Pathogenesis of Malignant Melanoma

It has long been known that cancer arises most frequently from cells in tissues which undergo constant renewal [12]. For example, epithelial tissues of the skin and intestine are composed of cells which are renewed throughout life and are also often the source of adult malignancies [4, 64]. Although the process is periodic rather than constant, melanocytes also undergo frequent renewal and thus increase the risk of malignant transformation. In the hair follicle bulge region melanocyte stem cells produce daughter cells for each hair cycle and are themselves considered a possible source for melanoma [31, 88]. By contrast, epidermal melanocyte proliferation is stimulated by UV radiation [43, 77]. Sun exposure is believed to be involved in the malignant transformation of cutaneous melanocytes, as epidemiological studies point to increased incidence rates among fair-skinned peoples living at lower (and sunnier) latitudes [62]. Excessive and cumulative exposure to UV radiation results in increasing levels of DNA damage to proliferating melanocytes, which eventually overcome the capacity for DNA repair mechanisms to compensate [74]. Usually this evokes mechanisms which precipitate apoptotic cell death [48], but occasionally a cell undergoes malignant transformation and nucleates a melanoma. No one genetic aberration has been identified as the sole cause for malignant transformation, rather it is thought that melanoma is initiated by aggregated genetic changes within different loci. Genes that are frequently changed in melanoma include those which code for p16, B-raf, N-ras, PTEN, p53, Mitf, c-Kit, and Mc1r. Consequently, these genes are high on the list of suspects whose mutation, deletion, or amplification are thought to contribute to melanocytic transformation.