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

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.

• Authors: Sophia Frentzas, Eve Simoneau, Victoria L Bridgeman, Peter B Vermeulen, Shane Foo, Eleftherios Kostaras, Mark 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 Ritsma, Jacco Van Rheenen, Alla Khashper, Gina Brown, Hanna Nystrom, Malin Sund, Steven Van Laere, Evelyne Loyer, Luc Dirix, David Cunningham, Peter Metrakos, Andrew R Reynolds
• Journal: Nature medicine (Nat Med) Vol. 22 Issue 11 Pg. 1294-1302 (11 2016) ISSN: 1546-170X [Electronic] United States
• PMID: 27748747 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• ARPC3 protein, human
• Actin-Related Protein 2-3 Complex
• Angiogenesis Inhibitors
• Bevacizumab

Topics

• Actin-Related Protein 2-3 Complex (genetics)
• Adult
• Aged
• Aged, 80 and over
• Angiogenesis Inhibitors (therapeutic use)
• Antineoplastic Combined Chemotherapy Protocols (therapeutic use)
• Bevacizumab (therapeutic use)
• Breast Neoplasms (pathology)
• Carcinoma (blood supply, drug therapy, secondary)
• Carcinoma, Ductal, Breast (secondary)
• Carcinoma, Lobular (secondary)
• Cell Movement (genetics)
• Colorectal Neoplasms (drug therapy, pathology)
• Drug Resistance, Neoplasm
• Female
• Gene Knockdown Techniques
• HT29 Cells
• Humans
• Liver Neoplasms (blood supply, drug therapy, secondary)
• Male
• Middle Aged
• Neoplasm Grading
• Neovascularization, Pathologic (drug therapy)