Abnormalities in growth regulation of transformed rat tracheal epithelial cells.

We have examined the changes in growth regulation which take place during multistage transformation of rat tracheal epithelial (RTE) cells exposed to chemical carcinogens in vitro. Transformed RTE cells demonstrate: (1) altered negative growth factor sensitivity and (2) altered positive growth factor dependence and gene expression compared with primary RTE cells in culture. Primary RTE cells are sensitive to the growth inhibitory effects of retinoic acid and transforming growth factor beta (TGF beta). Enhanced growth variants of RTE cells, recognized 4-6 weeks after carcinogen treatment, lose sensitivity to the antiproliferative effects of retinoic acid. Likewise, many immortalized RTE cell lines lose responsiveness to growth inhibition by TGF beta. We also examined positive growth factor requirements and gene expression in primary and transformed RTE cells propagated in serum-free media. Many transformed cell lines lose dependence on epidermal growth factor in the media. These cell lines also overexpress TGF alpha mRNA and protein. Since TGF alpha acts at the epidermal growth factor receptor, these data suggest that TGF alpha plays an autocrine role in growth regulation of transformed RTE cells. Thus, alterations in both negative and positive growth factor regulation contribute to expression of the transformed phenotype in RTE cells.