VEGF Inhibits Tumor Cell Invasion and Mesenchymal Transition through a MET/VEGFR2 Complex

• Published in: Cancer cell Vol. 22; no. 1; pp. 21 - 35
• Main Authors: Lu, Kan V., Chang, Jeffrey P., Parachoniak, Christine A., Pandika, Melissa M., Aghi, Manish K., Meyronet, David, Isachenko, Nadezda, Fouse, Shaun D., Phillips, Joanna J., Cheresh, David A., Park, Morag, Bergers, Gabriele
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 10.07.2012
• Subjects: Antibodies, Monoclonal, Humanized - pharmacology; Antibodies, Monoclonal, Humanized - therapeutic use; Bevacizumab; Brain Neoplasms - drug therapy; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Epithelial-Mesenchymal Transition - physiology; Glioblastoma - drug therapy; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Phosphorylation; Proto-Oncogene Proteins c-met - genetics; Proto-Oncogene Proteins c-met - metabolism; Signal Transduction; Vascular Endothelial Growth Factor A - antagonists & inhibitors; Vascular Endothelial Growth Factor A - metabolism; Vascular Endothelial Growth Factor A - physiology; Vascular Endothelial Growth Factor Receptor-2 - metabolism
• ISSN: 1535-6108; 1878-3686; 1878-3686
• DOI: 10.1016/j.ccr.2012.05.037

Inhibition of VEGF signaling leads to a proinvasive phenotype in mouse models of glioblastoma multiforme (GBM) and in a subset of GBM patients treated with bevacizumab. Here, we demonstrate that vascular endothelial growth factor (VEGF) directly and negatively regulates tumor cell invasion through enhanced recruitment of the protein tyrosine phosphatase 1B (PTP1B) to a MET/VEGFR2 heterocomplex, thereby suppressing HGF-dependent MET phosphorylation and tumor cell migration. Consequently, VEGF blockade restores and increases MET activity in GBM cells in a hypoxia-independent manner, while inducing a program reminiscent of epithelial-to-mesenchymal transition highlighted by a T-cadherin to N-cadherin switch and enhanced mesenchymal features. Inhibition of MET in GBM mouse models blocks mesenchymal transition and invasion provoked by VEGF ablation, resulting in substantial survival benefit. ► VEGF blocks HGF-induced tumor invasion by recruiting PTP1B to a MET/VEGFR2 complex ► VEGF inhibition enhances MET activity, mesenchymal transformation, and invasion in GBM ► Combined VEGF and MET inhibition blocks invasion and prolongs survival in GBM