Host Defense Mechanisms in Melanoma Pathogenesis

 描述（由申请人提供）： 黑色素瘤比任何其他皮肤恶性肿瘤造成更多的死亡。对于退伍军人来说，这是一个特别的问题，他们广泛暴露于其两个最常见的病因因素-紫外线辐射和致癌的多环芳烃，并且已被证明患有这种类型的恶性肿瘤的风险增加。晚期和转移性黑色素瘤的治疗已取得实质性进展。许多黑色素瘤开始为癌前发育不良痣，数月至数年后，进展为侵袭性肿瘤。尽管在癌前发育不良痣变成侵袭性黑色素瘤之前有一个很长的滞后期，但在预防方法的开发方面几乎没有进展。这至少部分是因为动物很少。 可以评估预防策略的模型。我们建立了一个小鼠黑色素瘤模型，其中色素性病变开始为癌前发育不良痣，然后演变为转移到淋巴结的侵袭性黑色素瘤。RAS突变和p16缺失，这两者在人类黑色素瘤中是常见的，存在于色素性病变中。这与其他小鼠黑色素瘤模型形成对比，在其他小鼠黑色素瘤模型中，黑色素瘤在没有发育不良痣的情况下迅速发展。此外，在这些其他模型中研究宿主免疫应答是困难的，因为突变基因存在于由转基因启动子定义的所有组织特异性细胞中。我们已经观察到细胞因子IL-23在该模型中阻止黑素瘤的发展。我们还发现，针对突变RAS蛋白的小鼠免疫将防止表达突变的非黑色素瘤皮肤癌的发展。在本提案中，我们将测试细胞因子IL-23可以预防黑色素瘤及其转移的假设。我们将首先评估参与黑色素瘤发病机制的分子改变是否在IL-23 KO小鼠中更频繁地发生，以及IL-23的施用是否可以用作免疫预防剂。然后，我们将描述IL-17在黑素细胞肿瘤发生中的作用。最后，我们将确定我们成功用于预防非黑色素瘤皮肤癌的免疫程序是否可用于预防肿瘤生长和黑色素瘤的转移潜力。这一应用的发现可能为这种恶性肿瘤的新免疫预防策略奠定基础，这种恶性肿瘤在退伍军人中发生的频率越来越高。

 DESCRIPTION (provided by applicant): Melanomas are responsible for more deaths than any other cutaneous malignancy. They are a particular problem for Veterans who have extensive exposure to its two most common etiologic factors - ultraviolet radiation and carcinogenic polyaromatic hydrocarbons, and who have been shown to be at increased risk for this type of malignancy. There has been substantial progress in the treatment of advanced and metastatic melanomas. Many melanomas begin as premalignant dysplastic nevi, which after months to years, progress to become progress to become invasive neoplasms. Despite the fact that there is a long lag period before premalignant dysplastic nevi become invasive melanomas, there has been little headway in the development of methods for their prevention. This is due at least in part to the fact that there are few animal models that can evaluate preventive strategies. We have created a murine model of melanoma development in which pigmented lesions begin as preneoplastic dysplastic nevi and then evolve into invasive melanomas that metastasize to lymph nodes. RAS mutations and deletions in p16, both of which are common in human melanomas are present in the pigmented lesions. This contrasts with other murine models of melanoma, in which melanomas rapidly develop without the prior existence of dysplastic nevi. In addition, it is difficult to study host immune responsesin these other models, because mutant genes are present in all tissue specific cells as defined by the transgene promoter. We have observed that the cytokine IL-23 prevents the development of melanoma in this model. We have also found that immunization of mice against the mutant RAS protein will prevent non-melanoma skin cancers that express the mutation from developing. In this proposal, we will test the hypothesis that the cytokine IL-23 protects against melanomas and their metastases. We will first evaluate whether molecular alterations that participate in the pathogenesis of melanoma occur more frequently in IL-23KO mice and whether administration of IL-23 can be used as an immunopreventive agent. We will then characterize the role of IL-17 in the genesis of melanocytic tumors. Last, we will determine whether the immunization procedure we have successfully employed for prevention of non-melanoma skin cancers can be used to prevent tumor growth and the metastatic potential of melanomas. The findings of this application may form the foundation for new immunopreventive strategies for this malignancy that is occurring with increasing frequency in Veterans.