Analysis for the role of vascular endothelial growth factor (VEGF family) on the growth and metastasis of pancreatic cancer

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In the present study we characterized VEGF and VEGF-C expression and its signaling cascade in cultured human pancreatic cancer cell lines and determined whether the presence of VEGF and VEGF-C in human pancreatic cancers is associated with clinicopathological characteristics. VEGF and VEGF-C mRNA transcripts were present in all 6 tested cell lines. Immunoblotting also revealed the presence ofVEGF and VEGF-C protein in all the cell lines. Northern blot analysis revealed significant increase in VEGF and VEGF-C mRNA transcript in the cancer samples by comparison with the normal pancreas. Immunohistochemical analysis confirmed the expression of VEGF and VEGF-C protein and their receptors flt-1, KDR and lt-4 in the cancer cells. Immunohistochemical analysis of pancreatic cancer tissues revealed that the presence of VEGF and VEGF-C were associated with increased tumor size and lymphatic vessels invasion and lymph node metastasis, respectively. In some cell lines VEGF receptors were also expressed and VEGF stimulation enhanced cell growth through its receptor phosphorylation, mitogen activated protein kinase (MAPK) and c-fos activation. Furthermore, anti-VEGF neutralizing antibody and selective MAPK inhibitor abolished the growth stimulation by VEGF. In vitro analysis, hypoxia inducing compound SNAP and TNFa up-regulated VEGF expression, but did not effect on VEGF-C expression. However, IL-6 up-regulated both VEGF and VEGF-C expression in some pancreatic cancer cell lines. Immunohistochemical analysis revealed the co-localization qf VEGF, VEGF-C and IL-6 in the same pancreatic cancer nests. These findings indicate that VEGF and VEGF-C and their receptors are commonly overexpressed in human pancreatic cancer and that this factor may contribute to the tumor growth and metastasis in this disorder. Furthermore, these findings also suggested the possibility of anti-angiogenic and molecular targeting strategies in pancreatic cancer.