Abstract
Insulin-like-factor-binding-protein 3 (IGFBP-3) is known to modulate the activity of insulin-like growth factors (IGFs) besides having a number of IGF-independent effects on cell growth and survival. IGFBP-3 has been reported to decrease significantly in the blood serum of patients affected by certain cancers. In the present work, we have evaluated the levels of IGFBP-3 in the blood serum and tissues of patients affected by cutaneous melanoma, showing that loss of IGFBP-3 from both is strongly correlated with disease progression and reduced survival. In vitro treatment with IGFBP-3 of human and murine metastatic melanoma cell lines specifically inhibited the cells' migratory and invasive behaviour, inducing up-regulation of melanocytic differentiation markers such as tyrosinase activity and melanin content. A molecular analysis of the cellular pathways transducing the effect of IGFBP-3 implicated the Akt-GSK3β axis. Moreover, administration of IGFBP-3 in vivo to SCID mice inoculated with human metastatic melanoma cells strongly reduced or completely inhibited tumor growth. In summary, IGFBP-3 appears to exert a specific inhibitory effect on melanoma growth and dissemination, suggesting that it may qualify as a useful therapeutic agent in melanomas and perhaps other cancers, at the least as a valid adjuvant therapy during treatment with conventional anti-tumoral drugs.
Highlights
Melanoma is an aggressive malignancy whose incidence is increasing worldwide
We showed that serum levels of insulin-like growth factor binding protein (IGFBP)-3 are lowered significantly in stage-IV melanoma patients [15]
In this study we show that IGFBP-3 has a remarkable antitumoral activity on malignant melanoma, both in vitro and in vivo
Summary
Melanoma is an aggressive malignancy whose incidence is increasing worldwide Much of this increase could depend on the higher frequency of early diagnosis; from 1990 to 2002 the mortality rate has decreased by only 0.3% per year, mainly because there are no standard systemic therapies to improve the survival of stage-IV melanoma patients [1,2]. Rather than as a single disease, melanoma should be viewed as a heterogeneous cluster of disorders with defects influencing important cellular processes such as cell cycle regulation, cell signalling pathways, cell adhesion, cell differentiation and cell death [3]. This heterogeneity in molecular faults emphasizes the need for individualisation of melanoma diagnosis, prognosis and treatment. More research is needed to identify other diagnostic and prognostic molecular markers that could open possibilities for achieving better and more personalised treatments
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