NEOPLASTIC PROGRESSION OF HUMAN AND RAT INTESTINAL-CELL LINES AFTER TRANSFER OF THE RAS AND POLYOMA MIDDLE T-ONCOGENES

Background: Activation of the p21ras and pp60c-src on-coproteins occurred at high incidence in the early stage of human colorectal carcinogenesis. Our study aimed to investigate the role of these signal-transduction pathways in the process of initiation and promotion of the malignant phenotype in intestinal cells. Methods: The human Ha-ras and the polyoma middle T (Py-MT) viral oncogenes were transferred into large T oncogene of simian virus 40 immortalized rat intestinal epithelial SLC-44 cells and human colonic adenocarcinoma Caco-2 cells. Results: These transfers conferred the tumorigenic and invasive phenotypes on immortalized SLC-44 cells and potentiated the tumorigenicity of Caco-2 cells and markedly repressed the terminal differentiation of this cell line. In SLC-44T cells, induction of the invasive phenotype by the activated Ha-ras oncogene correlated with weak expression of E-cadherin and reduced accumulation of the transcripts encoding the basement membrane components α1 (IV) collagen, nidogen, and BM40, which might result partly from the inactivation of the transforming growth factor β signaling pathway. The down-regulation of the α1 (IV) collagen messenger RNA in SLC-44T cells was not due to the protein kinase C-dependent pathways or the secretion of autocrine factor(s). Conclusions: These results suggest that the activation of the p21ras and Py-MT/pp60c-src oncogenic pathways are critical effectors at different stages of colorectal carcinogenesis and in Caco-2 cells interferes with the program of enterocyte differentiation. © 1993.