到了深入研究，并在综述中进行了阐述。然而，关于 HIF 依赖性调节肿瘤和基质细胞中营养命运的信息有限。肿瘤和基质细胞可能会产生功能所需的营养物质（代谢共生），或者消耗营养物质，从而导致肿瘤细胞和免疫细胞之间可能发生竞争，这是由于营养命运的改变所致。HIF 和肿瘤微环境（TME）中的营养素除了内在的肿瘤细胞代谢外，还会影响基质和免疫细胞的代谢。HIF 依赖性代谢调节将不可避免地导致 TME 中必需代谢物的积累或消耗。作为回应，TME 中的各种细胞类型将通过激活 HIF 依赖性转录来改变营养物质的摄取、输出和利用，从而对这些缺氧依赖性改变做出反应。近年来，对于包括葡萄糖、乳酸盐、谷氨酰胺、精氨酸和色氨酸在内的关键底物，已经提出了代谢竞争的概念。在这篇综述中，我们讨论了 HIF 介导的机制如何控制 TME 中的营养感应和可用性、营养物质的竞争以及肿瘤和基质细胞之间的代谢串扰。
