The transforming growth factor-betas (TGF-betas) are multifunctional regulators of cellular growth and function and potent inhibitors of epithelial cell proliferation. The widespread expression of TGF-beta indicates a pivotal role in epithelial homeostasis. These features make the TGF-betas attractive candidates for new therapeutic intervention approaches to the prevention and treatment of cancer. TGF-beta plays a major role in adult physiology, as well as in the control of differentiation and morphogenesis in embryonic development. The tissue distribution pattern of the TGF-betas, which include TGF-betas 1, 2, and 3 in mammals, has possible significance for signaling roles in epithelial-mesenchymal interactions during embryogenesis, as well as in cancer and carcinogenesis. TGF-beta is secreted by a variety of normal and malignant cells. The TGF-betas function through a set of cell surface protein receptors that includes TGF?beta type I (RI) and type II (RII). TGF-beta RII can bind TGF-beta directly to form a complex, which then is able to bind TGF-beta RI, and TGF-beta RII is then able to phosphorylate TGF-beta RI, which is necessary for signal transduction. The TGF-beta signaling system has been implicated as a tumor suppressor pathway in several organ systems. Loss of functional TGF-beta RI or RII contributes to loss of TGF-beta responsiveness, resulting in tumor progression. Defects in responsiveness to TGF-beta have been implicated in the pathogenesis of several human epithelial cancers, suggesting that TGF-beta has tumor suppressor properties. But, many advanced tumors show increased expression of TGF-beta, and parallel poor prognosis, suggesting that TGF-beta also has properties of a tumor suppressor. The complex mechanisms of action of TGF-beta in its capacity as a tumor suppressor and a tumor promoter and the target genes that are regulated by TGF-beta in these different capacities must be clearly defined to be able to exploit this gene for clinical therapeutic intervention purposes. ? ? Our broad goal is to determine how TGF-beta signaling regulates the development and malignant transformation of epithelial cells, now with a primary emphasis on lung epithelial cells. Our approach is based on the hypotheses that (1) Signaling pathways for TGF-beta occur that are separate from the growth inhibitory pathway and these pathways may be operational in lung cancer cells that are resistant to growth inhibition by TGF-beta; (2) The integrity of the TGF-beta signaling pathways is important for the normal regulation of downstream target molecules of TGF-beta and dysregulation of the activity of these signaling pathways during progressive stages of lung tumorigenesis impacts on the regulation of these target genes; (3) The tumor suppressor and tumor promoter activities of TGF-beta differentially regulate target genes that contribute to these activities. Our research efforts are focused around the proposal that there is a delicate balance between the tumor suppressor and tumor promoter roles of TGF-beta in epithelial tissues. Our premise is that the ability of TGF-beta to act as a tumor suppressor is primary to that of a tumor promoter in normal epithelial cells, and that the ability of TGF-beta to act as a tumor promoter takes on added significance as cells that are sensitive to TGF-beta become transformed and eventually resistant to TGF-beta, expand clonally, and ultimately progress to malignancy. Awareness of the timing of the phenotypic switch from TGF-beta sensitivity to TGF-beta resistance that occurs during tumorigenesis is likely to be important in designing and applying strategies for tumor prevention and treatment. ? ? Our recent efforts have examined TGF-beta 1-induced apoptosis in normal lung alveolar type II epithelial C10 cells that our studies show are responsive to TGF-beta 1.
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