Suppression of angiogenesis and tumor growth by adenoviral-mediated gene transfer of pigment epithelium-derived factor

Abstract

Pigment epithelium-derived factor (PEDF) was identified from retinal pigment epithelial cells and has been shown to display neurotrophic effects. In addition it has been found to induce a potent inhibition of angiogenesis. In this study we have explored whether overexpression of PEDF by a gene transfer approach can block tumor angiogenesis and reduce tumor growth. We found that cells infected with an adenovirus encoding PEDF under the control of the CMV promoter (AdPEDF) secreted PEDF protein into the medium that exhibited strong inhibitory effects on migration and tube formation of endothelial cells cultured in the presence of vascular endothelial growth factor. Moreover, the systemic administration of AdPEDF was able to inhibit angiogenesis in Matrigel assay in vivo, and treatment with this adenovirus of established hepatocellular carcinoma tumor in nude mice resulted in strong suppression of tumor growth. This anti-tumor effect could also be seen in a mouse lung carcinoma model by systemic administration of vector. In that model, treatment of tumor by intratumoral injection of AdPEDF also caused significant inhibition of tumor growth. The anti-tumor effect was related to a decrease in density of microvessels in tumors after treatment with AdPEDF. These data suggest that the antiangiogenic properties of PEDF can be exploited to inhibit the establishment of tumor neovasculature and reduce tumor growth.

Expression of Pigment Epithelium-Derived Factor Decreases Liver Metastasis and Correlates with Favorable Prognosis for Patients with Ductal Pancreatic Adenocarcinoma

“…In the in vivo gene transfer model of PEDF, the ability of PEDF gene transfer to inhibit angiogenesis was evaluated by immunohistochemical analysis of MVD. With this model, MVD was significantly less dense in tumors treated with PEDF when compared with controls (31,32). In the present study, PEDF expression significantly correlates with the MVD, pathological stage, liver metastasis, and prognosis of patients.…”

Autocrine activation of an osteopontin-CD44-Rac pathway enhances invasion and transformation by H-RasV12

“…Included in this group are N-myc downstream regulated gene 2 (Cluster 6), pigment epitheliumderived factor (Cluster 6), transmembrane protein semaphorin 6C (Cluster 4) and slit-1 (Cluster 6) (Wu et al, 1999;Qu et al, 2002;Choi et al, 2003;Deng et al, 2003;Wang et al, 2003). The last two genes are particularly interesting since both have been typically associated with inhibiting nerve cell migration (Wu et al, 1999;Qu et al, 2002), and our findings suggest that these same genes may hinder cancer cell motility.…”

Protein C inhibitor inhibits breast cancer cell growth, metastasis and angiogenesis independently of its protease inhibitory activity

“…To date, various proteins of the SERPIN family including cleaved AT, 32 PAI-1, 35 and PEDF 36 have been reported to inhibit angiogenesis. In the present study, we compared the anti-angiogenic activity among various SERPIN proteins using in vitro tube formation assay, and found that PCI strongly inhibits angiogenesis, this anti-angiogenic effect being almost similar to that of cleaved AT.…”