Melanoma: from melanocyte to genetic alterations and clinical options

Abstract

Metastatic melanoma remained for decades without any effective treatment and was thus considered as a paradigm of cancer resistance. Recent progress with understanding of the molecular mechanisms underlying melanoma initiation and progression revealed that melanomas are genetically and phenotypically heterogeneous tumors. This recent progress has allowed for the development of treatment able to improve for the first time the overall disease-free survival of metastatic melanoma patients. However, clinical responses are still either too transient or limited to restricted patient subsets. The complete cure of metastatic melanoma therefore remains a challenge in the clinic. This review aims to present the recent knowledge and discoveries of the molecular mechanisms involved in melanoma pathogenesis and their exploitation into clinic that have recently facilitated bench to bedside advances.

Figure 1

General overview of melanocyte physiology. Melanocytes derived from the neural crest in the form of undifferentiated and unpigmented precursors, the melanoblasts, migrate to their final destination, the epidermis, where they synthesize melanin in melanosomes. Pax3, Sox10, endothelin3 (ED-3) and its receptor (Endrb), c-Kit and Mitf play a critical role in the development of melanocytes. Melanin is then transferred to neighboring keratinocytes to ensure skin protection against the deleterious effect of ultraviolet radiation.

Figure 2

Melanoma susceptibility alleles (adapted from Manolio et al.).

Figure 3

Hypothetical model of Melanoma development. In 25% of cases, melanoma derives from a pre-existing nevus through a multistep process regulated by a key set of genes. Cells must acquire successive genetic lesions prior to forming tumors and metastases. Asterisks indicate genes mutated in the germline.