Vessel Co-option Induce Resistance to Anti-Angiogeneic Therapy

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A multinational and multi-disciplinary research collaboration lead by Institute of Cancer Research, London (UK) and McGill University Health Centre in Montreal (Canada), discovered that cancer can spread and metastasize not only through sprouting angiogenesis but also vascularize by an nonangiogenic mechanism of vessel co-option, a process whereby cancer cells, instead of inducing new vessel growth, incorporate pre-existing vessels from surrounding tissue.

Promising anti-angiogenic agents such as bevacizumab were designed to target sprouting angiogenesis, but not the process of vessel co-option. Accordingly, vessel co-option has been suggested as a potential mechanism of resistance to anti-angiogenic therapy.

The research team addressed whether vessel co-option could be a significant mechanism of resistance to anti-angiogenic therapy in patients with colorectal cancer liver metastases. They found that vessel co-option is the predominant mechanism of vascularization in 40% of the lesions examined in their study and those metastases that use vessel co-option process respond poorly to bevacizumab–chemotherapy treatment. Their observations strongly suggest that vessel co-option can blunt the therapeutic benefit of anti-angiogenic therapy in metastatic colorectal cancer.

Their findings also have relevance for breast cancer. Clinical trials using bevacizumab combined with chemotherapy in metastatic breast cancer have consistently failed to demonstrate a survival benefit for the addition of bevacizumab. Indeed the majority of breast cancer liver metastases utilize vessel co-option. Vessel co-option does occur also in breast cancer metastases to the lymph nodes, skin, lungs and brain. The prevalence of vessel co-option in breast cancer could explain, partly why anti-angiogenic therapy has not shown success in metastatic breast cancer.

The authors then proposed that therapeutic strategies to block vessel co-option in tumors should be developed. In this regard, they tested whether knockdown of Arp2/3-mediated cancer cell motility suppresses vessel co-option in a preclinical model of advanced liver metastasis. Results showed that combined inhibition of angiogenesis and vessel co-option was more effective at controlling tumor burden than targeting angiogenesis alone.

This study opens the door to a new field of research: designing new therapies that block both vessel co-option and angiogenesis. This could be more effective therapeutic strategy than existing treatments, which only block angiogenesis. 

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Frentzas S, Simoneau E, Bridgeman VL, Vermeulen PB, Foo S, Kostaras E, Nathan MR, Wotherspoon A, Gao ZH, Shi Y, Van den Eynden G, Daley F, Peckitt C, Tan X, Salman A, Lazaris A, Gazinska P7, Berg TJ1, Eltahir Z, Ritsma L, van Rheenen J, Khashper A, Brown G2, Nyström H, Sund M, Van Laere S, Loyer E, Dirix L, Cunningham D, Metrakos P, Reynolds AR. Vessel co-option mediates resistance to anti-angiogenic therapy in liver metastases. Nat Med. 2016 Oct 17. doi: 10.1038/nm.4197.
Nature Medicine