When tumors are (co-)opting to resist anti-angiogenic treatment

The role of angiogenesis, i.e., the growth of new blood vessels, in tumor biology revolutionized targeted cancer therapy when it was introduced approximately 10–15 years ago (1). Today, however, we know that anti-angiogenic treatment with either antibodies or small molecular inhibitors of the vascular endothelial growth factor (VEGF)-A—VEGF receptor (VEGFR)-2 axis are less effective in most malignant indications than initially expected (2). Such agents are, however, very effective at blocking tumor growth in most pre-clinical models, due to their potent effects on regressing the tumor vasculature leading to tumor hypoxia and necrosis. Recent scrutiny of the differences between such pre-clinical models and the clinical reality have lifted up a number of issues with the most commonly used mouse tumor models that could be important to understand the discrepancies observed in the effects of anti-angiogenic drugs, including age, genetic variability, the tissue in which the tumor grows etc. (1). Another emerging difference of potentially critical importance is the circadian rhythmicity of the host which is generally non-perturbed in tumor baring mice but often disrupted in cancer patients (3-5). This commentary is dedicated to discussing recent clinical and pre-clinical evidence in support of a mechanism that previously has not gained much attention but may be critical for our understanding of how anti-angiogenic resistance develops in cancer. That mechanism is vascular co-option