Constitutive overexpression of pigment epithelium-derived factor inhibition of ocular melanoma growth and metastasis.

Uveal melanoma is the most common primary intraocular malignant tumor in adults and comprises nearly 85% of all ocular melanomas.1 The worldwide incidence of uveal melanoma is 5.3 to 10.9 cases per million population, representing approximately 4.25% of all melanomas.1 Despite progress in the diagnosis and treatment of the primary melanoma, the death rate from uveal melanoma has remained unchanged for the past 25 years.1,2 Nearly 40% of primary uveal melanomas metastasize to the liver, ultimately leading to death.1,2 Therefore, a better understanding of the cellular and molecular mechanisms of uveal melanoma progression is essential to develop novel and specific therapies to prevent or eliminate uveal melanoma metastasis. Pigment epithelium–derived factor (PEDF) is a 50-kDa secreted glycoprotein that was first described in the late 1980s, after being identified and isolated from conditioned media of cultured primary human fetal retinal pigment epithelial cells.3 PEDF is a noninhibitory member of the serpin (serine protease inhibitor) superfamily of proteins, and its gene, located on human chromosome 17p13.3, is highly conserved.4,5 PEDF is endogenously produced, widely expressed in fetal and adult tissues, including the eye, liver, bone, adult brain, spinal cord, heart, and lung, and exhibits multiple and varied biological activities.6–11 Expression of PEDF in the uvea and retina has been found in human and mouse eyes.12–15 PEDF has been established as a potent antiangiogenic molecule and has been reported to inhibit choroidal neovascularization and to treat ocular diseases, such as age-related macular degeneration and proliferative diabetic retinopathy.16–18 Uveal melanoma most often arises in the choroid and becomes vascularized, presumably via angiogenic mechanisms. In this study, we hypothesize that PEDF will inhibit uveal melanoma migration in vitro and angiogenesis in a mouse model of uveal melanoma, thus exhibiting direct and indirect antitumor activity. Tumors may express low levels of PEDF.19 Low levels or loss of expression of PEDF has been correlated with an increased incidence of metastasis and with poor prognoses in cutaneous melanoma, prostate carcinoma, pancreatic carcinoma, neuroblastoma, and glioma.19–26 The antitumor effects of PEDF include antiangiogenesis, protumor differentiation, and direct tumor suppression by apoptosis.25–29 Previous in vivo studies have shown that cutaneous melanoma expresses PEDF, and overexpression of PEDF in human cutaneous malignant melanoma cell lines has been achieved by stable transfection with PEDF plasmids and retroviral expression vectors, significantly reducing intratumoral microvessel density, primary tumor growth, and metastasis.30,31 To date, the therapeutic potential of PEDF in uveal melanoma has not been tested. In this study, we demonstrate the expression of PEDF in mouse melanoma cell lines and human uveal melanoma cells and show that low expression of PEDF is associated with greater murine ocular melanoma and more hepatic micrometastases. We also demonstrate that constitutive overexpression of PEDF induced by a lentiviral vector-mediated PEDF gene inhibits tumor growth and hepatic micrometastasis.