Cooperative Interactions Involving Cellular and Viral Oncogenes in the Development of Malignant Tumors
A group of cellular and viral oncogenes including the plt gene of polyoma virus (large T protein), the E1A genes of adenoviruses and rearranged forms of the c-myc oncogene cooperate with oncogenes of a second class, including the cellular ras oncogenes and the pmt gene of polyoma virus in the oncogenic transformation fat embryo fibroblasts (1). The myc, plt and E1A genes induce by themselves an early stage of transformation (“immortalization”). The properties of cells at this stage are of interest, since they may constitute a useful experimental model for the study of a very early stage of tumor progression. Transfer of the genes did not result in the immediate appearance of a tumorigenic potential in vivo, and, in fact most of the properties of cells grown in vitroremained similar to those of the normal controls. In primary rat embryo fibroblast cultures, the only phenotypes consistently associated with the expression of these genes in cell culture were a change in the hormonal growth, indicated by a decrease in their requirement in serum factors, and the ability of long term growth (2). When rearranged myc genes were transferred into cells of an established line (FR3T3) together with the neor drug-resistance gene, selection in G418 medium produced cell lines which, upon successive generations in culture, exhibited a characteristic high frequency of spontaneous transformation and acquisition of a tumorigenic potential in syngeneic animals. Fluctuation assays indicated a wide distribution of frequencies between parallel sub-cultures, indicative of the random occurrence of secondary genetic events leading to tumorigenesis (3).
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