The design of model systems of chemical carcinogenes has been extremely useful in advancing the understanding of the mechanisms of tumorigenesis. We have been using the polycyclic aromatic hydrocarbon DMBA to induce in rabbits the formation of skin tumors. A protocol was utilized to obtain a particular type of tumor, keratoacanthoma, that is benign and self-regressing. This proposal approaches the less frequently studied field of benign tumors with the added interesting point of looking into a tumor regression process. Already completed work has identified activated H-ras as an important component of this system and using a combination of pathology, molecular biology and immunohistochemistry the different phases of this tumor system will be investigated. Using PCR amplification and oligonucleotide hybridization the early stages of tumor development will be analyzed as well as the progression from keratoacanthoma to squamous cell carcinoma. Parallel studies with samples from human keratoacanthoma will be undertaken to correlate them with the animal studies. The role of the H-ras oncogene in the process of tumor regression will be studied in great detail making use of specific antibodies for the mutant protein. To complete the analysis of the regression process, retinoids and TGF beta, agents of epithelial differentiation will be introduced in the system to study their correlation with H-ras oncogene expression. The study of this benign and self-regressing tumor in both humans and the rabbit DMBA induced model should provide important information on the role of ras oncogenes in the different stages of tumorigenesis.
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