Overexpression of Pigment Epithelium-Derived Factor Decreases Angiogenesis and Inhibits the Growth of Human Malignant Melanoma Cells in Vivo

Abstract

Pigment epithelium-derived factor (PEDF) has recently been shown to be the most potent inhibitor of angiogenesis in the mammalian eye, and is involved in the pathogenesis of angiogenic eye disease such as proliferative diabetic retinopathy. However, a functional role for PEDF in tumor growth and angiogenesis remains to be determined. In this study, we have investigated both the in vitro and in vivo growth characteristics of human malignant melanoma G361 cell lines, stably transfected to overexpress human PEDF. Expression levels of PEDF proteins in melanoma cell lines G361 and A375 were comparable with that of human cultured melanocytes, whereas vascular endothelial growth factor levels in two tumor cell lines were much stronger than that in normal melanocytes. Overexpression of PEDF was found to significantly inhibit tumor growth and vessel formation in G361 nude mice xenografts. Furthermore, in vitro proliferation rates of G361 cells were decreased in PEDFtransfected cells. PEDF proteins showed dose-dependent induced growth retardation and apoptotic cell death in nontransfected G361 cells, which were completely prevented by treatment with antibodies against the Fas ligand. Our present study highlights two beneficial effects of PEDF treatment on melanoma growth and expansion; one is the suppression of tumor angiogenesis, and the other is induction of Angiogenesis, a process by which new vascular networks are formed from pre-existing capillaries, is required for tumors to grow, invade, and metastasize.

The molecular impact of pigment epithelium-derived factor, PEDF, on lung cancer cells and the clinical significance

“…Although PEDF has been shown to inhibit tumour-induced angiogenesis (27), our present study shows that rhPEDF exerts an inhibitory effect on the growth of vascular cells only at much higher concentrations (>100 ng/ml). Collectively, it suggests that PEDF influences angiogenesis through affecting the angiogenesis process without significantly affecting the proliferation of vascular endothelial cells.…”

Endogenous Inhibitors of Angiogenesis

“…One is the suppression of tumor angiogenesis. Overexpression of PEDF was found to significantly inhibit melanoma growth and vessel formation in G361 nude mice xenografts (170). PEDF is also expressed strongly in normal murine kidney, and the loss of angioinhibitory activity may contribute to pathologic angiogenesis in Wilms' tumor (171).…”

Pigment epithelium-derived factor overexpression inhibits orthotopic osteosarcoma growth, angiogenesis and metastasis

“…The mechanisms through which PEDF exerts its antitumor activity seems to be multiple, with studies showing widespread activities against tumor proliferation, cellular invasion, migration, differentiation and tumor angiogenesis. 17 To date, a few studies have tested the therapeutic potential of PEDF against a number of tumor models, both in vitro and in vivo, and have demonstrated inhibition of growth and the suppression of metastasis in cancers, such as pancreatic carcinoma, 18 prostate carcinoma, 19 melanoma, 20 neuroblastoma 21 and ovarian cancer. 22 In these studies, however, all have used models that have developed following ectopic implantation of cancer cell lines.…”