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PMID:22789536

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Citation

Lu, KV, Chang, JP, Parachoniak, CA, Pandika, MM, Aghi, MK, Meyronet, D, Isachenko, N, Fouse, SD, Phillips, JJ, Cheresh, DA, Park, M and Bergers, G (2012) VEGF inhibits tumor cell invasion and mesenchymal transition through a MET/VEGFR2 complex. Cancer Cell 22:21-35

Abstract

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.

Links

PubMed Online version:10.1016/j.ccr.2012.05.037

Keywords

Antibodies, Monoclonal, Humanized/pharmacology; Antibodies, Monoclonal, Humanized/therapeutic use; 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

Significance

Annotations

Gene product Qualifier GO Term Evidence Code with/from Aspect Extension Notes Status

HUMAN:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P18031

F

Seeded From UniProt

complete

HUMAN:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35918

F

Seeded From UniProt

complete

HUMAN:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35968

F

Seeded From UniProt

complete

MOUSE:MET

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P35918

F

Seeded From UniProt

complete

HUMAN:PTN1

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08581

F

Seeded From UniProt

complete

MOUSE:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08581

F

Seeded From UniProt

complete

MOUSE:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P16056

F

Seeded From UniProt

complete

HUMAN:VGFR2

enables

GO:0005515: protein binding

ECO:0000353: physical interaction evidence used in manual assertion

UniProtKB:P08581

F

Seeded From UniProt

complete


See also

References

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