Anti-VEGF antibody therapy does not promote metastasis in genetically engineered mouse tumour models.

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Adenocarcinoma, Angiogenesis Inhibitors, Animals, Antibodies, Anti-Idiotypic, Disease Models, Animal, Drug Therapy, Combination, Genetic Engineering, Indoles, Kaplan-Meier Estimate, Lung Neoplasms, Mice, Neoplasm Metastasis, Neuroendocrine Tumors, Pancreatic Neoplasms, Proto-Oncogene Proteins p21(ras), Pyrroles, Small Cell Lung Carcinoma, Vascular Endothelial Growth Factor A

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J Pathol 2012 Aug; 227(4):417-30.




Resistance to anti-angiogenic therapy can occur via several potential mechanisms. Unexpectedly, recent studies showed that short-term inhibition of either VEGF or VEGFR enhanced tumour invasiveness and metastatic spread in preclinical models. In an effort to evaluate the translational relevance of these findings, we examined the consequences of long-term anti-VEGF monoclonal antibody therapy in several well-validated genetically engineered mouse tumour models of either neuroendocrine or epithelial origin. Anti-VEGF therapy decreased tumour burden and increased overall survival, either as a single agent or in combination with chemotherapy, in all four models examined. Importantly, neither short- nor long-term exposure to anti-VEGF therapy altered the incidence of metastasis in any of these autochthonous models, consistent with retrospective analyses of clinical trials. In contrast, we observed that sunitinib treatment recapitulated previously reported effects on tumour invasiveness and metastasis in a pancreatic neuroendocrine tumour (PNET) model. Consistent with these results, sunitinib treatment resulted in an up-regulation of the hypoxia marker GLUT1 in PNETs, whereas anti-VEGF did not. These results indicate that anti-VEGF mediates anti-tumour effects and therapeutic benefits without a paradoxical increase in metastasis. Moreover, these data underscore the concept that drugs targeting VEGF ligands and receptors may affect tumour metastasis in a context-dependent manner and are mechanistically distinct from one another. J Pathol 2012 Aug; 227(4):417-30.