Taxanes act as vascular disrupting agents and increase rate of metastasis when combined with anti-angiogenic therapy

Abstract

Taxanes are known to have a profound effect on endothelial cells and the vasculature even at low doses. Here, we show that taxanes, rather than being anti-angiogenic, function more as vascular disrupting agents (VDAs), although they exert a different mechanism of vascular permeabilization when compared to traditional VDAs such as combretastatins. In the tumor context, this VDA-effect leads to a rapid vascular collapse and acute hypoxia. Concomitant treatment with anti-VEGF drugs aggravates hypoxia by blocking vasculogenic rescue mechanisms. While this results in a strong growth-suppressing effect on the tumor, it also increases its invasiveness and metastatic potential. We demonstrate that combination of anti-angiogenic drugs with taxanes blocks tumor reperfusion, intensifies intravasation of circulating tumor cells (CTCs) and strongly increases metastasis. Anti-VEGF drugs are commonly applied in combination with cytotoxic drugs including taxanes. Our findings have significant implications for the clinical use of this drug combination.