We have examined the possible role of transforming growth factor-β (TGF-β) in metastatic malignancy by analyzing the production and activation of TGF-β, and -β₂ and the regulation of TGF-β-responsive genes in oncogene-transformed metastatic fibrosarcomas. All transformed lines derived from either 10T¹/₂; or N1H 3T3 bv either H-ras or protein-kinase encoding oncogenes produced more TGF-β than parental cells. However, onlv highlv metastatic fibrosarcomas secreted activated TGF-β at rates that were greater than parental fibroblasts. Immunohistochemical staining for TGF-β, showed widespread intra- and extracellular distribution in metastatic lung nodules and adjacent tissue. Cells isolated from tumors successfully metastasizing to the lung had TGF-β₁, mRNA levels which were increased 19-fold over in ritro controls. Despite the greatly enhanced rate of secretion of activated TGF-β, metastatic cells exhibited markedly altered responses of TGF-β₁, and TGF-β₂., being unable to either increase collagen secretion or enhance collagen a2(l) or TGF-β₁, mRNA levels. This lack of response was not due to either altered TGF-β receptor affinity or numbers. Metastatic progression was, therefore, associated with an increase in the secretion of activated TGF-β₁ and a loss of the ability to deregulate TGF-β-responsive genes.