Vessel Co-option Induce Resistance to Anti-Angiogeneic Therapy

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.