Division of Drug Discovery and Safety, Leiden Academic Centre of Drug Research, Leiden University, Leiden, The Netherlands.
Mol Biol Rep. 2022 Nov;49(11):10961-10973. doi: 10.1007/s11033-022-07802-6. Epub 2022 Sep 3.
Hypoxia has been linked to elevated instances of therapeutic resistance in breast cancer. The exposure of proliferating cancer cells to hypoxia has been shown to induce an aggressive phenotype conducive to invasion and metastasis. Regions of the primary tumors in the breast may be exposed to different types of hypoxia including acute, chronic or intermittent. Intermittent hypoxia (IH), also called cyclic hypoxia, is caused by exposure to cycles of hypoxia and reoxygenation (H-R cycles). Importantly, there is currently no consensus amongst the scientific community on the total duration of hypoxia, the oxygen level, and the possible presence of H-R cycles. In this review, we discuss current methods of hypoxia research, to explore how exposure regimes used in experiments are connected to signaling by different hypoxia inducible factors (HIFs) and to distinct cellular responses in the context of the hallmarks of cancer. We highlight discrepancies in the existing literature on hypoxia research within the field of breast cancer in particular and propose a clear definition of acute, chronic, and intermittent hypoxia based on HIF activation and cellular responses: (i) acute hypoxia is when the cells are exposed for no more than 24 h to an environment with 1% O or less; (ii) chronic hypoxia is when the cells are exposed for more than 48 h to an environment with 1% O or less and (iii) intermittent hypoxia is when the cells are exposed to at least two rounds of hypoxia (1% O or less) separated by at least one period of reoxygenation by exposure to normoxia (8.5% O or higher). Our review provides for the first time a guideline for definition of hypoxia related terms and a clear foundation for hypoxia related in vitro (breast) cancer research.
缺氧与乳腺癌治疗抵抗的发生率升高有关。研究表明，增殖癌细胞暴露于缺氧环境中会诱导有利于侵袭和转移的侵袭表型。乳腺原发肿瘤的某些区域可能会受到不同类型的缺氧的影响，包括急性缺氧、慢性缺氧或间歇性缺氧。间歇性缺氧（IH）也称为周期性缺氧，是由缺氧和再氧合（H-R 循环）的循环引起的。重要的是，科学界目前尚未就缺氧的总持续时间、氧水平以及 H-R 循环的可能存在达成共识。在这篇综述中，我们讨论了当前的缺氧研究方法，以探讨实验中使用的暴露方案如何与不同缺氧诱导因子（HIFs）的信号转导以及癌症特征背景下的不同细胞反应相关。我们强调了乳腺癌领域特别是缺氧研究领域现有文献中的差异，并根据 HIF 激活和细胞反应提出了急性、慢性和间歇性缺氧的明确定义：（i）急性缺氧是指细胞在不超过 24 小时的时间内暴露于 1% O 或更低的环境中；（ii）慢性缺氧是指细胞在超过 48 小时的时间内暴露于 1% O 或更低的环境中；（iii）间歇性缺氧是指细胞至少经历两轮缺氧（1% O 或更低），每轮缺氧之间至少有一次通过暴露于正常氧（8.5% O 或更高）来复氧的循环。我们的综述首次为与缺氧相关的术语定义提供了指南，并为体外（乳腺癌）癌症研究中与缺氧相关的研究提供了明确的基础。
