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The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of through the induction of angiogenesis, tumor vascularization can occur through the nonangiogenic mechanism of vessel co-option. Here we show that vessel co-option is associated with a poor response to the anti-angiogenic agent bevacizumab in patients with colorectal cancer liver metastases. Moreover, we find that vessel co-option is also prevalent in human breast cancer liver metastases, a setting in which results with anti-angiogenic therapy have been disappointing. In preclinical mechanistic studies, we found that cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3) is required for vessel co-option in liver metastases in vivo and that, in this setting, combined inhibition of angiogenesis and vessel co-option is more effective than the inhibition of angiogenesis alone. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option might be a warranted therapeutic strategy., Author(s): Sophia Frentzas [1, 2]; Eve Simoneau [3]; Victoria L Bridgeman [1]; Peter B Vermeulen [1, 4]; Shane Foo [1]; Eleftherios Kostaras [1]; Mark R Nathan [1]; Andrew Wotherspoon [2]; [...]

Inhibitors of [[alpha].sub.v][[beta].sub.3] and [[alpha].sub.v][[beta].sub.5] integrin have entered clinical trials as antiangiogenic agents for cancer treatment but generally have been unsuccessful. Here we present in vivo evidence that low (nanomolar) concentrations of RGD-mimetic [[alpha].sub.v][[beta].sub.3] and [[alpha].sub.v][[beta].sub.5] inhibitors can paradoxically stimulate tumor growth and tumor angiogenesis. We show that low concentrations of these inhibitors promote VEGF-mediated angiogenesis by altering [[alpha].sub.v][[beta].sub.3] integrin and vascular endothelial growth factor receptor-2 trafficking, thereby promoting endothelial cell migration to VEGF. The proangiogenic effects of low concentrations of RGD-mimetic integrin inhibitors could compromise their efficacy as anticancer agents and have major implications for the use of RGD-mimetic compounds in humans., Inhibitors of angiogenesis can suppress tumor growth in preclinical models and have entered the clinic as prospective anticancer therapeutics (1,2). Tumor angiogenesis is predominantly driven by vascular endothelial growth factor [...]