Review Article

Extrafollicular Dermal Melanocyte Stem Cells and Melanoma

Figure 1

A model summarizing how important signalling pathways, and some DNA repair and transcription factors in melanocyte and keratinocyte stem cells or in their derivatives, might be impaired by UV irradiation, leading to the development of melanoma stem cells. Lower levels of the repair enzyme, human 8-oxoguanine-DNA glycosylase (OGGI), UV-damaged DNA-binding protein (UV-DDB), along with an attenuated p53 apoptotic response will increase survival of cells in the melanocyte lineage with mutational loads and genetic instability (GI). Increased expression of Nrf2 will further prevent UVA-induced apoptosis and thus promote survival of cells, increasing the retention and accumulation of mutations. Mutations in critical genes for transcription factors regulating melanocyte stem cell proliferation and differentiation (MITF, PAX3 and SOX10) or in signaling pathways (Notch and Wnt) will have profound and cascading effects on those pathways regulating the quiescence, expansion and differentiation of melanocyte stem cells. Increased β-catenin stimulate proliferation, abnormal differentiation, and self-renewal of melanocyte stem cells. Alterations in c-kit tyrosine kinase receptor (KIT) and its ligand, (stem cell factor (SCF)), will alter the homeostatic balance between keratinocytes and melanocytes. All of these factors may interact and contribute to the transformation of an epidermal MSC into a melanoma stem cell.
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