There is an important and strong, but complex influence of the tumor microenvironment on tumor cells' phenotype, aggressiveness, and treatment sensitivity. One of the most frequent and best-studied aspects of the tumor microenvironment is hypoxia. Low oxygen tension often occurs in tumor cells by several mechanisms, for example, poor angiogenesis and increased oxygen consumption. Hypoxia is a heterogeneous concept with oxygen tensions ranging from <0.01% (anoxia) to 5%, and can be chronic, acute, or cycling, all with differential effects on tumor cells. Quantification of tumor hypoxia can be performed directly or indirectly, and with exogenous or endogenous markers. Tumor cells launch different intracellular signaling pathways to survive hypoxia, such as hypoxia-inducible factor 1-mediated gene expression, the unfolded protein response, and AKT-mammalian target of rapamycin signaling. These pathways induce aggressive, metastatic, and treatment-insensitive tumors and are considered potential targets for (additive) therapy. Hypoxia leads to important, yet currently not well-understood changes in microRNA expression, epigenetics, and metabolism. Further, treatment-insensitive tumors arise through hypoxia-induced Darwinian selection of apoptosis-deficient, p53-mutated tumor cells. In conclusion, hypoxia has profound and largely still poorly understood effects on tumor cells with a major effect on the tumor's biology.
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