Pancreatic cancer cell-derived vascular endothelial growth factor is biologically active in vitro and enhances tumorigenicity in vivo

Vascular endothelial growth factor (VEGF) is a potent angiogenic stimulator that acts by binding to high-affinity transmembrane receptors, Although bo th VEGF and its receptors are overexpressed in human pancreatic ductal aden ocarcinoma (PDAC), this malignancy is not generally considered to be highly vascular. It is not known, therefore, whether the abundance of VEGF in PDA C is biologically relevant, To address this issue, we measured the angiogen ic effects of pancreatic cancer cell-derived VEGF in an in vitro endothelia l cell proliferation assay and characterized the consequences of suppressin g VEGF expression on pancreatic tumor growth in an athymic nude mouse model . We found that human pancreatic cancer cell lines secrete large quantities of biologically active VEGF into conditioned medium (GM), Stable transfect ion of an anti-sense VEGF(189) (AS-VEGF(189)) expression construct: into PA NG-I pancreatic cancer cells resulted in decreased VEGF expression and secr etion, a decreased capacity of the resultant GM to enhance endothelial cell proliferation and a significant attenuation of tumor cell proliferation in vitro. Furthermore. when injected into athymic nude mice, AS-VEGF(189)-exp ressing cells exhibited an 80% decrease in tumor growth compared with contr ol cells, These results support the hypothesis that VEGF promotes pancreati c cancer growth in vivo and suggest that anti-VEGF therapy may be useful in the treatment of this disease. (C) 2001 Wiley-Liss. Inc.