IN VITRO MODEL SYSTEMS OF CARCINOGENESIS: INTERACTION BETWEEN c-Ha-ras ONCOGENE AND IMMORTALIZED CELLS

In vivo carcinogenesis has been shown to be a multistage process [4]. There is sufficiently convincing experimental evidence that malignant transformation of cells in vitro is also the result of successive activation of several (at least two) oncogenes [7, ii]. Attempts have been made to create model cell systems with which to study this process at the molecular level. One of the most convenient models for this purpose consists of primary rodent cells transformed through transfection with two oncogenes [7, 8]. In a simplified form the functions of oncogenes which participate in transformation processes can be reduced to the following: an immortalizer gene of the myc type, the early gene of adenoviruses, and the gene of the large T-antigen of polyoma and SV40 virus bring about "immortality" of the cell, whereas the transforming gene, ras for example, terminates this process, inducing malignant conversion of the immortalized cells [7, ii]. Data obtained in various world laboratories are evidence that transformation of primary rodent cells by one oncogene, such as c-Ha-ras, is impossible [9, 14], although morphologically normal NIH3T3 mouse cells are readily transformed by this gene [5]. Despite the fact that much experimental evidence on the cooperative action of two oncogenes has been gathered, the mechanism of transformation of the primary ceils by them has been inadequately studied. In particular, tumors arising in syngeneic and athymic (nude) animals after receiving injections of cells transformed by two oncogenes, are small in size and rapidly regress [8].