The Biology of the Melanocyte

Introduction

Pigmentation of the hair and skin is not only one of the most striking visible human traits, it also represents a major determinant of sensitivity to ultraviolet radiation (UVR) and risk of both melanoma and non-melanoma skin cancer (NMSC). An appreciation of the biology of the melanocyte is required in order to understand the physiology of normal constitutive and facultative pigmentation, as well as the biology of melanoma and the pathophysiology of disorders of pigmentation that predispose affected individuals to the development of skin cancer. A classic example of the latter is type 1 oculocutaneous albinism (OCA), a genodermatosis in which pigmentary dilution of the skin, hair and eyes due to absent or decreased tyrosinase activity results in a markedly increased risk of UVR-induced squamous cell carcinoma. With regard to melanoma, knowledge of melanosomal proteins such as tyrosinase, gp100/Pmel17 and MelanA/MART1 is critical to the use of immunohistochemical methods of diagnosis, the understanding of immune responses such as melanoma-associated leukoderma, and the development of vaccine therapies. Furthermore, the elucidation of signaling pathways for proliferation and differentiation in normal melanocytes is fundamental to the understanding of melanoma tumorigenesis and progression.

Within the realm of physiologic pigmentation, the melanocyte melanocortin-1 receptor (MC1R), via interactions with melanocyte-stimulating hormone (MSH), plays a key role in the determination of skin type and hair color. Loss-of-function variants of the MC1R gene, which result in increased production of pheomelanin rather than eumelanin, have been shown to largely account for the red hair phenotype in humans and to have a strong association with fair skin and a decreased ability to tan even in individuals without red hair. These MC1R variants also confer a risk of melanoma and NMSC that is independent of pigmentary phenotype.

History

Although human epidermal melanocytes were first observed by Riehl in 1884, the cytologic basis of human pigment production was not yet known in the early twentieth century when Raper and others defined the metabolic pathway converting tyrosine to melanin in invertebrates. In 1917, research in human melanocyte biology began when Bloch developed a technique to stain pigment-producing cells by using dihydroxyphenylalanine (DOPA) as a substrate for melanin formation. Tyrosinase was identified in human melanocytes several decades later and in 1961, Seiji et al. isolated and characterized the melanosome, the subcellular localization of melanin biosynthesis. Since that time, advances in molecular biology have facilitated the discovery of many genes, proteins and regulatory pathways important to melanogenesis.