Hypoxia-induced DNA hypermethylation: another reason to normalize tumor vessels

As solid tumors grow, regions within the tumors often experience a deficit in oxygen, known as hypoxia. Hypoxia results from an imbalance in oxygen supply and demand. There is an increase in oxygen demand as cells proliferate or get recruited to build the tumor biomass, while oxygen supply becomes limited as the blood vessels within the growing tumor are absent and/or become abnormal in their structure and function (1,2). In addition to causing cell death, hypoxia can also promote tumor progression, immunosuppression, and treatment resistance. Indeed, tumor hypoxia is associated with poor patient outcome (3). This somewhat counter-intuitive relationship is, in part, due to the ability of tumors to adapt to and evolve in oxygen- and nutrient-deficient microenvironments. A recent report by Thienpont et al. demonstrated that one such mechanism may be through epigenetic regulation of gene expression by the ten-eleven translocation (TET) methylcytosine dioxygenases (4). This exciting finding provides another rationale to normalize the tumor vasculature to alleviate hypoxia and its consequences.