Antiangiogenic property of pigment epithelium-derived factor in hepatocellular carcinoma.
Pigment epithelium-derived factor (PEDF) is one of the most powerful endogenous antiangiogenic reagents discovered to date. Its antiangiogenic potential in neoplastic disease remains unclear. In this study, we investigated antiangiogenic property of PEDF in hepatocellular carcinoma (HCC), a typical hypervascular tumor. In HCC cell lines, constitutive messenger RNA and protein expression of PEDF varied. Genomic DNA encoding the PEDF gene was the same in the cell lines examined by Southern blotting. In chemically induced hypoxic conditions, secreted PEDF protein was suppressed in contrast to elevation of vascular endothelial growth factor protein. When PEDF was overexpressed by gene transfer, proliferation and migration of endothelial cells were inhibited in conditioned media derived from all HCC cell lines. However, the serum concentration of PEDF, as measured by enzyme-linked immunosorbent assay, was decreased in patients with cirrhosis or HCC complicated by cirrhosis compared to healthy volunteers and patients with chronic hepatitis. According to the endothelial cell proliferation assay, the serum PEDF of patients with HCC had antiangiogenic activity. Moreover, intratumoral injection of a PEDF-expressing plasmid in athymic mouse models caused significant inhibition of preestablished tumor growth. In conclusion, PEDF plays a role in the angiogenic properties of HCC. Reduction of serum PEDF concentration associated with the development of chronic liver diseases may contribute to the progression of HCC. In addition, gene therapy using PEDF may provide an efficient treatment for HCC.
Matsumoto
Kojiro
K
First Department of Internal Medicine, Nagasaki University School of Medicine, Sakamoto, Japan.
Ishikawa
Hiroki
H
Nishimura
Daisuke
D
Hamasaki
Keisuke
K
Nakao
Kazuhiko
K
Eguchi
Katsumi
K
D000818:Animals; D006528:Carcinoma, Hepatocellular / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D002455:Cell Division / Q000187:drug effects; D015687:Cell Hypoxia; D002478:Cells, Cultured; D018450:Disease Progression; D004730:Endothelium, Vascular / Q000166:cytology; D005136:Eye Proteins; D005786:Gene Expression Regulation; D006801:Humans; D008103:Liver Cirrhosis / Q000097:blood; D008113:Liver Neoplasms / Q000097:blood / Q000378:metabolism / Q000473:pathology / Q000503:physiopathology*; D008297:Male; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009389:Neovascularization, Pathologic / Q000473:pathology*; D009414:Nerve Growth Factors; D011506:Proteins / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D015843:Serpins / Q000097:blood / Q000235:genetics / Q000378:metabolism / Q000494:pharmacology*; D014162:Transfection; D014471:Umbilical Veins / Q000166:cytology; D000099174:Pigment Epithelium-Derived Factor
D005136:Eye Proteins; D009414:Nerve Growth Factors; D011506:Proteins; D015843:Serpins; D000099174:Pigment Epithelium-Derived Factor