Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases

Sophia Frentzas, Eve Simoneau, Victoria L. Bridgeman, Peter B. Vermeulen, Shane Foo, Eleftherios Kostaras, Mark R. Nathan, Andrew Wotherspoon, Zu Hua Gao, Yu Shi, Gert Van Den Eynden, Frances Daley, Clare Peckitt, Xianming Tan, Ayat Salman, Anthoula Lazaris, Patrycja Gazinska, Tracy J. Berg, Zak Eltahir, Laila RitsmaJacco Van Rheenen, Alla Khashper, Gina Brown, Hanna Nyström, Malin Sund, Steven Van Laere, Evelyne Loyer, Luc Dirix, David Cunningham, Peter Metrakos, Andrew R. Reynolds

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Abstract

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.

Original languageEnglish
Pages (from-to)1294-1302
Number of pages9
JournalNature Medicine
Volume22
Issue number11
DOIs
Publication statusPublished - 1 Nov 2016
Externally publishedYes

Cite this

Frentzas, S., Simoneau, E., Bridgeman, V. L., Vermeulen, P. B., Foo, S., Kostaras, E., ... Reynolds, A. R. (2016). Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nature Medicine, 22(11), 1294-1302. https://doi.org/10.1038/nm.4197