Abramson Family Cancer Research Institute, Perelman School of Medicine, Philadelphia, Pennsylvania 19104, USA.
Department of Cell and Developmental Biology, University of Pennsylvania, Philadelphia, Pennsylvania 19104, USA.
Cold Spring Harb Perspect Med. 2024 Feb 1;14(2):a041542. doi: 10.1101/cshperspect.a041542.
Molecular oxygen (O) is essential for cellular bioenergetics and numerous biochemical reactions necessary for life. Solid tumors outgrow the native blood supply and diffusion limits of O, and therefore must engage hypoxia response pathways that evolved to withstand acute periods of low O Hypoxia activates coordinated gene expression programs, primarily through hypoxia inducible factors (HIFs), to support survival. Many of these changes involve metabolic rewiring such as increasing glycolysis to support ATP generation while suppressing mitochondrial metabolism. Since low O is often coupled with nutrient stress in the tumor microenvironment, other responses to hypoxia include activation of nutrient uptake pathways, metabolite scavenging, and regulation of stress and growth signaling cascades. Continued development of models that better recapitulate tumors and their microenvironments will lead to greater understanding of oxygen-dependent metabolic reprogramming and lead to more effective cancer therapies.
分子氧（O）是细胞生物能量学和生命所必需的众多生化反应所必需的。实体瘤的生长速度超过了其原生血液供应和 O 的扩散限制，因此必须参与到为耐受急性低 O 而进化出的缺氧反应途径中。缺氧激活协调的基因表达程序，主要通过缺氧诱导因子（HIFs），以支持生存。这些变化中的许多都涉及代谢重编程，例如增加糖酵解以支持 ATP 的生成，同时抑制线粒体代谢。由于低 O 通常与肿瘤微环境中的营养应激相关，缺氧的其他反应包括激活营养摄取途径、代谢物清除以及应激和生长信号级联的调节。更好地再现肿瘤及其微环境的模型的持续发展将导致对氧依赖性代谢重编程的更深入理解，并导致更有效的癌症治疗方法。
