Transforming growth factor type (3 (TGF-f3), when injected subcutaneously in newborn mice, causes formation of granulation tissue (induction of angiogenesis and activation offibroblasts to produce collagen) at the site of injection.These effects occur within 2-3 days at dose levels of <1 jg. Parallel in vitro studies show that TGF-(3 causes marked increase of either proline or leucine incorporation into collagen in either an NRK rat fibroblast cell line or early passage human dermal fibroblasts. Epidermal growth factor (EGF) and platelet-derived growth factor (PDGF) do not cause these same in vivo and in vitro effects; in both rat and human fibroblast cultures, EGF antagonizes the effects of TGF-(3 on collagen formation. We have obtained further data to support a role for

Type .8 transforming growth factor is a two-chain polypeptide of 25,000 daltons isolated from many tissues, including bovine kidney, human placenta, and human platelets. It has been characterized by its ability to stimulate reversible transformation of nonneoplastic murine fibroblasts, as measured by the formation of colonies of these cells in soft agar (ED50 = 4 pM TGF-/3 for NRK fibroblasts). We now show that the response of cells to TGF-,8 is bifunctional, in that TGF-IJ inhibits the anchorage-dependent growth of NRK fibroblasts and of human tumor cells by increasing cell cycle time. Moreover, the anchorage-independent growth of many human melanoma, lung carcinoma, and breast carcinoma cell lines is inhibited by TGF-fJ at concentrations in the same range as those that stimulate colony formation of NRK fibroblasts (average ED50 = 10-30 pM TGF-36 for inhibition). Whereas epidermal growth factor and TGF-. synergize to induce anchorage-independent growth of NRK fibroblasts, their effects on the growth of A-549 human lung carcinoma cells are antagonistic. The bifunctional response of cells to TGF-(3 is further demonstrated in Fischer rat 3T3 fibroblasts transfected with a cellular myc gene. In these cells TGFf3 synergizes with platelet-derived growth factor to stimulate colony formation but inhibits the colony formation induced by epidermal growth factor. The data indicate that the effects of TGF-8 on cells are not a function of the peptide itself, but rather of the total set of growth factors and their receptors that is operant in the cell at a given time.

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