VEGF-A/VEGFR-2 signaling plays an important role for the motility of pancreas cancer cells.
BACKGROUND
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.


METHODS
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.


RESULTS
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.


CONCLUSIONS
VEGF-A/VEGFR-2 signaling plays an important role in inducing invasion and migration of pancreatic cancer cells.
Department of Surgical Oncology, Osaka City University Graduate School of Medicine, Osaka, Japan.
Yosuke
Y
Doi
Masakazu
M
Yashiro
Nobuya
N
Yamada
Ryosuke
R
Amano
Satoru
S
Noda
Kosei
K
Hirakawa
D020533:Angiogenesis Inhibitors / Q000494:pharmacology; D061067:Antibodies, Monoclonal, Humanized / Q000494:pharmacology; D000068258:Bevacizumab; D015153:Blotting, Western; D002465:Cell Movement / Q000187:drug effects / Q000502:physiology*; D002478:Cells, Cultured; D017077:Culture Media, Conditioned / Q000494:pharmacology; D004797:Enzyme-Linked Immunosorbent Assay; D061307:Human Umbilical Vein Endothelial Cells / Q000166:cytology / Q000187:drug effects / Q000378:metabolism; D006801:Humans; D007211:Indoles / Q000494:pharmacology; D048369:MAP Kinase Kinase 1 / Q000235:genetics / Q000378:metabolism; D020935:MAP Kinase Signaling System; D010190:Pancreatic Neoplasms / Q000188:drug therapy / Q000378:metabolism* / Q000473:pathology*; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D010766:Phosphorylation / Q000187:drug effects; D051057:Proto-Oncogene Proteins c-akt / Q000235:genetics / Q000378:metabolism; D011758:Pyrroles / Q000494:pharmacology; D012333:RNA, Messenger / Q000235:genetics; D034741:RNA, Small Interfering / Q000235:genetics; D060888:Real-Time Polymerase Chain Reaction; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction; D000077210:Sunitinib; D042461:Vascular Endothelial Growth Factor A / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D040301:Vascular Endothelial Growth Factor Receptor-2 / Q000037:antagonists & inhibitors / Q000235:genetics / Q000378:metabolism*; D014945:Wound Healing
D020533:Angiogenesis Inhibitors; D061067:Antibodies, Monoclonal, Humanized; D017077:Culture Media, Conditioned; D007211:Indoles; D011758:Pyrroles; D012333:RNA, Messenger; D034741:RNA, Small Interfering; C467484:VEGFA protein, human; D042461:Vascular Endothelial Growth Factor A; D000068258:Bevacizumab; D019869:Phosphatidylinositol 3-Kinases; D040301:Vascular Endothelial Growth Factor Receptor-2; D051057:Proto-Oncogene Proteins c-akt; D048369:MAP Kinase Kinase 1; D000077210:Sunitinib