We have found that when carcinogen-altered preneoplastic and neoplastic tracheal epithelial cells (TEC) and normal TEC are cocultured in vivo in devitalized tracheal grafts the normal cells markedly reduce the survival of the altered cells. A similar effect was observed in culture. The inhibition in culture is at least partially due to the presence of an inhibitor present in normal TEC conditioned medium (CM). Inhibitory TEC-CM has been found to contain transforming growth factor type Beta. It is not clear, however, whether the inhibition of altered TEC by normal TEC in vivo is associated with the production of TGF-Beta. The proposed experiments are intended to ultimately determine the relevance, if any, of TGF-Beta/GI detected in TEC-CM to the control of growth and differentiation in the intact trachea. Similarly, we will investigate the relevance of changes in production or sensitivity to TGF-Beta/GI observed during neoplastic progression to the loss of growth control characteristic of neoplastic disease. Using combinations of in vivo, in vivo-in vitro, and in vitro techniques developed as part of the rat tracheal cell model we will investigate: (1) influence of proliferation and differentiation on TGF-Beta/GI production by normal epithelial cells; (2) effects of carcinogen-exposure on sensitivity to inhibition by, and production of TGF-Beta/GI; (3) changes in proliferation and differentiation induced by TGF-Beta in sensitive target cells; (4) define cofactor requirements for TGF-Beta/GI inhibition of TEC; and (5) determine the influence of cell shape on TGF-Beta/GI inhibition of TEC.
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