NEOPLASTIC TRANSFORMATION OF HUMAN EPITHELIAL CELLS BY ONCOGENES OR CARCINOGENS

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Five families of activated protooncogenes, ras, raf, jun, erbB-2, and myc so far have been associated with human bronchogenic carcinoma. Human bronchial epithelial cells in vitro are being used to investigate the functional role of these specific oncogenes and growth regulatory genes in carcinogenesis and tumor progression. Human bronchial epithelial cells have been neoplastically transformed with Ha-ras oncogene. Whereas the expression of the activated ras gene is not necessary for in vitro growth of the cells, Ha-ras expression is associated with a selective growth advantage in vivo. An inverse correlation of steady state thrombospondin mRNA and protein expression with malignant progression of oncogene (Ha-, k- and N-ras)-transformed human bronchial epithelial cells has been observed. Dysregulation of the G1 checkpoint in the cell cycle may lead to neoplastic transformation. Overexpression of transfected cyclin D1 gene in human esophageal cells leads to enhanced growth to the negative growth factor, TGF-beta1. Genomic instability in human bronchial epithelial cells is induced by transfection of protein phoshatase genes, cdc25A or cdc25B. In contrast, genomic instability or mutations were not detected in human bronchial epithelial cells exposed to nitric oxide.