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. (HEPATOLOGY 2004;40:252-259.) N eovascularization is essential for the growth of solid malignant tumors larger than 1 to 2 mm in diameter. 1,2 Cancer cells constantly require high oxygen and nutrient concentrations because of their rapid cell division. Therefore, these cells are always exposed to a certain degree of vascular starvation, and blood vessels in the area attempt to sprout from preexisting vessels. This phenomenon is called angiogenesis. 2,3 Many secretory agents involved in angiogenesis, such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor, and angiopoietin-1, have been discovered and are well studied in various types of cancer. [4][5][6] Conversely, several endogenous antiangiogenic factors also have been identified.
Pigment epithelium-derived factor (PEDF) was first discovered in 1989 by Tombran-Tink as a neurotrophic serpin that was secreted by retinal pigment epithelial cells. 7,8 Recently, PEDF was implicated in inhibition of angiogenesis in a dose-dependent manner both in vitro and in vivo. 9 -11 The antiangiogenic efficiency of PEDF is more potent than that of other endogenous angiogenic inhibitors, including angiostatin, thrombospondin-1, and endostatin. 12 PEDF is found throughout the body and is particularly highly expressed in the normal liver. 13,14 In this regard, in hepatocellular carcinoma (HCC), it is speculated that PEDF expression is disadvantageous for tumor progression, but paradoxically, HCC is known to be one of the most hypervascular cancers. PEDF expression has not been well investigated in neoplastic diseases, including HCC. Furthermore, because the clinical nature of premalignant conditions associated with HCC are clearly elucidated, including chronic hepatitis (CH) or liver cirrhosis (LC) resulting from hepatitis B or C virus infection, 15 patterns of PEDF expression in these liver diseases also are of interest.