Host Defense Mechanisms in Melanoma Pathogenesis

黑色素瘤发病机制中的宿主防御机制

• 批准号: 9290943
• 负责人: Craig A Elmets
• 金额: --
• 依托单位: BIRMINGHAM VA MEDICAL CENTER
• 依托单位国家: 美国
• 财政年份: 2016
• 资助国家: 美国
• 起止时间: 2016-07-01 至 2020-06-30
• 项目状态: 已结题
• 来源: https://reporter.nih.gov/project-details/9290943
• 关键词: Animal Model; Animals; Area; Aromatic Polycyclic Hydrocarbons; Automobiles; Basic Science; Biochemical; Biological Markers; C57BL/6 Mouse; Carcinogens; Cells; Cellular Immunity; Cessation of life; Charcoal; Chemopreventive Agent; Clinical; Cutaneous; Development; Diagnosis; Disease; Dysplastic Nevus; Environmental Carcinogens; Etiology; Exposure to; Food; Fossil Fuels; Foundations; Frequencies; General Population; Genes; Growth and Development function; Host Defense Mechanism; Human; Immune; Immune system; Immunization; Immunologic Factors; Immunologic Monitoring; Immunologics; Immunotherapeutic agent; Incidence; Interleukin-17; Investigation; Lesion; Malignant Neoplasms; Medical Genetics; Melanocytic Neoplasm; Melanocytic nevus; Metastatic Melanoma; Methods; Military Personnel; Modality; Modeling; Molecular; Mus; Mutation; Neoplasm Metastasis; Neoplasms; Oncogenes; Pathogenesis; Patients; Pigments; Pre-Clinical Model; Premalignant; Prevention; Prevention strategy; Procedures; Reporting; Risk; Role; Skin Carcinoma; Sun Exposure; T-Lymphocyte; Testing; Time; Tissues; Tobacco smoke; Transgenes; Transgenic Mice; Ultraviolet Rays; Vaccination; Veterans; base; carcinogenicity; cytokine; environmental mutagens; human disease; immunological intervention; in vivo Model; interleukin-23; lymph nodes; melanocyte; melanoma; method development; mouse model; mutant; novel; prevent; promoter; protective effect; public health relevance; ras Proteins; skin squamous cell carcinoma; translational study; trend; tumor growth; vaccination strategy

 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.

 描述（由申请人提供）： 黑色素瘤比任何其他皮肤恶性肿瘤都多。对于那些广泛接触其两个最常见的病因因素的退伍军人来说，这是一个特殊的问题 - 紫外线辐射和致癌多芳族碳氢化合物，并且已被证明有这种恶性肿瘤的风险增加。晚期和转移性黑色素瘤的治疗取得了长足的进步。许多黑色素瘤开始是前塑性障碍的NEVI，几个月到几年后，它发展成为侵入性肿瘤。尽管事实上有一个较长的滞后时期，但前塑性不良的NEVI变成了侵入性黑色素瘤，但预防方法的发展发展几乎没有进展。这至少部分是由于几乎没有动物的事实 可以评估预防策略的模型。我们创建了一种黑色素瘤发育模型，在该模型中，猪的病变始于肿瘤性异增生性NEVI，然后演变为浸润性黑色素瘤，从而转移至淋巴结。 P16中的RAS突变和缺失，在人类黑色素瘤中都存在于PIKENTED病变中。这与其他黑色素瘤的其他鼠模型形成鲜明对比，黑色素瘤迅速发育而没有事先存在异型性NEVI。此外，在这些其他模型中很难研究宿主免疫反应，因为突变基因存在于转换启动子所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阻止了该模型中黑色素瘤的发展。我们还发现，针对突变的RAS蛋白的小鼠免疫将防止表达突变发育突变的非黑色素瘤皮肤癌。在此提案中，我们将检验以下假设：细胞因子IL-23可防止黑色素瘤及其转移酶。我们将首先评估参与黑色素瘤发病机理的分子改变是否在IL-23KO小鼠中更频繁地发生，以及是否可以将IL-23的给药用作免疫预防剂。然后，我们将表征IL-17在黑素细胞肿瘤起源中的作用。最后，我们将确定我们成功地采取了用于预防非黑色素瘤皮肤癌的免疫程序，可用于预防肿瘤生长和黑色素瘤的转移潜力。该应用的发现可能构成了这种恶性肿瘤的新免疫预防策略的基础，而这种恶性肿瘤随着退伍军人的频率增加而发生。