title: 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 PEDF-transfected 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 Fas ligand-dependent apoptosis in tumor cells. PEDF therefore might be a promising novel therapeutic agent for treatment of patients with melanoma.
authors.affiliation: Department of Dermatology, Hokkaido University Graduate School of Medicine, Sapporo, Japan. aberi@med.hokudai.ac.jp
authors.forename: Riichiro
authors.initials: R
authors.lastname: Abe
authors.forename: Tadamichi
authors.initials: T
authors.lastname: Shimizu
authors.forename: Sho-Ichi
authors.initials: S
authors.lastname: Yamagishi
authors.forename: Akihiko
authors.initials: A
authors.lastname: Shibaki
authors.forename: Shinjiro
authors.initials: S
authors.lastname: Amano
authors.forename: Yosuke
authors.initials: Y
authors.lastname: Inagaki
authors.forename: Hirokazu
authors.initials: H
authors.lastname: Watanabe
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Sugawara
authors.forename: Hideki
authors.initials: H
authors.lastname: Nakamura
authors.forename: Masayoshi
authors.initials: M
authors.lastname: Takeuchi
authors.forename: Tsutomu
authors.initials: T
authors.lastname: Imaizumi
authors.forename: Hiroshi
authors.initials: H
authors.lastname: Shimizu
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000502:physiology; D015153:Blotting, Western; D045744:Cell Line, Tumor; D005136:Eye Proteins; D006801:Humans; D008546:Melanoma, Experimental / Q000473:pathology*; D051379:Mice; D008856:Microscopy, Fluorescence; D009389:Neovascularization, Pathologic / Q000503:physiopathology*; D009414:Nerve Growth Factors; D014176:Protein Biosynthesis; D011506:Proteins / Q000235:genetics; D015843:Serpins / Q000096:biosynthesis* / Q000235:genetics; D014162:Transfection; D042461:Vascular Endothelial Growth Factor A / Q000378:metabolism; D000099174:Pigment Epithelium-Derived Factor
chemical_list: D005136:Eye Proteins; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D042461:Vascular Endothelial Growth Factor A; D000099174:Pigment Epithelium-Derived Factor