Journal Article

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

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

2016

Overview

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.

• Publisher: Nature Publishing Group UK,Nature Publishing Group
• Subject: 13/1 / 13/106 / 13/51 / 13/89 / 14/1 / 14/19 / 14/63 / 631/67/2328 / 64/60 / 692/699/67/2328 / Actin-Related Protein 2-3 Complex - genetics / Adult / Aged / Aged, 80 and over / Angiogenesis / Angiogenesis inhibitors / Angiogenesis Inhibitors - therapeutic use / Antineoplastic Combined Chemotherapy Protocols - therapeutic use / Bevacizumab - therapeutic use / Biomedicine / Breast Neoplasms - pathology / Cancer metastasis / Cancer Research / Carcinoma - blood supply / Carcinoma - drug therapy / Carcinoma - secondary / Carcinoma, Ductal, Breast - secondary / Carcinoma, Lobular - secondary / Cell Movement - genetics / Colorectal carcinoma / Colorectal Neoplasms - drug therapy / Colorectal Neoplasms - pathology / Coronary vessels / Drug Resistance, Neoplasm / Drug therapy / Female / Gene Knockdown Techniques / HT29 Cells / Humans / Infectious Diseases / Inhibition / Liver / Liver cancer / Liver Neoplasms - blood supply / Liver Neoplasms - drug therapy / Liver Neoplasms - secondary / Male / Metabolic Diseases / Metastasis / Middle Aged / Molecular Medicine / Neoplasm Grading / Neovascularization, Pathologic - drug therapy / Neurosciences / Patient outcomes