Ferriola P C, Steigerwalt R, Robertson A T, Nettesheim P
Laboratory of Pulmonary Pathobiology, National Institute of Environmental Health Sciences, Research Triangle Park, N.C.
Pathobiology. 1990;58(1):28-36. doi: 10.1159/000163562.
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.
我们研究了体外暴露于化学致癌物的大鼠气管上皮（RTE）细胞在多阶段转化过程中发生的生长调节变化。与培养中的原代RTE细胞相比，转化的RTE细胞表现出：（1）负生长因子敏感性改变；（2）正生长因子依赖性和基因表达改变。原代RTE细胞对视黄酸和转化生长因子β（TGFβ）的生长抑制作用敏感。在致癌物处理后4 - 6周识别出的RTE细胞增强生长变体，对视黄酸的抗增殖作用失去敏感性。同样，许多永生化RTE细胞系对TGFβ的生长抑制失去反应性。我们还研究了在无血清培养基中培养的原代和转化RTE细胞的正生长因子需求和基因表达。许多转化细胞系在培养基中失去了对表皮生长因子的依赖性。这些细胞系还过度表达TGFα mRNA和蛋白。由于TGFα作用于表皮生长因子受体，这些数据表明TGFα在转化的RTE细胞的生长调节中起自分泌作用。因此，负生长因子和正生长因子调节的改变都有助于RTE细胞中转化表型的表达。
