FGF2 in Human Melanoma Progression: The Antithetical Functions of Different Isoforms

Background: Aberrant fibroblast growth factor 2 (FGF2) expression is correlated with different types of human cancer, included melanoma, where it is thought to contribute to its development and progression. An alternative translational process gives rise to five FGF2 isoforms with specific localization and functions: a low molecular weight (LMW, 18 KDa) and four high molecular weight (HMWs, 22, 22.5, 24, 34 KDa) isoforms. Alternative translation of FGF2 mRNA is regulated by an internal ribosome entry site (IRES) that controls the expression of all the isoforms except for the 34 KDa HMW, which depends instead on the canonical cap-dependent mechanism. To date, very extensive studies have been performed on LMW FGF2, while HMWs isoforms have to be better investigated. Methods: To disclose the differential contribution of FGF2 isoforms in melanoma progression, we forced the expression of IRES-dependent isoforms- LMW (18 KDa) and HMWs (22, 22.5, 24 KDa)- in human melanoma cells. We then evaluated their biological roles by studying migration, anoikis resistance, homing, chemoresistance and tumor angiogenesis. Results: We demonstrated that while LMW FGF2 expression confers stem-like traits and a pro-angiogenic profile to melanoma cells, HMWs isoforms are involved in the migratory processes and in the maintenance of tumor perfusion, when endothelial cell-driven angiogenesis is lacking, by promoting vasculogenic mimicry. Conclusions: This comparative study shows the differential contribution of FGF2 isoforms in melanoma progression, pointing out that, even behaving in specific/antithetical manners, they cooperate in different steps of metastatic cascade, providing melanoma cells with higher malignancy and aggressiveness.