Transforming growth factor-beta suppresses the invasiveness of human fibrosarcoma cells in vitro by increasing expression of tissue inhibitor of metalloprotease.
We have investigated the effects of TGF-beta 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-beta (1-10ng/ml) caused a dose-dependent inhibition of HT1080 cell invasion. Unexpectedly, TGF-beta (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-beta induced the 92kDa type IV collagenase to a lesser degree. HT1080 cells exposed to TGF-beta also produced more tissue inhibitor of metalloprotease (TIMP) at both the mRNA (10-fold) and protein levels (5-fold). Although TGF-beta 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-beta. The data suggest that the inhibition of invasiveness is due, at least in part, to the increased TIMP expression. These data suggest that TGF-beta may play a role in tumor cell invasion by increasing the expression of TIMP.
Kubota
S
S
Laboratory of Developmental Biology and Anomalies, National Institute of Dental Research, National Institutes of Health, Bethesda, MD 20892.
Fridman
R
R
Yamada
Y
Y
D002460:Cell Line; D005354:Fibrosarcoma / Q000473:pathology*; D015870:Gene Expression / Q000187:drug effects; D006023:Glycoproteins / Q000235:genetics* / Q000494:pharmacology; D006801:Humans; D003012:Microbial Collagenase / Q000037:antagonists & inhibitors / Q000235:genetics*; D009361:Neoplasm Invasiveness; D009693:Nucleic Acid Hybridization; D012333:RNA, Messenger / Q000187:drug effects / Q000235:genetics; D011994:Recombinant Proteins / Q000494:pharmacology; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta / Q000494:pharmacology*
D006023:Glycoproteins; D012333:RNA, Messenger; D011994:Recombinant Proteins; D019714:Tissue Inhibitor of Metalloproteinases; D016212:Transforming Growth Factor beta; D003012:Microbial Collagenase