SULFATED GLYCOSAMINOGLYCANS ENHANCE TUMOR-CELL INVASION IN-VITRO BY STIMULATING PLASMINOGEN ACTIVATION

Metastasizing tumor cells invade host tissues by degrading extracellul ar matrix constituents. We report here that the highly sulfated glycos aminoglycans, heparin and heparan sulfate, as well as the sulfated pol ysaccharide, fucoidan, significantly enhanced tumor cell invasion in v itro into fibrin, the basement membrane extract, Matrigel, or through a basement membrane-like extracellular matrix. The enhancement of tumo r cell invasion was due to a stimulation of the proteolytic cascade of plasminogen activation since the effect required plasminogen activati on and was abolished by inhibitors of urokinase-type plasminogen activ ator (uPA) or plasmin. Sulfated polysaccharides enhanced five reaction s of tumor-cell initiated plasminogen activation in a dose-dependent m anner. They amplified plasminogen activation in culture supernatants u p to 70-fold by stimulating (i) pro-uPA activation by plasmin and (ii) plasminogen activation by uPA. (iii) In addition, sulfated polysaccha rides partially protected plasmin from inactivation by alpha(2)-antipl asmin. Sulfated polysaccharides also stimulated tumor-cell associated plasminogen activation, e.g., (iv) cell surface pro-uPA activation by plasmin and (v) plasminogen activation by cell surface uPA. These resu lts suggest that sulfated glycosaminoglycans Liberated by tumor-cell m ediated extracellular matrix degradation in vivo might amplify pericel lular plasminogen activation and locally enhance tumor cell invasion i n a positive feedback manner. (C) 1998 Academic Press.