BACKGROUND AND DEFINITIONS

Cutaneous melanoma is among the most aggressive types of human cancer, and if untreated, virtually every melanoma has the potential to metastasize. While patients with locoregional disease and low tumor thickness can be cured in 90% of cases by surgery, the majority of patients with advanced disease die because of the inefficiency of current therapy regimens.

Cutaneous melanoma is historically defined as a malignant tumor derived from the transformation and proliferation of epidermal melanocytes, enabling a stepwise progression from common melanocytic nevus to radial growth phase melanoma, vertical growth phase melanoma, and finally, metastatic disease. However, recent data suggest that a considerable proportion – around 60% to 75% – of melanomas develop de novo, without any precursor lesions. On the basis of these observations and repeated findings on melanoma heterogeneity, an alternative hypothesis has been put forth in light of the emerging cancer stem cell (CSC) concept. Mounting evidence suggests that melanoma may arise from a multipotent CSC that is able to self-renew via asymmetric division, differentiate into diverse progenies, and drive continuous growth. In this context, the term melanoma stem cell represents an operational definition indicating a multipotent tumor-initiating cell subset that – although monoclonal in origin – can give rise to a three-dimensional, heterogeneous progeny that caricatures the tissue of origin. According to this, melanoma would become functionally heterogeneous as a result of gradual differentiation of cells and not due to the coexistence of multiple genetic subclones resulting from independent somatic mutations.