Melanoma, Melanin, and Melanogenesis: The Yin and Yang Relationship

Abstract

Melanin pigment plays a critical role in the protection against the harmful effects of ultraviolet radiation and other environmental stressors. It is produced by the enzymatic transformation of L-tyrosine to dopaquinone and subsequent chemical and biochemical reactions resulting in the formation of various 5,6-dihydroxyindole-2-carboxylic acid (DHICA) and 5,6-dihydroxyindole (DHI) oligomers—main constituents of eumelanin, and benzothiazine and benzothiazole units of pheomelanin. The biosynthesis of melanin is regulated by sun exposure and by many hormonal factors at the tissue, cellular, and subcellular levels. While the presence of melanin protects against the development of skin cancers including cutaneous melanoma, its presence may be necessary for the malignant transformation of melanocytes. This shows a complex role of melanogenesis in melanoma development defined by chemical properties of melanin and the nature of generating pathways such as eu- and pheomelanogenesis. While eumelanin is believed to provide radioprotection and photoprotection by acting as an efficient antioxidant and sunscreen, pheomelanin, being less photostable, can generate mutagenic environment after exposure to the short-wavelength UVR. Melanogenesis by itself and its highly reactive intermediates show cytotoxic, genotoxic, and mutagenic activities, and it can stimulate glycolysis and hypoxia-inducible factor 1-alpha (HIF-1α) activation, which, combined with their immunosuppressive effects, can lead to melanoma progression and resistance to immunotherapy. On the other hand, melanogenesis-related proteins can be a target for immunotherapy. Interestingly, clinicopathological analyses on advanced melanomas have shown a negative correlation between tumor pigmentation and diseases outcome as defined by overall survival and disease-free time. This indicates a “Yin and Yang” role for melanin and active melanogenesis in melanoma development, progression, and therapy. Furthermore, based on the clinical, experimental data and diverse effects of melanogenesis, we propose that inhibition of melanogenesis in advanced melanotic melanoma represents a realistic adjuvant strategy to enhance immuno-, radio-, and chemotherapy.

Amelanotic Uveal Melanomas Evaluated by Indirect Ophthalmoscopy Reveal Better Long-Term Prognosis Than Pigmented Primary Tumours—A Single Centre Experience

“…The reason for such contrasting observations may be the ambivalent role of melanin and melanogenesis in the development of melanoma [ 39 ].…”

Necroptosis-associated classification combined with tumor microenvironment characteristic analysis of cutaneous melanoma

“…Melanogenesis is the most characteristic feature of melanoma 10 . Cellular melanogenesis could affect the regulated cell death of melanoma cells.…”

“…In this study, the pigmentation score of the high-risk group was visibly higher than those of the low-risk group. In addition, melanogenesis was associated with clinical outcomes of melanoma patients 10 . Brożyna et al 47 indicated that patients with melanotic melanomas have the significantly shorter OS and DFS than those with amelanotic lesions.…”

“…Melanin pigmentation regulates the expression of multiple genes and plays a critical role in many cellular processes in melanoma cells 10 – 12 . It can affect the behavior of melanoma cells, their surrounding environment, susceptibility to the therapy, and viability of immune cells 10 , 13 , 14 .…”

“…Melanin pigmentation regulates the expression of multiple genes and plays a critical role in many cellular processes in melanoma cells 10 – 12 . It can affect the behavior of melanoma cells, their surrounding environment, susceptibility to the therapy, and viability of immune cells 10 , 13 , 14 . Slominski et al 11 reported that induction of melanogenesis is associated with marked upregulation of HIF-1α and HIF-1-dependent pathways, resulting in increased aggressiveness of melanoma.…”