AUTOCRINE GROWTH-STIMULATION BY TRANSFORMING GROWTH-FACTOR-ALPHA IN ASBESTOS-TRANSFORMED RAT MESOTHELIAL CELLS

Although the association between asbestos exposure and mesothelioma de velopment has been established for decades, very little is known regar ding the molecular mechanism(s) by which asbestos fibers induce this d isease. In this series of experiments, the potential for transforming growth factor alpha (TGF-alpha) to act as an autocrine growth factor i n transformed mesothelial cells was examined in rats, a model system f requently used to assess the tumorigenic potential of fibrous particul ates. Both asbestos-transformed cells and spontaneously transformed ce lls expressed functional EGF receptors, although only the asbestos-tra nsformed cells expressed TGF-alpha. Expression of TGF-alpha transcript s was correlated with secretion of picogram amounts of growth factor i nto conditioned medium by the asbestos-transformed cells. In addition, whereas TGF-alpha inhibited the growth of spontaneously transformed m esothelial cells, it stimulated the growth of asbestos-transformed cel ls. Neutralizing antibody that recognized TGF-alpha secreted by the as bestos-transformed cells was able to inhibit the growth of these cells . Taken together, these data indicate that TGF-alpha acts as an autocr ine growth factor for asbestos-transformed fat mesothelial cells. Ther efore, in asbestos-transformed mesothelial cells, altered production a nd responsiveness to TGF-alpha distinguish these cells from spontaneou sly transformed mesothelial cells. These data suggest that differences in mesothelioma etiology may be reflected in differences in the molec ular alterations present in these tumors.