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

Area of Science:

• Oncology
• Cancer Biology
• Translational Medicine

Background:

• Efficacy of angiogenesis inhibitors is limited by resistance mechanisms.
• Tumor vascularization can occur via vessel co-option, a nonangiogenic pathway.
• Vessel co-option is poorly understood as a resistance mechanism.

Purpose of the Study:

• Investigate the role of vessel co-option in resistance to anti-angiogenic therapy.
• Determine the prevalence of vessel co-option in colorectal and breast cancer liver metastases.
• Evaluate therapeutic strategies combining angiogenesis and vessel co-option inhibition.

Main Methods:

• Analysis of patient samples for vessel co-option.
• Preclinical studies using in vivo models of liver metastases.
• Assessment of cancer cell motility mediated by the actin-related protein 2/3 complex (Arp2/3).

Main Results:

• Vessel co-option is associated with poor response to bevacizumab in colorectal cancer liver metastases.
• Vessel co-option is prevalent in breast cancer liver metastases, where anti-angiogenic therapy has disappointing results.
• Arp2/3-mediated cancer cell motility is required for vessel co-option in liver metastases.
• Combined inhibition of angiogenesis and vessel co-option is more effective than inhibiting angiogenesis alone.

Conclusions:

• Vessel co-option is a clinically relevant mechanism of resistance to anti-angiogenic therapy.
• Combined inhibition of angiogenesis and vessel co-option represents a potential therapeutic strategy for liver metastases.