Growing evidence indicates that tumor progression, including the acquisition of the metastatic phenotype, is a consequence of a series of sequential genetic lesions that include activating mutations of oncogenes and loss or inactivation of tumor suppressor genes (TSG). In the model of chemically induced mouse skin cancer, oncogene activation has been linked to tumor initiation and there is no clear evidence of their participation in later stages of tumor development. Consequently we hypothesize that TSG could participate in this process. This is based on mounting evidence originating in other model systems and human tumors that points to the role of TSG such as p53, and the retinoblastoma gene in the development of epithelial neoplasia. The principal objective of this proposal is to detect known and putative TSG in normal keratinocytes and skin tumor cells produced by different protocols of chemical carcinogenesis and to demonstrate probable alterations that could contribute to tumor progression. In order to achieve this objective we plan to: 1) Detect and determine differences in known and putative tumor suppressor genes and their expression in normal skin, primary mouse skin tumors and tumor-derived cell lines. The known TSG, RB-1 and p53, as well as the putative ras related TSG Krev-1 and NTS-1 will be investigated. 2) Study the role of TSG in skin tumor invasion and metastasis. The possibility that TSG intervene in the process of tumor progression will be investigated in metastatic skin tumors and highly tumorigenic cell lines. 3) Introduce by transfection or retroviral-mediated gene transfer one or more of the TSG into mouse skin carcinoma cell lines. The eventual reversion of the malignant phenotype will be investigated in vitro and in vivo. 4) Evaluate the eventual effects of tumor progressors (agents that accelerate mouse skin tumor progression e.g., benzoyl peroxide, NMU) on TSG and their expression.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Research Project (R01)
Project #
1R01CA053713-01
Application #
3198377
Study Section
Metabolic Pathology Study Section (MEP)
Project Start
1991-01-01
Project End
1995-12-31
Budget Start
1991-01-01
Budget End
1991-12-31
Support Year
1
Fiscal Year
1991
Total Cost
Indirect Cost
Name
Fox Chase Cancer Center
Department
Type
DUNS #
042250712
City
Philadelphia
State
PA
Country
United States
Zip Code
19111
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