Melanin pigmentation and melanoma

In this issue of Experimental Dermatology covering melanoma, vitiligo and other pigmented lesions, we have selected papers related to melanin pigmentation and mechanisms regulating it, which is a result of a complex interaction processes between different biological functions and is controlled by a number of genes[1] as well as by hormonal and nutritional factors.[2,3] It is also clear that melanogenesis may affect the natural history of melanoma and the outcome of the therapy.[4,5] It must be emphasized that despite significant progress in melanoma diagnosis and therapy,[6,7] there is still no satisfactory therapy for metastatic disease, which poses a challenge for patients, clinicians and melanoma researchers.[8] To explain the role of pigmentation in life, studies of inducible pigmentation clarify that epidermal hyperplasia has a relevant role in UVBinduced acute DNA damage, whereas melanin pigment, which is concentrated in the basal layers of the epidermis, has a major role in protecting against UV overexposure. UVBdriven p53 responses in keratinocytes are relevant for regulation of melanin synthesis and that future steps in the pigmentation process may depend on other mechanisms, some of which are UVA related. The process of melanin synthesis is associated with a wider skin homeostasis and celltocell communication.[2] Skin melatonin metabolism can correlate with the amount of melanin present on the skin and is involved in the antioxidative pattern of the skin against UVinduced oxidative stress in induction of DNA repair mechanisms. This indicates that the process can have a pleiotropic effect on skin homeostasis. The demonstration that melanocytes and melanoma cells express functional olfactory receptors is an indication that the process is also controlled by isoprenoid molecules. These receptors belong to the Gproteincoupled receptors, as does MC1R indicating that signal transmission to these receptors is relevant in controlling cell proliferation of melanocytes. The loss of function of MC1R polymorphism is associated with fair skinned and photosensitive types and with an alteration of the DNArepairing enzymes, all dependent on cAMP activation. Studies on cAMP signalling pathways have demonstrated that MC1R signallinginduced pigment induction is independent of MC1Rmediated enhancement of genome maintenance. This is intriguing as it suggests that a possible activation of Gcoupled receptors through the induction of lipid pathways can activate nuclear receptors such as PPARγ (peroxisome proliferating activated receptor), which control several cellular functions and might be a relevant therapeutic target for pathologies of the pigmentary system. The control of skin pigmentation also depends on the balance between the production and destruction of melanosomes. This seems to be associated with a specific autophagic process providing new possible therapeutic targets for hyperpigmentation. However, melanin can also have a different side to it. Eumelanin and, to a lesser extent, pheomelanin, which are generally considered to be protective compounds, can also produce lightindependent proinflammatory and prooxidant effects on keratinocytes, indicating that melanin can play a role both in the light and in the dark. The interaction of the melanogenesis process with the surrounding cells is suggested by the molecular and histological characterization of age spots where genes associated with a hyperactivation of the dermal compartment are involved in inducing hyperpigmentation. Moreover, the relevance of the network in melanoma biology is confirmed by the combined activity of temozolomide and the mTOR inhibitor temsirolimus in metastatic melanoma, which is associated with the downregulation of the antiapoptotic protein Mcl1 and the upregulation of the WNT antagonist Dickkopf homolog 1. This factor is also produced by fibroblasts suggesting that the microenvironment might regulate the possible metastatisation of the melanoma. The fact that a subset of melanoma patients develops vitiligolike lesions and that the therapy with antiPDL1 may be associated with hypopigmented lesions has provided some insights into the pathogenesis and possible therapeutic targets of vitiligo. Moreover, the possibility of controlling the alteration of the oxidant and antioxidant status in vitiligo melanocytes appears to be a strategy capable of decreasing melanocyte damage from outside prooxidants. Finally, we have included some news on bioimaging devices, which may be the pathway to study and follow the physiological and pathological status of pigmented cells. Skin pigmentation is one of the peculiarities of human beings. The development of pigmentation is an evolutionary process related to several protective effects including UV exposure, temperature control and skin barrier function.[9,10] The skin phototype resembles a biochemical marker of an individual. All the data accumulated over the past couple of years indicate that the pigment of the skin is also an external representation of the body’s inner working.[1,2,10]