The goal of this study is to determine whether local immunologic mechanisms play is role in host resistance against the induction, growth, and metastasis of primary skin cancers and whether alterations in cutaneous immune cells by carcinogenic agents contribute to the pathogenesis of skin cancer.
The specific aims are 1) to characterize changes in the number, appearance, and functional activity of cutaneous immune cells following treatment of mice with various carcinogens; 2) to determine the function of certain normal immunologic components of mouse skin; and 3) to assess the significance of changes in immunologic parameters for the induction, growth, progression, and metastasis of primary skin cancers. Primary skin cancers will be produced in Sencar mice with n-methyl-n-nitrosoquanidine, an agent that produces metastatic squamous carcinomas, and with benzpyrene, an agent that produces localized carcinomas. Two-stage carcinogenesis using dimethylbenzathracene and phorbol myristate acetate will be compared in newborn C57B1 mice, which develop tumors from this treatment, and in adult C57V1 mice, which are resistant to tumor development. Skin from mice undergoing carcinogenesis will be examined for the presence of epidermal Langerhans cells and Thy-1+ dendritic epidermal cells. Immune function will be tested using contact hypersensitivity in vivo and alloantigen presentation in vitro. Cells involved in the presentation of cutaneous antigens to effector and suppressor immune pathways will be identified. Primary tumors will be characterized histologically, immunologically, and for metastatic potential in NK-deficient nude mice. Hypotheses concerning the role of cutaneous immune cells in tumor development and progression will be tested by selectively increasing or decreasing populations of immune cells in the skin and assessing the effect on tumor incidence, progression, and metastasis.
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