氧气在寒武纪大爆发期间多细胞生物的进化中发挥了关键作用。毫不奇怪，对氧气浓度波动的反应是癌症进化不可或缺的一部分，癌症是一种以多细胞破坏为特征的疾病。组织不良的肿瘤脉管系统会导致血流的混乱模式，其特征是肿瘤内氧浓度的巨大空间和时间变化。缺氧诱导生长因子 (HIF-1) 在使细胞适应低氧条件、代谢和增殖方面发挥着关键作用。 HIF-1 在癌症中通常被组成性激活，这强调了它在癌症进展中的重要性。在这里，我们认为 HIF-1 介导的表型变化除了使癌细胞适应其局部环境外，还“预适应”它们在远处转移部位的增殖。 HIF-1 介导的适应包括向无氧呼吸或糖酵解的代谢转变、表型可塑性和表观遗传重编程等细胞生存机制的激活以及通过血管生成形成肿瘤脉管系统。缺氧诱导的表观遗传重编程可以触发癌细胞的上皮细胞向间质细胞的转变——这是转移级联反应的第一步。高度糖酵解细胞通过酸化肿瘤微环境来促进局部侵袭。由于血管生成而形成的新血管为癌细胞提供了通往循环系统的管道。此外，癌细胞在原发部位获得的生存机制使它们能够重塑转移部位的组织，产生促进肿瘤的微环境。因此，原发肿瘤中的缺氧促进了有利于转移级联的所有阶段的适应，从最初逃逸进入血管、血管内存活、外渗到远处组织以及继发性肿瘤的建立。版权所有©2024。由Elsevier Ltd.出版。

Oxygen played a pivotal role in the evolution of multicellularity during the Cambrian Explosion. Not surprisingly, responses to fluctuating oxygen concentrations are integral to the evolution of cancer-a disease characterized by the breakdown of multicellularity. Poorly organized tumour vasculature results in chaotic patterns of blood flow characterized by large spatial and temporal variations in intra-tumoral oxygen concentrations. Hypoxia-inducible growth factor (HIF-1) plays a pivotal role in enabling cells to adapt, metabolize, and proliferate in low oxygen conditions. HIF-1 is often constitutively activated in cancers, underscoring its importance in cancer progression. Here, we argue that the phenotypic changes mediated by HIF-1, in addition to adapting the cancer cells to their local environment, also "pre-adapt" them for proliferation at distant, metastatic sites. HIF-1-mediated adaptations include a metabolic shift towards anaerobic respiration or glycolysis, activation of cell survival mechanisms like phenotypic plasticity and epigenetic reprogramming, and formation of tumour vasculature through angiogenesis. Hypoxia induced epigenetic reprogramming can trigger epithelial to mesenchymal transition in cancer cells-the first step in the metastatic cascade. Highly glycolytic cells facilitate local invasion by acidifying the tumour microenvironment. New blood vessels, formed due to angiogenesis, provide cancer cells a conduit to the circulatory system. Moreover, survival mechanisms acquired by cancer cells in the primary site allow them to remodel tissue at the metastatic site generating tumour promoting microenvironment. Thus, hypoxia in the primary tumour promoted adaptations conducive to all stages of the metastatic cascade from the initial escape entry into a blood vessel, intravascular survival, extravasation into distant tissues, and establishment of secondary tumours.Copyright © 2024. Published by Elsevier Ltd.