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

Nat Med. 2016 Nov;22(11):1294-1302. doi: 10.1038/nm.4197. Epub 2016 Oct 17.

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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • 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*
  • Carcinoma / drug therapy
  • Carcinoma / secondary
  • Carcinoma, Ductal, Breast / secondary
  • Carcinoma, Lobular / secondary
  • Cell Movement / genetics
  • Colorectal Neoplasms / drug therapy*
  • Colorectal Neoplasms / pathology
  • Drug Resistance, Neoplasm*
  • Female
  • Gene Knockdown Techniques
  • HT29 Cells
  • Humans
  • Liver Neoplasms / blood supply*
  • Liver Neoplasms / drug therapy
  • Liver Neoplasms / secondary
  • Male
  • Middle Aged
  • Neoplasm Grading
  • Neovascularization, Pathologic / drug therapy*

Substances

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