Objective: To evaluate whether the vascular endothelial growth factor (VEGF) pathway can be used as a target for effective treatment of pancreatic cancer.
Summary background data: VEGF and its receptors (VEGF-RI and -RII) are the predominant regulators of tumor neoangiogenesis, a key element for tumor growth and progression. However, VEGF receptor expression has been thought to be limited to endothelial cells, limiting the possibility of targeting it for therapy of pancreatic cancer.
Methods: Protein localization and mRNA were studied in pancreatic cancer specimens, normal pancreas, human pancreatic cancer cell lines, and an endothelial cell line. Cell proliferation was determined by [ H] thymidine uptake. Both VEGF receptors were genetically eliminated by antisense technology. The same approach was used in a murine model of pancreatic cancer in a therapeutic approach.
Results: VEGF-RI mRNA and VEGF-RII mRNA were expressed in 17 and 15 of 24 pancreatic cancer samples, respectively. VEGF receptors were found not only in blood vessels but also in pancreatic cancer cells. VEGF-RII expression correlated with poor tumor differentiation and was associated with poorer survival, while VEGF-RI expression did not correlate. VEGF treatment led to extensive growth stimulation in six of seven pancreatic cancer cell lines, which was completely inhibited by antisense treatment against VEGF-RII. Liposome-mediated gene transfer in nude mice with pancreatic tumors markedly reduced local tumor growth and decreased metastatic tumor spread.
Conclusions: The VEGF/VEGF-RII pathway regulates angiogenesis and local tumor growth and spread in pancreatic cancer. Genetic targeting of VEGF-RII blocks local growth and metastatic spread of pancreatic cancer cells in vivo and therefore offers a potential new therapeutic option for patients with this disease.