Targeting Signaling Pathways of Vegfr1 and Vegfr2 As A Potential Target in the Treatment of Breast Cancer

Background and aim: tumor angiogenesis allows tumor cells to grow and migrate toward the bloodstream and initiate the metastasis process. the interactions of vascular endothelial growth factors (vegf) a and b, as the important regulating factors for blood vessel growth, with vegfr1 and vegfr2 trigger angiogenesis process. thus, preventing these interactions led to the effective blockade of vegf/vegfrs signaling pathways.methods: in this study, the inhibitory effect of a 23-mer linear peptide (vgb4), which binds to both vegfr1 and vegfr2, on vegf-stimulated highly metastatic human breast cancer cell mda-mb-231 proliferation and migration was examined using mtt and wound healing assays. likewise, to further assess the anti-migratory potential of vgb4, human umbilical vein endothelial cell (huvec) wound healing assay was carried out at later time points (48 and 72 h). in addition, downstream signaling pathways of vegf involved in mediating cell migration and invasion were investigated by quantification of mrna and protein expression levels using real-time quantitative pcr and western blot in 4t1 tumor tissues and mda-mb-231 cells.results: the results of our work revealed that vgb4 significantly impeded proliferation and migration of mda-mb-231 cells, in a dose- and time-dependent way, and migration of huvecs for a prolonged time. a statistically significant reduction of the transcript level of focal adhesion kinase (fak), paxillin, matrix metalloproteinase-2 (mmp-2), ras-related c3 botulinum substrate 1 (rac1), p21-activated kinase-2 (pak-2) and cofilin-1 was observed in vgb4-treated 4t1 tumor tissues. the protein level of phospho-vegfr1, phospho-vegfr2, vimentin, ?-catenin and snail was markedly decreased in both vgb4-treated mda-mb-231 cells and vgb4-treated 4t1 tumor tissues as evidenced by western blotting.conclusion: the obtained results, plus our previous studies, confirm that dual blockage of vegfr1 and vegfr2, due to the inactivation of more signaling mediators, has the prominent role in suppressing tumor growth and metastasis.