Tumour invasion and metastasis: Reduction by concurrent inhibition of c-MET and VEGF signalling


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Donald M. McDonald
University of California, San Francisco, USA

Abstract

Treatment with inhibitors that block vascular endothelial growth factor (VEGF) signalling can make tumours more aggressive in some preclinical models. The mechanism of this form of resistance is not fully understood, but vascular pruning, intratumoural hypoxia, and increased expression of the receptor for hepatocyte growth factor (c-MET) are potential contributing factors. We found that treatment of pancreatic neuroendocrine tumours in RIP-Tag2 mice with a neutralizing anti-VEGF antibody or with sunitinib, a receptor tyrosine kinase inhibitor that blocks VEGFR and related receptors, reduced tumour burden and vascularity, but increased intratumoural hypoxia, HIF-1α, and expression and activation of c-MET. Invasion into the exocrine pancreas and metastasis to the liver also increased. Importantly, inhibition of c-MET inhibitors by PF-04217903 or crizotinib (PF-02341066) together with anti-VEGF therapy significantly reduced local invasion and liver metastasis as well as tumour growth and vascularity. Similar benefits were found after treatment with cabozantinib (XL184), a multitargeted tyrosine kinase inhibitor that simultaneously blocks c-MET and VEGF receptors. These findings in RIP-Tag2 tumours were corroborated by parallel experiments on orthotopic Panc-1 pancreatic adenocarcinomas. Together, these results indicate that inhibition of VEGF signalling can promote vascular pruning, intratumoural hypoxia, HIF-1α accumulation, and activation of c-MET. Concurrent inhibition of c-MET and VEGF signalling not only can slow tumour growth but also reduce invasion and metastasis. Inhibition of c-MET and VEGF signalling pathways together combines the favourable tumour growth-slowing effects of inhibiting angiogenesis with suppression of invasion and metastasis, despite the intratumoural hypoxia due to vascular pruning.