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

Abstract

Summary Inhibition of VEGF signaling leads to a pro-invasive 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.

MIR517Cinhibits autophagy and the epithelial-to-mesenchymal (-like) transition phenotype in human glioblastoma through KPNA2-dependent disruption of TP53 nuclear translocation

“…Our finding further supported a role for CDH13 in the acquisition of the EMT-like phenotype in GBM, consistent with the results of a previous study. 31 Our study further indicated that inhibition of the EMT by MIR517C occurred via the inhibition of autophagy. Autophagy is a process of dynamic flux involving sequestration of phagophores, generation of autophagosomes or amphisomes, and fusing to lysosomes (autolysosomes).…”

“…Moreover, MIR517C inhibited the conversion of CDH13 to CDH2, which is thought to provide a mechanism for transendothelial migration. 31 Other EMT markers, such as VIM (cytoplasmic) and the EMT regulators SNAI2 (nuclear) and ZEB1 (nuclear), were downregulated in tumors derived from MIR517C (oe) cells.…”

Protein tyrosine phosphatase PTP1B in cell adhesion and migration

“…12,[20][21][22] An inhibitory role has been described in fibroblasts, 23,24 primary aortic smooth muscle cells, 25 ovarian cancer cells, 26 and in glioblastoma multiforme tumor cell invasion in mice. 27 Remarkably, the positive role of PTP1B in cell motility was frequently associated with the stimulation of integrin-dependent signaling. 3,4,12,17,18,22 In contrast, the negative effect of PTP1B on cell motility was related to antagonizing signaling from growth factor receptor tyrosine kinases.…”

“…3,4,12,17,18,22 In contrast, the negative effect of PTP1B on cell motility was related to antagonizing signaling from growth factor receptor tyrosine kinases. [24][25][26][27] In a recent quantitative study, we analyzed the intrinsic motility and migration parameters of PTP1B-null cells (KO cells) in an isotropic 2-D fibronectin substratum. 28 Directionality and average velocity of KO cells were significantly reduced when compared with KO cells reconstituted with wild-type PTP1B (WT cells).…”

Targeting Angiogenesis in Cancer Therapy: Moving Beyond Vascular Endothelial Growth Factor

“…Proangiogenic effects of HGF/MET on tumors occur primarily by direct activation of endothelialcellstoundergomotogenic ormorphogenic changes and by indirect stimulation of the production of proangiogenic factors, including VEGF [61]. Comparisons of bevacizumabresistant glioblastoma with pretreatment tumors from the same patients found increased MET expression in the former, suggesting that MET may play a role in antiangiogenic therapy resistance by compensating for the inhibition of VEGF and promoting an invasive tumor phenotype [62,63]. The role of HGF/MET signaling in tumor angiogenesis continues to be a topic of intense investigation because better understanding could facilitate the development of MET-targeted therapies [59].…”