TGF-beta inhibits human cutaneous melanoma cell migration and invasion through regulation of the plasminogen activator system

Abstract

Over the past decades, the incidence of cutaneous melanoma in developed countries has increased faster than any other cancer. Although most patients have localized disease at the time of diagnosis and are cured by surgical excision of the primary tumor, melanoma can be highly malignant and the survival dramatically decreases for advanced stage melanomas. It is thus necessary to understand the progression of this disease. Cell migration and invasion promote tumor metastasis, the major cause of melanoma cancer morbidity and death. In this study, we investigated the role of the TGFβ/Smad signaling pathway in melanoma tumor progression and found TGFβ to potently inhibit both cell migration and invasion in human melanoma cell lines, established from different patients. Furthermore, we elucidated the molecular mechanisms by which TGFβ exerts its effects and found the plasminogen activation system (PAS) to play a central role in the regulation of these effects. We found TGFβ to strongly up-regulate the Plasminogen Activator Inhibitor-1 (PAI-1) in melanoma cells, leading to reduced plasmin generation and activity and, in turn to inhibition of cell migration and invasion. Together, our results define TGFβ as a potent suppressor of tumor progression in cutaneous melanoma, inhibiting both cell migration and invasion.