Sophia Frentzas 1 , 2 , Eve Simoneau 3 , Victoria L. Bridgeman 1 , Peter B. Vermeulen 1 , 4 , Shane Foo 1 , Eleftherios Kostaras 1 , Mark Nathan 1 , Andrew Wotherspoon 2 , Zu-hua Gao 3 , Yu Shi 3 , Gert Van den Eynden 4 , Frances Daley 5 , Clare Peckitt 2 , Xianming Tan 6 , Ayat Salman 3 , Anthoula Lazaris 3 , Patrycja Gazinska 7 , Tracy J. Berg 1 , Zak Eltahir 2 , Laila Ritsma 8 , Jacco Van Rheenen 8 , Alla Khashper 3 , Gina Brown 2 , Hanna Nystrom 9 , Malin Sund 9 , Steven Van Laere 4 , Evelyne Loyer 10 , Luc Dirix 4 , David Cunningham 2 , Peter Metrakos 3 , Andrew R. Reynolds 1
17 October 2016
The efficacy of angiogenesis inhibitors in cancer is limited by resistance mechanisms that are poorly understood. Notably, instead of inducing angiogenesis, some cancers vascularize by the non-angiogenic 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 prevails in human breast cancer liver metastases, a setting where results with anti-angiogenic therapy have been disappointing. In our preclinical mechanistic studies, we show that cancer cell motility mediated by the Arp2/3 complex is required for vessel co-option in liver metastases in vivo and that combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone in this setting. Vessel co-option is therefore a clinically relevant mechanism of resistance to anti-angiogenic therapy and combined inhibition of angiogenesis and vessel co-option may be a warranted therapeutic strategy.