Aberrant TGF-beta production and regulation in metastatic malignancy

We have examined the possible role of transforming growth factor-beta (TGF-beta) in metastatic malignancy by analyzing the production and activation of TGF-beta 1 and -beta 2 and the regulation of TGF-beta-responsive genes in oncogene-transformed metastatic fibrosarcomas. All transformed lines derived from either 10T1/2 or NIH 3T3 by either H-ras or protein-kinase encoding oncogenes produced more TGF-beta than parental cells. However, only highly metastatic fibrosarcomas secreted activated TGF-beta at rates that were greater than parental fibroblasts. Immunohistochemical staining for TGF-beta 1 showed widespread intra- and extracellular distribution in metastatic lung nodules and adjacent tissue. Cells isolated from tumors successfully metastasizing to the lung had TGF-beta 1 mRNA levels which were increased 19-fold over in vitro controls. Despite the greatly enhanced rate of secretion of activated TGF-beta, metastatic cells exhibited markedly altered responses of TGF-beta 1 and TGF-beta 2, being unable to either increase collagen secretion or enhance collagen alpha 2(1) or TGF-beta 1 mRNA levels. This lack of response was not due to either altered TGF-beta receptor affinity or numbers. Metastatic progression was, therefore, associated with an increase in the secretion of activated TGF-beta 1 and a loss of the ability to deregulate TGF-beta-responsive genes.