A melanin-independent interaction between Mc1r and Met signalling pathways is required for HGF-dependent melanoma

Melanocortin 1 receptor (MC1R) signaling stimulates black eumelanin production through a cAMP-dependent pathway. MC1R polymorphisms can impair this process, resulting in a predominance of red phaeomelanin. The red hair, fair skin and UV sensitive phenotype is a well-described melanoma risk factor. MC1R polymorphisms also confer melanoma risk independent of pigment. We investigated the effect of Mc1r deficiency in a mouse model of UV-induced melanoma. C57BL/6-Mc1r+/+-HGF transgenic mice have a characteristic hyperpigmented black phenotype with extra-follicular dermal melanocytes located at the dermal/epidermal junction. UVB induces melanoma, independent of melanin pigmentation, but UVA-induced and spontaneous melanomas are dependent on black eumelanin. We crossed these mice with yellow C57BL/6-Mc1re/e animals which have a non-functional Mc1r and produce predominantly yellow phaeomelanin. Yellow C57BL/6-Mc1re/e-HGF mice produced no melanoma in response to UVR or spontaneously even though the HGF transgene and its receptor Met were expressed. Total melanin was less than in C57BL/6-Mc1r+/+-HGF mice, hyperpigmentation was not observed and there were few extra-follicular melanocytes. Thus, functional Mc1r was required for expression of the transgenic HGF phenotype. Heterozygous C57BL/6-Mc1re/+-HGF mice were black and hyperpigmented and, although extra-follicular melanocytes and skin melanin content were similar to C57BL/6-Mc1r+/+-HGF animals, they developed UV-induced and spontaneous melanomas with significantly less efficiency by all criteria. Thus, heterozygosity for Mc1r was sufficient to restore the transgenic HGF phenotype but insufficient to fully restore melanoma. We conclude that a previously unsuspected melanin-independent interaction between Mc1r and Met signaling pathways is required for HGF-dependent melanoma and postulate that this pathway is involved in human melanoma

UV-B radiation: a health risk in the Arctic?

Seasonal stratospheric ozone depletion in the Arctic has raised the question of whether the associated increases in ultraviolet-B (290-320 nm) constitute a significant health risk in Arctic populations. Increases in skin cancer in Europe and the USA from excess UV-B resulting from ozone depletion have been predicted. Skin cancer is, however, rare in Inuit populations. UV-B also causes a selective down regulation of the immune system which may be a natural regulatory mechanism evolved to prevent autoimmune attack on sunlight-altered skin. The action spectrum for UV-B immunosuppression implicated a unique skin photoreceptor molecule, urocanic acid (UCA), which isomerizes from the trans to the cis isomer on exposure to UV-B, the cis isomer being immunosuppressive. This form of immunosuppression is important in skin cancer and possibly in infectious diseases. The epidemiology of non-Hodgkin's lymphoma shows a relationship with UV exposure, postulated to be via the immunosuppressive effects of UV-B. Cancers which show an excess in Inuit populations include nasopharyngeal and salivary gland cancer. Genetic factors appear to be involved, but these are thought to be virally related cancers possibly associated with the high viral load in these populations. In several studies on non-Arctic populations, salivary gland cancer has been linked to ultraviolet exposure. A potential role for UV-B exposure in these cancers in the Arctic needs to be explored. In view of the high levels of POPS in some Arctic regions, potential interactions between the immunosuppression caused by some of these pollutants and the effects of UV-B need to be investigated

Functional melanocortin 1 receptor Mc1r is not necessary for an inflammatory response to UV radiation in adult mouse skin.

The G-protein coupled receptor, Mc1r, plays a major role in pigment production and has been reported to be important in the inflammatory response. We have investigated the effect of deficiency in Mc1r on UV inflammation. Mice on the same genetic background were used- C57BL/6-c (albino), C57BL/6 (black), C57BL/6-Mc1r(e/e) deficient (yellow). FACS analysis of disaggregated skin showed a similar dose-dependent increase in Ly6G(+) and CD11b(+) cells in response to UV radiation in all groups. No differences in UV-induced edema or in DNA damage were detected between groups. The contact hypersensitivity response, neonatal immune tolerance and UV immunosuppression were all similar in C57BL/6 and C57BL/6-Mc1r(e/e) mice. We conclude that the absence of Mc1r does not impair the inflammatory response to UV radiation or the generation of immunosuppression

Human thoracic duct cannulation: Manipulation of tumor‐specific blocking factors in a patient with malignant melanoma

Thoracic duct lymph was drained for 28 days from a patient with disseminated malignant melanoma. Lymphocytes were separated from the lymph by centrifugation, and returned to the patient daily. Biochemical and hematologic parameters were monitored in blood and lymph, and were maintained at satisfactory levels throughout the period. Cell‐mediated immunity and specific blocking activity directed against melanoma antigens were examined by the leukocyte adherence inhibition test. Blocking factors in drained lymph fell to undetectable levels after 6 days' thoracic duct drainage, whereas it took 9 days for serum blocking factors to fall to similar levels. Peripheral blood leukocytes demonstrated cell‐mediated immunity against melanoma antigens before and throughout the period of drainage, except for the immediate postoperative period. Within 24 hours of closure of the thoracic duct fistula, serum blocking activity had returned, and 17 days later the patient died