Association between melanoma and dermal mast cell prevalence in sun-unexposed skin.

BACKGROUND: Both exposure to intermittent intense sunlight during childhood and ultraviolet (UV) radiation-induced immunomodulation have been directly associated with melanoma development. In mice, the prevalence of dermal mast cells determines susceptibility to UVB-induced systemic suppression of contact hypersensitivity responses and thus may affect immunological responses to melanoma antigens. OBJECTIVES: To determine the relevance of murine studies of dermal mast cell prevalence to human melanoma pathogenesis. METHODS: The prevalence of mast cells was examined in sun-unexposed buttock skin of 45 melanoma patients and 68 control volunteers who had no history of skin cancer development. Buttock skin was studied because mast cell prevalence is stable with ageing and the confounding effects of environmental UV exposure are minimized. RESULTS: Using tissue immunostaining, the buttock skin from melanoma patients had a significantly higher dermal mast cell prevalence (mean +/- SEM 38 +/- 2 mast cells mm(-2)) than controls (32 +/- 2 mast cells mm(-2)) (P = 0.02). Analysis by binary logistic regression showed that the association between mast cell prevalence and melanoma outcome was not significantly altered by skin phototype. CONCLUSIONS: The immunomodulatory effects of mast cell products in UV-irradiated skin may contribute significantly to the initiation and development of human cutaneous malignant melanoma.

Topical retinoic acid enhances, and a dark tan protects, from subedemal solar-simulated photocarcinogenesis.

Studies into the effects of topical retinoic acid on photocarcinogenesis have yielded ambiguous findings. This may be due to different Experimental protocols and ultraviolet spectra. Retinoic acid is commonly used for a range of dermatologic conditions, and therefore it is important to resolve whether it affects skin tumor formation. To address this issue we used a protocol to mimic as closely as possible human use of retinoic acid. Two mouse strains were used: Skh:HR-1 (albino) and Skh:HR-2 (lightly pigmented). The pigmented mice more closely resemble Caucasian skin as they develop a light tan in response to ultraviolet radiation. This tan is greatly augmented by retinoic acid. As these are congenic mice, any differences can be attributed to the development of a tan. Mice were exposed to solar-simulated ultraviolet radiation, followed by treatment with 0.05% retinoic acid. This modeled exposure to sunlight during the day followed by retinoic acid treatment and a night-time period in the absence of sunlight. As it is recommended that ultraviolet exposure is minimized when using topical retinoic acid, the mice were only exposed to one-third of minimal edemal dose of ultraviolet radiation per day. This retinoic acid protocol augmented photocarcinogenesis. Retinoic acid decreased the latency period, reduced the probability that a mouse would survive without a tumor, and increased the number of tumors per mouse. All tumors induced were squamous cell carcinomas, and the skin between the tumors on mice treated with retinoic acid was found to contain carcinoma in situ upon histologic diagnosis. The light tan of the solvent-treated pigmented mice did not provide any protection, whereas the dark tan, which developed in Skh:HR-2 mice in response to retinoic acid, reduced photocarcinogenesis but did not overcome the augmenting effect of retinoic acid. Thus, using this experimental design, topical retinoic acid augmented photocarcinogenesis, and the ability to develop a dark but not light tan provided some, but limited, protection.

Effect of inhibitors of oxygen radical and nitric oxide formation on UV radiation-induced erythema, immunosuppression and carcinogenesis.

We investigated whether supplementation of a sunscreen containing the UVB absorber 2-ethyl-hexyl-methoxycinnamate (cinnamate) with oxygen radical inhibitors (ORI) would improve protection from sunburn, immunosuppression and carcinogenesis. Mice were exposed to solar-simulated UV radiation (ssUV) containing a mixture of UVB and UVA. In initial studies, the ORI 2,2'-dipyridyl and N(G)-monomethyl-L-arginine acetate (L-NMMA) were shown to prevent UVA-induced suppression of contact sensitivity (CS) in mice. Addition of these inhibitors to the sunscreen did not affect the sun protection factor (SPF), but lowered the level of edema when mice were exposed to ssUV. Combination of both inhibitors with the sunscreen, however, increased the SPF from 5 to 5.5. The immune protection factor (IPF) of the sunscreen was only 1.18, but addition of neither dipyridyl nor L-NMMA singly or in combination measurably improved immune protection. However, the ORI improved the ability of the sunscreen to prevent carcinogenesis. The results indicate that reactive oxygen or nitrogen species produced in response to UV radiation are important for erythema, immunosuppression and carcinogenesis, and addition of inhibitors improves the protective capacity of sunscreens.