Vessel Co-Option and Impact of the Metastatic Tumor Microenvironment on Antiangiogenic Drug Efficacy

There are currently nine antiangiogenic drugs approved around the world for over ten different types of cancer. These drugs inhibit angiogenesis primarily, or only, by targeting the VEGF pathway. They include antibodies and/or TKIs. The indications include colorectal, lung, breast, ovarian, cervical, liver, renal and gastric carcinomas. However, the survival benefits of these drugs are incremental. These transient benefits are thought largely a consequence of innate and acquired resistance. Many mechanisms have been proposed to account for resistance to such agents, such as increased hypoxia and thus induced angiogenesis growth factor redundancy.

We have developed several new models of localized orthotopic primary tumors or postsurgical advanced metastatic disease to study antiangiogenic drug therapeutics. Using one such model, three different antiangiogenic drugs showed clear efficacy when treating primary breast tumors, but failed to do so when treating advanced visceral metastatic disease – which recapitulated prior phase III clinical trial outcomes. Analysis of the tumor vasculature revealed the likely reason for the discrepant outcomes: the primary tumors showed evidence of neoangiogenesis, whereas the metastases did not. Instead they appeared to ‘hijack’ the existing lung vasculature – a phenomenon known as “vessel co-option”. We also have found evidence in another model that liver tumors responding to sorafenib can become invasive and then switch to a co-option phenotype – and thus stop responding to the drug – a form of acquired or evasive resistance.

Vessel co-option should now be assessed as a potential target for ‘anti-vascular’ therapy.