Importance of Gender in the Chemoprevention of UV induced Skin Cancer

描述(由申请人提供)： 非黑色素瘤皮肤癌(NMSC)是人类最常见的癌症形式，每年在美国发现100多万新病例。事实上，被诊断出患有某种皮肤癌的美国人将比所有其他癌症的总和还要多。流行病学研究表明，NMSC的发展存在性别差异，男性患NMSC的可能性是女性的两倍，患鳞状细胞癌的可能性是女性的三倍。这种差异被归因于生活方式的选择，因为从历史上看，男性的职业需要更多的时间在阳光下，而不太可能使用防晒霜。然而，还没有研究确定当男性和女性接受相同的累积紫外线照射时，皮肤肿瘤发生的性别差异是否会发生。我们实验室最近的研究表明，紫外线对男性和女性皮肤的损害作用的途径是不同的，在男性皮肤中阻断紫外线诱导的炎症在减少肿瘤发展方面可能不如女性皮肤有效。建议研究的主要目的是确定男性和女性皮肤对UVB反应的潜在机制差异，并确定性别在紫外线诱导的鳞状细胞癌的启动、促进和进展方面的差异。提出了两个特定的目标来验证这一假说，即男性皮肤中抗氧化剂活性水平的降低、活性氧(ROS)产生的增加和DNA氧化损伤的增加不仅影响对UVB照射的急性皮肤反应，而且也是导致NMSC发生的性别差异的原因之一。具体目标1的研究将确定抗氧化剂和炎症产生的活性氧物种在未受辐射的皮肤和在雄性和雌性SKH-1小鼠皮肤的急性UVB诱导的炎症反应期间对DNA损伤的不同贡献。在特定目标2中的研究旨在确定局部治疗与抗氧化剂(维生素E)、抗炎药(Celebrex)、天然抗氧化剂/抗炎剂(黑树莓提取物)或两者的组合对紫外线诱导的雄性与雌性SKH-1小鼠肿瘤的启动、促进和进展的不同化学预防效果。更清楚地了解男性和女性皮肤的差异，最终将有助于制定更有针对性的预防和治疗战略。与公众健康相关：暴露在紫外线下被认为是皮肤癌发生的唯一最重要的病因因素。流行病学研究表明，非黑色素瘤皮肤癌(NMSC)的发病存在性别差异，男性患NMSC的可能性是女性的两倍，患鳞状细胞癌的可能性是女性的三倍。这种差异被归因于生活方式的选择，因为从历史上看，男性的职业需要更多的时间在阳光下，而不太可能使用防晒霜。我们实验室最近使用SKH-1小鼠模型进行的研究表明，男性和女性的皮肤存在固有的生物学差异。目前提案中的研究旨在了解男性和女性皮肤对急性和慢性紫外线照射的不同反应。更清楚地了解男性和女性皮肤的差异，最终将有助于为这种人类最常见的癌症制定更有针对性的预防和治疗策略。

DESCRIPTION (provided by applicant): Non-melanoma skin cancers (NMSC) are the most common form of cancer in humans, with over 1 million new cases identified in the United States each year. In fact, more Americans will be diagnosed with some form of skin cancer than all other cancers combined. Epidemiological studies have shown that there are gender differences in the development of NMSC, with men being as twice as likely to NMSC in general and three times as likely to develop squamous cell carcinomas as women. This disparity has been attributed to lifestyle choices, since males historically have had professions requiring more time out in the sun and are less likely to use sun protection. However, no studies had determined if gender differences in skin tumor development occur when males and females receive equivalent cumulative UV exposure. Recent studies from our laboratory suggest that the pathways by which UV exerts its damaging effects in male and female skin are not the same and that blocking UV-induced inflammation in male skin may not be as effective in decreasing tumor development as in female skin. The primary goals of the proposed studies are to determine the underlying mechanistic differences in the UVB response of male and female skin and to identify differences between the genders in initiation, promotion and progression of UV-induced SCC. Two specific aims are proposed to test the hypothesis that decreased levels of antioxidant activity, increased reactive oxygen species (ROS) production and increased oxidative DNA damage in male skin not only influence the acute cutaneous response to UVB exposure but also contribute to the observed gender disparity in the development of NMSC. Studies in Specific Aim 1 will determine the differential contribution of antioxidants and inflammation generated reactive oxygen species to DNA damage in unirradiated skin and during an acute UVB-induced inflammatory response in male and female Skh-1 murine skin. Studies in Specific Aim 2 are designed to determine the differential chemopreventive effects of topical treatment with an antioxidant (vitamin E), an anti-inflammatory drug (celebrex), a natural antioxidant/anti-inflammatory agent (Black Raspberry extract) or a combination of the two on UV induced tumor initiation, promotion and progression in male vs. female Skh-1 mice. A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies. PUBLIC HEALTH RELEVANCE: Exposure to Ultraviolet light is believed to be the single most important etiological factor in the development on skin cancer. Epidemiological studies have shown that there are gender differences in the development of nonmelanoma skin cancer (NMSC) with men being as twice as likely to develop NMSC and three times as likely to develop squamous cell carcinoma as women. This disparity has been attributed to lifestyle choices, since males historically have had professions requiring more time out in the sun and are less likely to use sun protection. Recent studies from our laboratory using the Skh-1 mouse model have demonstrated inherent biological differences in the skin of males and females. The studies in the current proposal are designed to understand the differential response of male and female skin to both acute and chronic ultraviolet light exposure. A clearer understanding of the differences in the skin of males and females will ultimately allow for the development of more appropriately targeted prevention and treatment strategies for this most common form of cancer in humans.