VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex.
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.
Department of Neurological Surgery, University of California, Helen Diller Family Cancer Research Center, San Francisco, CA 94143, USA.
Kan V
KV
Lu
Jeffrey P
JP
Chang
Christine A
CA
Parachoniak
Melissa M
MM
Pandika
Manish K
MK
Aghi
David
D
Meyronet
Nadezda
N
Isachenko
Shaun D
SD
Fouse
Joanna J
JJ
Phillips
David A
DA
Cheresh
Morag
M
Park
Gabriele
G
Bergers
D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology / Q000627:therapeutic use; D000068258:Bevacizumab; D001932:Brain Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D058750:Epithelial-Mesenchymal Transition / Q000502:physiology*; D005909:Glioblastoma / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D006801:Humans; D010766:Phosphorylation; D019859:Proto-Oncogene Proteins c-met / Q000235:genetics / Q000378:metabolism*; D015398:Signal Transduction; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000378:metabolism / Q000502:physiology*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000378:metabolism*
D061067:Antibodies, Monoclonal, Humanized; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; C491743:MET protein, human; D019859:Proto-Oncogene Proteins c-met; D040301:Vascular Endothelial Growth Factor Receptor-2