Transgenic mouse models of human cancers present the opportunity to elucidate pathways of cancer development, through which a normal cell in its natural microenvironment is progressively converted into an aberrant cancer, acquiring characteristics that contribute to the resultant cancer phenotype. This laboratory has developed transgenic mice that express the human papillomavirus type 16 (HPV-16) oncogenes in basal keratinocytes; these 'K14-HPV16' mice develop squamous cell carcinomas of the epidermis, and, in concert with chronic estrogen treatment, cervical and vaginal squamous cancers. Both epidermal and cervical pathways to carcinoma are characterized by progression through histologically distinct stages. In humans, the oncogenes of HPV16 and related HPV subtypes are found in a majority of cervical carcinomas, and in premalignant lesions thought to precede those cancers. The overall goal of this proposal is to characterize and assess the function contributions of cellular parameters that appear during tumor progression in this mouse model of squamous carcinoma, parameters hypothesized to be influencing the developing cancers in distinct and complementary ways to those directly effected by the human viral oncogenes; these parameters are: 1. Selective upregulation of a fibroblast growth factor receptor in aggressive, metastatic cancers. 2. The acquired resistance to induction of apoptosis, the process of programmed cell suicide, which is implicated as a growth-limiting mechanism that must be controlled by successful cancers. 3. The upregulation of telomerase, an enzyme that protects the ends of chromosomes during cell proliferation and thereby sustains tumor growth potential, in aggressive epidermal carcinomas. 4. The apparent capability of CD8+ T cells to restrict the appearance of invasive squamous cancers. 5. Dermal infiltration by mast cells in epidermal dysplasias, and their role in malignant progression. The long term goal is to define the pathways to epidermal and cervical cancer in mice expressing oncogenes implicated in a relevant human cancer, identifying the critical cellular and molecular parameters governing progression, and eventually utilizing the knowledge of mechanism to design therapeutic and preventative interventions that can be evaluated in this preclinical model of human carcinogenesis.
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