Growth suppression of cervical carcinoma by pigment epithelium-derived factor via anti-angiogenesis

Pigment epithelium-derived factor (PEDF), an angiogenesis inhibitor with multiple other functions, balances angiogenesis in the eye and blocks tumor progression. Cervical cancer, an angiogenesis-dependent tumor, is the second most common cancer in women without effective treatment. It has been reported that PEDF can inhibit several types of tumors, however, the potential of PEDF for the treatment of cervical carcinoma has not been well explored. The present study was designed to investigate the effect of recombinant PEDF on the neovascularization and growth of cervical carcinoma. We found for the first time that PEDF was downregulated apparently in human cervical carcinoma nests compared to either normal cervical epithelium or nonneoplastic peritumoral epithelium, suggesting potential anti-angiogenesis function by supplement of PEDF in cervical carcinoma. Intraperitoneal injection of PEDF in xenografted cervical carcinoma mice suppressed tumor growth with 68% reduction. Microvessel density in tumor tissues treated with PEDF was significantly decreased. PEDF dose-dependently inhibited proliferation and induced apoptosis of endothelial cells, but had no direct effect on proliferation and apoptosis of Hela cells under both normoxia and hypoxia. These results suggested that PEDF suppressed tumor growth by blocking angiogenesis instead of a direct cytotoxic effect on tumor cells. VEGF, a major angiogenic stimulator, was downregulated by PEDF in Hela cells by downregulation of HIF-1 alpha, a crucial transcriptional factor for VEGF expression. Downregulation of VEGF expression in tumor cells through inhibiting HIF-1 alpha, thus attenuating the paracrine effect of VEGF on endothelial cells, may represent a mechanism for the anti-angiogenic activity of PEDF.