Transforming growth factors (TGFs) are acid-stable polypeptides that induce reversible phenotypic transformation of normal indicator cells. The purpose of this project is to determine the role that endogenously-produced TGF-beta may play in the growth of normal and transformed cells and to characterize its mode of action at a biochemical level. To this end, polyclonal antisera have been raised against TGF-beta and development of monoclonal antibodies is in progress. The effects of these antibodies on the anchorage-dependent and -independent growth of normal and transformed cells are being investigated and will be analyzed in terms of the biochemical functions affected. Since the first step in the interaction of TGF-beta with the cell is binding of the growth factor to the cell surface, initial investigations have concentrated on the characterization of cell surface receptors for TGF-beta. Development of a radio-receptor assay for TGF-beta has allowed identification of a specific high affinity receptor for TGF-beta on all normal and transformed cell lines studied so far. The receptor appears to be a disulphide-linked dimer that does not undergo ligand-induced autophosphorylation or clustering. Receptor properties are modulated by transformation but binding of TGF-beta to its receptor does not appear to be a major control point in TGF-beta action. Normal and transformed cells have been shown to secrete TGF-beta in an inactive form. Certain tumor cells have lost the ability to activate this latent form and thus cells can no longer limit their own growth in an autocrine manner. The nature of the latent form and of the activation process are being investigated, since activation is potentially an important control point in TGF-beta action and may become disrupted in transformed cells. Further characterization of the role of endogenously produced TGFs and their interaction with the cell surface receptor should help elucidate the role these molecules play in the process of carcinogenesis.
