Extrafollicular dermal melanocyte stem cells and melanoma

Abstract

Recent studies suggest that extrafollicular dermal melanocyte stem cells (MSCs) persist after birth in the superficial nerve sheath of peripheral nerves and give rise to migratory melanocyte precursors when replacements for epidermal melanocytes are needed on the basal epidermal layer of the skin. If a damaged MSC or melanocyte precursor can be shown to be the primary origin of melanoma, targeted identification and eradication of it by antibody-based therapies will be the best method to treat melanoma and a very effective way to prevent its recurrence. Transcription factors and signaling pathways involved in MSC self-renewal, expansion and differentiation are reviewed. A model is presented to show how the detrimental effects of long-term UVA/UVB radiation on DNA and repair mechanisms in MSCs convert them to melanoma stem cells. Zebrafish have many advantages for investigating the role of MSCs in the development of melanoma. The signaling pathways regulating the development of MSCs in zebrafish are very similar to those found in humans and mice. The ability to easily manipulate the MSC population makes zebrafish an excellent model for studying how damage to MSCs may lead to 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.