Activation of the FGF2/FGFR1 Autocrine Loop for Cell Proliferation and Survival in Uveal Melanoma Cells

PURPOSE. Constitutive activation of ERK1/2 controls proliferation of uveal melanoma cells. Because an autocrine fibroblast growth factor (FGF) activation loop controls ERK1/2 activation in many cancers, this study was conducted to examine the role of the FGF/FGF receptor autocrine loop in the ERK1/2dependent proliferation and survival of uveal melanoma cells. METHODS. Primary tumors and cell lines (OCM1, MKT-BR, SP6.5, Mel270 and 92.1) were used to define the role of the FGF/ FGFR system in human uveal melanoma. Cell proliferation was assessed by MTT-staining, and apoptosis was quantified by flow cytometry. Specific pharmacologic inhibitors of ERK1/2 and FGFR1, an anti-FGF2 neutralizing antibody and an antisense oligonucleotide directed against FGF2 were used to analyze signaling in the FGF/ FGFR autocrine loop. RESULTS. FGF1, FGF2, and their FGFR1 receptor were strongly expressed in the primary uveal melanomas. All five uveal melanoma cell lines expressed and secreted FGF2. They also expressed FGFR1. Cell proliferation was strongly reduced by the antisense oligonucleotide-mediated depletion of endogenous FGF2, immunoneutralization of secreted FGF2, and pharmacologic inhibition of FGFR1. The FGF2/FGFR1-mediated signaling pathway was identified by showing that inhibition of either FGF2 or FGFR1 reduced ERK1/2 activation, cell proliferation, and survival. CONCLUSIONS. The FGF/FGFR/ERK signaling pathway may be a target for therapeutic strategies against uveal melanoma. (Invest Ophthalmol Vis Sci. 2009; 50: 1047-1057) DOI: 10.1167/iovs.082378