title: Modulation of heparan-sulphate/chondroitin-sulphate ratio by glycosaminoglycan biosynthesis inhibitors affects liver metastatic potential of tumor cells.
abstract: 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.
authors.affiliation: First Institute of Pathology and Experimental Cancer Research, Semmelweis University of Medicine, Budapest, Hungary.
authors.forename: J
authors.initials: J
authors.lastname: Tímár
authors.forename: C
authors.initials: C
authors.lastname: Diczházi
authors.forename: I
authors.initials: I
authors.lastname: Bartha
authors.forename: G
authors.initials: G
authors.lastname: Pogány
authors.forename: S
authors.initials: S
authors.lastname: Paku
authors.forename: E
authors.initials: E
authors.lastname: Rásó
authors.forename: J
authors.initials: J
authors.lastname: Tóvári
authors.forename: A
authors.initials: A
authors.lastname: Ladányi
authors.forename: K
authors.initials: K
authors.lastname: Lapis
authors.forename: L
authors.initials: L
authors.lastname: Kopper
mesh_terms: D000818:Animals; D000963:Antimetabolites / Q000494:pharmacology; D000964:Antimetabolites, Antineoplastic / Q000494:pharmacology; D002809:Chondroitin Sulfates / Q000378:metabolism*; D003847:Deoxyglucose / Q000494:pharmacology; D003857:Deoxyuridine / Q000031:analogs & derivatives / Q000494:pharmacology; D012968:Etidronic Acid / Q000494:pharmacology; D006025:Glycosaminoglycans / Q000096:biosynthesis*; D006027:Glycosides / Q000494:pharmacology; D006497:Heparan Sulfate / Q000378:metabolism*; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy / Q000378:metabolism / Q000556:secondary*; D008545:Melanoma / Q000188:drug therapy / Q000378:metabolism*; D051379:Mice; D014407:Tumor Cells, Cultured
chemical_list: D000963:Antimetabolites; D000964:Antimetabolites, Antineoplastic; D002809:Chondroitin Sulfates; D003847:Deoxyglucose; D003857:Deoxyuridine; D012968:Etidronic Acid; D006025:Glycosaminoglycans; D006027:Glycosides; D006497:Heparan Sulfate; C010807:xylosides; C064952:5-hexyl-2'-deoxyuridine