Molecular basis underlying inhibition of metastasis of gastric cancer by anti-VEGFa treatment.

Neovascularization plays a substantial role in the invasiveness and metastasis of gastric cancer. However, the molecular mechanism underlying the control of neovascularization of gastric cancer remains undefined. Both vascular endothelial growth factor a (VEGFa) and matrix metalloproteinases 2 (MMP2) are essential for neovascularization by promoting endothelial mitogenesis and permeability and by promoting extracellular matrix degradation, respectively. Therefore, we were prompted to examine whether VEGFa and MMP2 may affect expression of each other to coordinate the neovascularization process. We found strong positive correlation of VEGFa and MMP2 levels in the gastric patients. Moreover, patients with metastasis of the original cancer had significantly higher levels of VEGFa and MMP2. Thus, we used a human gastric cancer cell line, SNU-5, to examine whether expression of VEGFa and MMP2 may affect each other. We found that overexpression of VEGFa in SNU-5 cells increased expression of MMP2, while inhibition of VEGFa in SNU-5 cells decreased expression of MMP2. On the other hand, overexpression of MMP2 in SNU-5 cells increased expression of VEGFa, while inhibition of MMP2 in SNU-5 cells decreased expression of VEGFa. These data suggest that expression of VEGFa and MMP2 may activate each other to reinforce a promoting effect on neovascularization. We then analyzed how VEGFa expression affects MMP2 level. Application of a specific Akt inhibitor to VEGFa-overexpressing SNU-5 cells substantially abolished the effect of VEGFa on MMP2 activation, suggesting that VEGFa may increase expression of MMP2 via PI3K/Akt signaling pathway. Since anti-VEGFa is a well-established therapy for many cancers, our data suggest that anti-VEGFa may not only inhibit neovascularization by prohibiting VEGFa-dependent endothelial mitogenesis and permeability increase but also by downregulating MMP2 to abolish the extracellular matrix degradation in gastric cancer.