Figure 2. Regulation of c-Met activity in glioblastoma during anti-VEGF therapy.

VEGFR2 exists in a complex with c-Met and, upon VEGF stimulation, recruits the phosphotyrosine phosphatase PTP1B to suppress HGF-mediated c-Met activation on tumor cells. The presence of VEGF simultaneously promotes angiogenesis and tumor growth. Following VEGF signaling blockade through either VEGF or VEGFR2-targeted therapies, the eventual development of proinvasive evasion can be facilitated by a hypoxia-induced increase in HGF or c-Met expression by tumor cells, or by ligand-independent activation of c-Met. In addition, inhibition of VEGF signaling also represses its negative regulation of c-Met by disengaging PTP1B and thereby unleashing HGF/c-Met activity on tumor cells in a hypoxia-independent manner and without the need to upregulate total c-Met levels. The resultant increase in c-Met activation leads to increased tumor cell invasion and transformation towards a more mesenchymal and aggressive phenotype. The addition of c-Met or HGF inhibitors to anti-VEGF therapy may prevent proinvasive evasion and prolong antiangiogenic efficacy.

VEGFR2: VEGF receptor 2.