VEGF-A/VEGFR-2 Signaling Plays an Important Role for the Motility of Pancreas Cancer Cells
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Pancreatic cancer is one of the most lethal solid tumors. Vascular endothelial growth factor receptors (VEGFRs) are expressed not only by endothelial cells but also by pancreatic cancer cells. VEGFRs might play an important role for the development of pancreatic cancer cells. The purpose of this study was to evaluate the efficacy of VEGF/VEGFR-2—targeted therapy in pancreatic carcinoma.
Five pancreatic carcinoma cell lines were used. The expression level of VEGFR-2 of cancer cells was examined by RT-PCR and Western blot. The effects of VEGFs, bevacizumab as an anti-VEGF antibody, sunitinib as a tyrosine kinase inhibitor against VEGFRs, and VEGF-R2 siRNA on the motility activity of pancreatic cancer cells were examined by invasion assay and wound healing assay. The effect of VEGF, bevacizumab, and sunitinib on the phosphorylation of VEGFR-2 and downstream effecter molecules, MAPK and PI3K, was examined by western blot.
Pancreatic cancer cell lines expressed VEGFR-2. VEGF-A significantly increased the motility of pancreas cancer cells, which was inhibited by VEGFR-2 siRNA. Conditioned medium from pancreas cancer cells significantly stimulated the motility of pancreas cancer cells. VEGF/VEGFR inhibitors, bevacizumab and sunitinib, significantly decreased the motility of pancreas cancer cells. VEGFR-2 phosphorylation level of pancreas cancer cells was increased by VEGF-A. Bevacizumab and sunitinib decreased the level of VEGFR-2 phosphorylation, p-ERK, and p-Akt expression. VEGF-A decreased zonula occludens (ZO-1) or ZO-2 expression in pancreas cancer cells.
VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.
KeywordsVascular Endothelial Growth Factor Pancreatic Cancer Bevacizumab Conditioned Medium Sunitinib
This work was supported by KAKENHI (Grant-in-Aid for Scientific Research, No. 18591475, 20591073, 18390369, 22390262, and 23390329) and by a Grant-in Aid for the Sagawa Foundation for Cancer Research.
Conflict of interest
The authors declare that they have no conflicts of interest to disclose.
Supplementary movie 1 Real-time living-cell imaging of MiaPaCa-2 cells was monitored by time-lapse video microscopy for 72 h at 15-min intervals. VEGF-A significantly increased the motility of MiaPaCa-2 cells by the wound healing assay (MOV 2,490 kb)
Supplementary movie 2 Real-time living-cell imaging of MiaPaCa-2 cells was monitored by time-lapse video microscopy for 72 h at 15-min intervals. Bevacizumab decreased the migrating activity of MiaPaCa-2 cells (MOV 2,400 kb)
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