Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases
Open Access
- 17 October 2016
- journal article
- research article
- Published by Springer Science and Business Media LLC in Nature Medicine
- Vol. 22 (11), 1294-1302
- https://doi.org/10.1038/nm.4197
Abstract
Poor responses of liver metastases to the anti-angiogenic agent bevacizumab in patients with colorectal and breast cancer correlate with tumor co-option of pre-existing blood vessels, a mechanism of tumor resistance that might be targeted by the inhibition of cancer cell motility. 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.This publication has 65 references indexed in Scilit:
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