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

Abstract

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.

• Authors: Mallika Singh, Suzana S Couto, William F Forrest, Anthony Lima, Jason H Cheng, Rafael Molina, Jason E Long, Patricia Hamilton, Angela McNutt, Ian Kasman, Michelle A Nannini, Hani Bou Reslan, Tim C Cao, Calvin C K Ho, Kai H Barck, Richard A D Carano, Oded Foreman, Jeffrey Eastham-Anderson, Adrian M Jubb, Napoleone Ferrara, Leisa Johnson
• Journal: The Journal of pathology (J Pathol) Vol. 227 Issue 4 Pg. 417-30 (Aug 2012) ISSN: 1096-9896 [Electronic] England
• PMID: 22611036 (Publication Type: Journal Article)
• Copyright: Copyright © 2012 Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.

Chemical References

• Angiogenesis Inhibitors
• Antibodies, Anti-Idiotypic
• Indoles
• Pyrroles
• Vascular Endothelial Growth Factor A
• Hras protein, mouse
• Proto-Oncogene Proteins p21(ras)
• Sunitinib

Topics

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