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

被引:478
作者
Lu, Kan V. [1 ,3 ]
Chang, Jeffrey P. [1 ,3 ]
Parachoniak, Christine A. [5 ,6 ]
Pandika, Melissa M. [1 ,3 ]
Aghi, Manish K. [1 ,3 ,4 ]
Meyronet, David [1 ,3 ]
Isachenko, Nadezda [1 ,3 ]
Fouse, Shaun D. [1 ,3 ]
Phillips, Joanna J. [1 ,3 ,4 ]
Cheresh, David A. [7 ,8 ]
Park, Morag [5 ,6 ]
Bergers, Gabriele [1 ,2 ,3 ,4 ]
机构
[1] Univ Calif San Francisco, Helen Diller Family Canc Res Ctr, Dept Neurol Surg, San Francisco, CA 94143 USA
[2] Univ Calif San Francisco, Helen Diller Family Canc Res Ctr, Dept Anat, San Francisco, CA 94143 USA
[3] Univ Calif San Francisco, Brain Tumor Res Ctr, San Francisco, CA 94143 USA
[4] Univ Calif San Francisco, UCSF Comprehens Canc Ctr, Helen Diller Family Canc Res Ctr, San Francisco, CA 94143 USA
[5] McGill Univ, Dept Biochem, Montreal, PQ H3G 1Y6, Canada
[6] McGill Univ, Goodman Canc Res Ctr, Montreal, PQ H3G 1Y6, Canada
[7] Univ Calif San Francisco, Dept Pathol, San Diego, CA 92093 USA
[8] Univ Calif San Francisco, Moores UCSD Canc Ctr, San Diego, CA 92093 USA
基金
加拿大健康研究院; 美国国家卫生研究院;
关键词
ENDOTHELIAL GROWTH-FACTOR; TYROSINE-PHOSPHATASE; 1B; ANTI-ANGIOGENIC THERAPY; FACTOR RECEPTORS; FUNCTIONAL-SIGNIFICANCE; SIGNAL-TRANSDUCTION; MET PROTOONCOGENE; MALIGNANT GLIOMA; CANCER-CELLS; C-MET;
D O I
10.1016/j.ccr.2012.05.037
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:21 / 35
页数:15
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