Inhibition of Xenografted Human Melanoma Growth and Prevention of Metastasis Development by Dual Antiangiogenic/Antitumor Activities of Pigment Epithelium-Derived Factor

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Abstract
Human melanoma mortality is associated with the growth of metastasis in selected organs including the lungs, liver, and brain. In this study, we examined the consequences of overexpression of pigment epithelium-derived factor (PEDF), a neurotrophic factor and potent angiogenesis inhibitor, on both melanoma primary tumor growth and metastasis development. PEDF overexpression by melanoma cells greatly inhibited subcutaneous tumor formation and completely prevented lung and liver metastasis in immunocompromised mice after tail vein injection of metastatic human melanoma cell lines. Whereas the effects of PEDF on primary tumor xenografts appear mostly associated with inhibition of the angiogenic tumor response, abrogation of melanoma metastasis appears to depend on direct PEDF effects on both migration and survival of melanoma cells. PEDF-mediated inhibition of melanoma metastases could thus have a major impact on existing therapies for melanoma.Grant support: Grants SAF-2001-1349 (B. Jimenez) and BMC-2001-1018 from Ministerio de Ciencia y Tecnología (J. Jorcano), Grant FIS 01/0556 from Ministerio de Sanidad y Consumo (F. Larcher), and Grant CAM 08.6/0004 (M. Del Rio). M. Garcia and N. Fernandez were supported by Comunidad Autónoma de Madrid fellowships.Peer Reviewe