Aberrant TGF-beta Production and Regulation in Metastatic Malignancy

We haw examined the possible role of transforming growth factor-beta (TGF-beta) in metastatic malignancy by analyhg 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-kinasc encoding oncogenes produced more TCF-beta than parental cells. However, only highly metastatic fibro-sarcomas 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. Meta-static 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.