During neoplastic progression in experimental models in vivo, tumor promoters cause the evolution of clonal cell populations with an altered phenotype from within an otherwise normal tissue. The mechanisms responsible for promoter-driven neoplastic progression are largely unknown, and the significance of most of the reported promoter-induced phenotypic alterations in initiating, maintaining or expanding the preneoplastic cell population is not known. In mouse skin promoted with phorbol esters, recent data from this laboratory has indicated that a key enzyme in polyamine metabolism, ornithine decarboxylase (ODC), is altered in its enzymatic properties and its cellular regulation in benign tumors compared to normal tissue. It is our hypothesis that aberrant regulation of this important regulatory enzyme confers on cells so endowed a selective advantage for progression towards a more abnormal phenotype. In this proposal, this hypothesis will be tested and the molecular mechanism responsible for the aberrant regulation of this protein determined. In mouse skin in vivo, the regulation of ODC gene expression will be studied at several levels and the biologic properties of cell populations expression abnormal regulation of ODC contrasted to cell populations whose ODC regulation is normal. In an in vitro model system, normal and transformed hamster fibroblasts, the mechanisms responsible for the differential regulation of ODC expression in this system, especially after phorbol ester treatment, will be studied. Finally, the regulation of ODC gene expression in normal, premalignant and malignant human tissue will be investigated. The organ sites to be studied are skin and colon, tissues in which there is suggestive evidence from experimental and/or human systems that ODC activity (at least) is quantitatively different in normal vs. tumor tissue. Our eventual goal is to understand basic mechanisms of aberrant gene expression in preneoplastic and neoplastic cells and identify potential targets for therapeutic intervention in neoplastic progression.
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| Prescott, J; Du, M; Wong, J Y Y et al. (2012) Paternal age at birth is associated with offspring leukocyte telomere length in the nurses' health study. Hum Reprod 27:3622-31 |
