Tumorigenic moisturizing creams: mechanisms and active constituents

描述（由申请人提供）：阳光诱导的非黑色素瘤皮肤癌是美国最常见的癌症，每年有超过一百万例病例（几乎与所有其他癌症的病例总和一样多），近年来这些癌症的数量一直在增加。这种增长的原因尚不清楚。虽然大多数非黑色素瘤皮肤癌可以通过手术切除治愈，但这些癌症的死亡仍在继续发生。 我们已经开发了一种新的动物模型，类似于人类的阳光诱导的皮肤癌，这些人在生命早期接受了大量的阳光照射，在生命后期在没有额外的阳光照射的情况下患上了皮肤癌。在该模型中，用低剂量UVB处理SKH-1小鼠20周，并停止UVB照射。这些小鼠没有肿瘤，但在没有进一步UVB照射的情况下，它们在接下来的几个月内具有发展皮肤肿瘤的高风险（高风险小鼠），并且这些小鼠可用于评估致瘤和化学预防剂。 在最近的一项研究中，我们发现，在没有进一步UVB照射的情况下，将几种不同的市售保湿霜局部应用于UVB预处理的高危小鼠，会增强皮肤肿瘤的形成（肿瘤促进作用）。(See Lu等人在J. Invest. Dermatol. 129：468-475，2009）。我们假设这些致瘤性商业乳膏在肿瘤形成之前和UVB预处理的高危小鼠的肿瘤中增加炎症，刺激增殖，并抑制表皮细胞凋亡。我们还假设局部应用十二烷基硫酸钠，矿物油和凡士林（我们研究的促肿瘤保湿霜和许多其他家庭护理产品中存在的物质）将在UVB预处理的高危小鼠中致瘤。我们的具体目标是：1.分析局部应用促肿瘤保湿霜及其成分对经UVB预处理2周的SKH-1小鼠表皮中的炎症、增殖和凋亡的影响（短期研究）。 2.评价UVB预处理的高危小鼠局部应用促肿瘤保湿霜对肿瘤形成前表皮以及荷瘤小鼠肿瘤和远离肿瘤的表皮区域的炎症、增殖和凋亡的影响（使用储存的石蜡块进行的机制研究）。 3.评估局部应用十二烷基硫酸钠、矿物油和矿脂对UVB预处理高危小鼠的促肿瘤活性。 公共卫生相关性：在美国，常用的保湿霜、化妆品和其他局部家庭护理产品可能导致非黑色素瘤皮肤癌的高发病率和不断增加的发病率（每年超过100万例），这是一个重要的问题，需要仔细的机制和流行病学研究。本建议试图确定在常用的保湿霜，可能会增加UVB诱导的致癌作用，并评估这些霜及其成分的致瘤作用的潜在机制的致瘤成分。我们的研究将有助于确定可用于设计流行病学研究的风险生物标志物，我们预计我们的研究也将导致设计更安全的保湿霜，化妆品和其他局部使用的家庭护理产品。

DESCRIPTION (provided by applicant): Sunlight-induced nonmelanoma skin cancer is the most revalent cancer in the United States with more than one million cases per year (almost as many cases as for all of the other cancers combined), and the number of these cancers has been increasing in recent years. The reasons for this increase are not known. Although most non-melanoma skin cancers are cured by surgical removal, deaths from these cancers continue to occur. We have developed a novel animal model that resembles sunlight-induced skin cancer in humans who receive heavy exposure to sunlight early in life and who develop skin cancer later in life in the absence of additional heavy sunlight exposure. In this model, SKH-1 mice are treated with low doses of UVB for 20 weeks and UVB irradiation is stopped. These mice have no tumors, but they have a high risk of developing skin tumors over the next several months in the absence of further UVB irradiation (high risk mice), and these mice can be used for evaluating tumorigenic and chemopreventive agents. In a recent study, we found that topical applications of several different commercially available moisturizing creams to UVB-pretreated high-risk mice, in the absence of further UVB irradiation, enhanced the formation of skin tumors (tumor-promoting effect). (See Lu et al in J. Invest. Dermatol. 129: 468-475, 2009.) We hypothesize that these tumorigenic commercial creams increase inflammation, stimulate proliferation, and inhibit apoptosis in the epidermis prior to tumor formation and in tumors of UVB pretreated high-risk mice. We also hypothesize that topical applications of sodium lauryl sulfate, mineral oil and petrolatum (substances present in the tumor-promoting moisturizing creams that we studied and in many other home care products) will be tumorigenic in UVB-pretreated high-risk mice. Our specific aims are: 1. Analyze the effects of topical applications of tumor-promoting moisturizing creams and their constituents on inflammation, proliferation, and apoptosis in the epidermis of SKH-1 mice pretreated with UVB for 2 weeks (short-term studies). 2. Evaluate the effects of topical applications of tumor-promoting moisturizing creams in UVB pretreated high risk mice on inflammation, proliferation, and apoptosis in the epidermis prior to tumor formation and in tumors and areas of the epidermis away from tumors in tumor-bearing mice (mechanism studies utilizing stored paraffin blocks). 3. Evaluate the tumor-promoting activity of topical applications of sodium lauryl sulfate, mineral oil and petrolatum in UVB-pretreated high-risk mice. PUBLIC HEALTH RELEVANCE: The possibility that commonly used moisturizing creams, cosmetics and other topical home care products contribute to the high and increasing incidence of nonmelanoma skin cancer in the United States (more than one million cases per year) is an important issue requiring careful mechanistic and epidemiology studies. The present proposal attempts to identify tumorigenic components in commonly used moisturizing creams that may increase UVB-induced carcinogenesis and to assess potential mechanisms for the tumorigenic effects of these creams and their constituents. Our study will be helpful for determining biomarkers of risk that can be used for designing epidemiology studies, and we anticipate that our research will also result in the design of safer moisturizing creams, cosmetics and other topically used home care products.