Immortalization and neoplastic transformation of fetal rat intestinal epithelial cells: morphological and cytogenetic analysis, (proto)oncogene expression and effect of gamma-interferon on cell growth.

The permanent SLC-11 and -41 intestinal epithelial cells respectively immortalized by the E1A and large T oncogenes and their clonal derivatives showed a cytogenetic heterogeneity characterized by a near diploidy in SLC-11 and -12 cells and a generalized polyploidy in SLC-41 and -44 cells. Persistence of chromosome translocations and trisomy 3 were observed. The expression of the E1A oncogene in immortalized SLC-11 cells is associated with a strong repression of c-fos transcription during the exponential growth, as compared to the resting phase or to control rat fetal intestinal epithelial cells. The transcription of c-myc was also reduced in SLC-11 cells, especially in confluent cells. A complex relationship between the levels and size of the c-fos, c-myc mRNAs and the expression of the E1A oncogene was therefore observed in SLC-11 cells. Immortalized SLC-11 and -41 cells showed a remarkable growth inhibition in response to recombinant rat gamma-IFN. Neoplastic transformation by activated human Ha-ras in SLC-12T and -44 T cells confer resistance to the antigrowth effects of IFN. The combination of culture conditions using defined medium, membrane matrix (laminin, collagen, proteoglycans) and intestinal mesenchyme revealed the persistence of the undifferentiated phenotype of the E1A, large T-immortalized and Ha-ras-transformed SLC cells in vitro or in the nude mice. In association with the intestinal chick endoderm, SLC-11 cells possess some inductive properties on the differentiation of villi projections arising from the chick endoderm in vivo. In contrast, SLC-41 cells were induced to differentiate in enterocyte-like cells by the intestinal chick mesenchyme. The immortalized and Ha-ras-transformed SLC cells therefore constitute new models in the sequential analysis of the molecular and genetic mechanisms involved in the proliferation, differentiation and oncogene-mediated neoplastic transformation in gut. Further attempts in SLC cell differentiation have to be accomplished using chemical inducers for prolonged periods of time, or by transfection of intestinal epithelial cells using temperature- or glucocorticoid-inducible vectors.