Several observations correlate increased expression of transforming growth factor (TGF) beta 1 with tumorigenesis, suggesting that expression of this multifunctional growth factor may provide an advantage in tumor formation. However, many tumor cells are inhibited in their proliferation by TGF-beta in vitro, thus suggesting that TGF-beta synthesis could exert an antiproliferative effect on tumor formation. To evaluate the physiological relevance of increased TGF-beta 1 synthesis in such tumor cells which are strongly inhibited in their proliferation by TGF-beta, we chose Meth A sarcoma cells as a model system. We established cell clones overexpressing TGF-beta 1 and determined its effect on tumor formation in mice that are not immunocompromised. Increased expression of biologically active TGF-beta 1 resulted in a profound growth inhibition in the transfected clones and increased adhesiveness in vitro. However, these cells were much more tumorigenic than Meth A cells that did not overexpress TGF-beta 1, as assessed by both tumor incidence and tumor growth. In addition, parental Meth A cells were inhibited in their tumor formation by neutralizing TGF-beta antibodies and stimulated by exogenous TGF-beta. Our results thus provide evidence that increased TGF-beta synthesis provides a major advantage for tumorigenesis, even if the cells are growth inhibited by their endogenous TGF-beta synthesis in culture. These results suggest that, in vivo, direct effects of TGF-beta on the tumor environment, such as increased extracellular matrix formation and cell-matrix interactions, and local suppression of the immune surveillance may provide a growth advantage which overrules any direct antiproliferative effects of TGF-beta, as suggested by the effects in culture.