MODULATION OF HEPARAN-SULFATE CHONDROITIN-SULFATE RATIO BY GLYCOSAMINOGLYCAN BIOSYNTHESIS INHIBITORS AFFECTS LIVER METASTATIC POTENTIAL OF TUMOR-CELLS

Previous data have indicated that the proteoglycan (PG) pattern is dif ferent on tumor cells with different liver metastatic potential. We se lected ''conventional'' glycosaminoglycan (GAG) biosynthesis inhibitor s, beta-D-xyloside (EX), 2-deoxy-D-glucose (2-DG), ethane-1-hydroxy-1, 1-diphosphonate (ETDP) and the newly discovered 5-hexyl-2-deoxyuridine (HUdR), to modulate PGs on highly metastatic/liver-specific 3LL-HH mu rine carcinoma and HT168 human melanoma cells and to influence their l iver colonization potential. These compounds all induced remarkable ch anges in GAG biosynthesis, but to varying degrees: glucosamine labelli ng was affected mainly by 2-DG, and HUdR and sulphation by BX and HUdR . Furthermore, the ratio of heparan sulphate/chondroitin sulphate (HS/ CS) of PGs was increased by ETDP and decreased after treatment by HUdR . In addition to changes in PG metabolism, tumor-cell proliferation an d adhesion to fibronectin were affected; EX and 2-DG stimulated cell p roliferation and adhesion, while HUdR inhibited both proliferation and adhesion. Most interestingly, HUdR, the most effective inhibitor of H S/HSPG, depressed the formation of liver colonies, while ETDP, the mos t effective inhibitor of CS/CSPG, stimulated the appearence of liver c olonies. These observations indicated that, at least in these experime ntal systems, tumor cells with a high HS/CS ratio are more likely to f orm liver metastases; consequently, anti-HS agents could also be anti- metastatic. (C) 1995 Wiley-Liss, Inc.