Modulation of heparan-sulphate/chondroitin-sulphate ratio by glycosaminoglycan biosynthesis inhibitors affects liver metastatic potential of tumor cells.

Previous data have indicated that the proteoglycan (PG) pattern is different on tumor cells with different liver metastatic potential. We selected "conventional" glycosaminoglycan (GAG) biosynthesis inhibitors, beta-D-xyloside (BX), 2-deoxy-D-glucose (2-DG), ethane-l-hydroxy-l,l-diphosphonate (ETDP) and the newly discovered 5-hexyl-2-deoxyuridine (HUdR), to modulate PGs on highly metastatic/liver-specific 3LL-HH murine carcinoma and HT168 human melanoma cells and to influence their liver colonization potential. These compounds all induced remarkable changes in GAG biosynthesis, but to varying degrees: glucosamine labelling 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 and adhesion to fibronectin were affected; BX and 2-DG stimulated cell proliferation and adhesion, while HUdR inhibited both proliferation and adhesion. Most interestingly, HUdR, the most effective inhibitor of HS/HSPG, depressed the formation of liver colonies, while ETDP, the most effective inhibitor of CS/CSPG, stimulated the appearance of liver colonies. These observations indicated that, at least in these experimental systems, tumor cells with a high HS/CS ratio are more likely to form liver metastases; consequently, anti-HS agents could also be anti-metastatic.