The universal characteristic of neoplastic cells is their aberrant proliferative activity with respect to growth and proliferation in normally restrictive environments in vivo. An in vitro model system has been developed in which the progression of non-neoplastic rat liver epithelial cells through specific stages of their cell cycle is absolutely dependent on extracellular Ca2+. Neoplastic derivatives of these rat liver epithelial cells are able to transit these Ca2+-dependent restriction points and thus proliferate in vitro under a normally restrictive environment. Tumor promoters are unique substances which by themselves do not induce cancer but in conjunction with subthreshold doses of carcinogens do promote cancer cells which will not only aberrantly proliferate in vivo but also in vitro in the above mentioned model system. Tumor promoters, such as 12-0-tetradecanoylphorobol-13-acetate, enable rat liver epithelial cells to overcome their Ca2+-dependent restriction points in their cell cycle with the result of poliferation under normally restrictive conditions. Preliminary evidence suggest that the mechanisms by which tumor promoters promote the acquisition of this property is related to phosphatidylinositol turnover, protein kinase C and intracellular Ca2+. Our long range goals are to identify these mechanisms and the alterations which allow this aberrant proliferative behavior to occur. It is the specific aim of this project to determine if the turnover of phosphatidylinositiol and subsequent activation of protein kinase C and increase in intracellular Ca2+ is involved in the tumor promoter effect which enables rat liver epithelial cells to overcome the normally Ca2+-induced restriction on their proliferative activity. Attainment of these objectives should allow us to begin investigations on methods to prevent or modify the carcinogenesis process.
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