Heparan sulfate proteoglycans (HSPGs) interact with numerous proteins of importance in animal development and homeostasis^{1, 2, 3}. Heparanase, which is expressed in normal tissues and upregulated in angiogenesis, cancer and inflammation, selectively cleaves -glucuronidic linkages in HS chains. In a previous study, we transgenically overexpressed heparanase in mice to assess the overall effects of heparanase on HS metabolism. Metabolic labeling confirmed extensive fragmentation of HS in vivo^{4, 5}. In the current study we found that in liver showing excessive heparanase overexpression, HSPG turnover is accelerated along with upregulation of HS N- and O-sulfation, thus yielding heparin-like chains without the domain structure typical of HS. Heparanase overexpression in other mouse organs and in human tumors correlated with increased 6-O-sulfation of HS, whereas the domain structure was conserved. The heavily sulfated HS fragments strongly promoted formation of ternary complexes with fibroblast growth factor 1 (FGF1) or FGF2 and FGF receptor 1. Heparanase thus contributes to regulation of HS biosynthesis in a way that may promote growth factor action in tumor angiogenesis and metastasis.

1. Department of Medical Biochemistry and Microbiology, University of Uppsala, The Biomedical Center, Box 582, Husargatan 3, SE-751 23 Uppsala, Sweden.
2. Department of Public Health and Caring Sciences, Molecular Geriatrics, Rudbeck Laboratory, University of Uppsala, Dag Hammarskjölds väg 20, SE-751 85 Uppsala, Sweden.
3. Department of Biochemistry, 280 Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Geert Grooteplein 28, route 259, 6500 HB Nijmegen, The Netherlands.
4. Cancer and Vascular Biology Research Center, The Bruce Rappaport Faculty of Medicine, 1 Efron Street, Technion, Haifa 31096, Israel.
5. These authors contributed equally to this work.

Correspondence to: Jin-Ping Li¹ Email: jin-ping.li@imbim.uu.se

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