Cell culture models of multistep carcinogenesis.

The cellular and molecular basis for the multistep process of carcinogenesis can be studied in part by the use of cell culture models. A model system for the study of carcinogen-induced neoplastic transformation of cells in culture is described. Different stages in the neoplastic development of Syrian hamster embryo (SHE) fibroblasts can be identified and quantitated. At least two steps are required for the neoplastic progression of these cells. Morphological alterations are observed early after carcinogen treatment; such cells are preneoplastic and, after further growth in culture, acquire the ability to grow in agar and to form tumours in animals. The induction of morphological transformation of SHE cells occurs within one week after carcinogen treatment in a dose-dependent manner consistent with a one-hit mechanism. Furthermore, this change is induced at frequencies (greater than 1% of the surviving cells) that are higher than those of specific locus mutations. Carcinogens that fail to induce measurable gene mutations induce cell transformation (e.g., diethylstilboestrol, asbestos and arsenic). All three of these carcinogens induce chromosomal changes--either numerical and/or structural aberrations--suggesting a role for such changes in the action of these carcinogens. Different preneoplastic cells vary in the rate of their progression to anchorage-independent growth and tumorigenicity. Cells with the ability to grow in agar arise at rates of 10(-4) to 10(-7) variants/cell per generation, depending on the preneoplastic cell line. Different preneoplastic cell lines also vary in their sensitivity to induction of neoplastic transformation by mutagens and by transfection with viral oncogenes. This heterogenicity of response suggests different intermediate states of neoplastic progression.