TRANSFORMING GROWTH-FACTOR-BETA SUPPRESSES THE INVASIVENESS OF HUMAN FIBROSARCOMA CELLS-INVITRO BY INCREASING EXPRESSION OF TISSUE INHIBITOR OF METALLOPROTEASE

We have investigated the effects of TGF-β on the ability of the human fibrosarcoma cell line, HT1080, to invade a reconstituted basement membrane (Matrigel) in vitro. Exposure of HT1080 cells to TGF-β (1-10ng/ml) caused a dose-dependent inhibition of HT1080 cell invasion. Unexpectedly, TGF-β (10ng/ml) significantly enhanced (10-fold) the mRNA expression of the 68-72kDa latent type IV collagenase. Zymogram analysis revealed a 7-fold increase in the 68-72kDa latent type IV collagenase concomitant with an increase in the activated form (62kDa). TGF-β induced the 92kDa type IV collagenase to a lesser degree. HT1080 cells exposed to TGF-β also produced more tissue inhibitor of metalloprotease (TIMP) at both the mRNA (10-fold) and protein levels (5-fold). Although TGF-β induced both type IV collagenases and TIMP, the net collagenolytic activity in the conditioned media after invasion assay was reduced in the presence of TGF-β. The data suggest that the inhibition of invasiveness is due, at least in part, to the increased TIMP expression. These data suggest that TGF-β may play a role in tumor cell invasion by increasing the expression of TIMP. © 1991.