PHENOTYPIC AND KARYOTYPIC CHANGES INDUCED IN CULTURED RAT HEPATIC EPITHELIAL-CELLS THAT EXPRESS THE OVAL CELL PHENOTYPE BY EXPOSURE TO N-METHYL-N'-NITRO-N-NITROSOGUANIDINE

Abstract

A diploid population of cultured rat hepatic epithelial cells that expresses the oval cell phenotype was exposed briefly and repetitively to N-methyl-N''-nitro-N-nitrosoguanidine (MNNG), and the effect on > 20 phenotypic properties was evaluated during the neoplastic transformation of the population. MNNG treatments of this hepatic epithelial cell population resulted in a progressively increasing phenotypic alteration and heterogeneity including changes in specific activities of several cellular enzymes and expression of isozymes, synthetic functions and various in vitro growth properties. Changes in phenotypic expression were clustered episodically and were associated with major karyotypic changes. The development of increasing phenotypic heterogeneity preceding and accompanying tumorigenicity in cultured liver epithelial cells in vitro and the specific phenotypes that occur resemble superficially the pattern of phenotypic changes that occur in hepatocytes during chemical hepatocarcinogenesis in vivo. The mechanistic and linkage relationship between specific pretumorigenic and paratumorigenic phenotypes and tumorigenicity need further investigation.