Clarify of the mechanism of anti-angiogenesis by PEDF and clinical application of PEDF gene therapy

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Pigment epithelium-derived factor (PEDF), which has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, is also expressed in the pancreas. Previously, we have screened the expression of PEDF by immunohistochemical analysis and demonstrated that PEDF expression is associated with increased risk of hepatic metastasis and short survival. In this study, we investigated both in vitro and in vivo growth characteristics of human pancreatic adenocarcinoma cell lines that were stably transfected to overexpress human PEDF. We discovered that cells secreted PEDF protein in the media, and this exhibited strong inhibitory effects on proliferation and migration of human umbilical vein endothelial cells. The size of PEDF-overexpressing pancreatic adenocarcinoma cells was significantly smaller than that of control cells in subcutaneous tumor models. Moreover, the growth of PEDF-overexpressing pancreatic adenocarcinoma cells was significantly suppressed in comparison with control cells in peritoneal metastasis models. In gene transfer models, intratumoral injection of a lentivirus. vector encoding PEDF (LV-PEDF) caused significant inhibition of tumor growth. The antitumor effect observed after treatment with LV-PEDF was associated with decreased microvessel density in tumors. The data presented here show that lentivirus-mediated gene transfer of PEDF could significantly reduce tumoral neoangiogenesis and tumor growth in animal models with human pancreatic adenocarcinoma. In conclusion, our data suggest that PEDF may exert a biological effect on tumor angiogenesis, and PEDF gene therapy may provide a new approach for treatment of pancreatic adenocarcinom