Glycobiology Advance Access published online on March 17, 2009
Glycobiology, doi:10.1093/glycob/cwp041
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Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells
1 Graduate School of Life Science, Hokkaido University, Sapporo, Japan
2 Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan
3 Vascular Mapping Center, Burnham Institute for Medical Research UCSB, University of California, Santa Barbara, CA
4 Medical Center for Translational Research, Osaka University Hospital, Suita, Japan
5 Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
6 Department of Chemistry, Bangalore University, Bangalore, India.
To whom correspondence may be addressed: Tel.: 81-(11)-706–9055; Fax: 81-(11)-706–9055; E-mail: tjohej{at}sci.hokudai.ac.jp
To whom correspondence may be addressed: Tel.: 81-(11)-706–9054; Fax: 81-(11)-706–9056; E-mail: k-sugar{at}sci.hokudai.ac.jp
Received on December 26, 2008; accepted on March 12, 2009
Cell surface heparan sulfate plays a critical role in regulating the metastatic behavior of tumor cells, whereas the role of chondroitin sulfate/dermatan sulfate (CS/DS) has been little understood in this context. Here, we characterized CS/DS chains from the murine osteosarcoma cell line LM8G7, which forms tumor nodules in liver. Structural analysis of the CS/DS chains showed a higher proportion of GlcUAβ1-3GalNAc(4,6-O-disulfate) (E-units) in LM8G7 (12%) than in its parental cell line LM8 (6%), which rarely forms tumors in the liver. Immunostaining with GD3G7, an antibody specific to E-units, confirmed the higher expression of the epitope in LM8G7 than LM8 cells. The tumor focal formation of LM8G7 cells to the liver in mice was effectively inhibited by the pre-administration of CS-E (rich in E-unit) or the pre-incubation of the antibody GD3G7 with the tumor cells. CS-E or GD3G7 inhibited the adhesion of LM8G7 cells to a laminin-coated plate in vitro. In addition, the invasive ability of LM8G7 cells in vitro was also reduced by the addition of CS-E or the antibody. Further, CS-E or the antibody inhibited the proliferation of LM8G7 cells dose-dependently. The binding of LM8G7 cells to VEGF in vitro was also significantly reduced by CS-E and GD3G7. Thus, the present study reveals the significance of highly sulfated CS/DS structures in the liver colonization of osteosarcoma cells and also provides a framework for the development of GAG-based anti-cancer molecules.
Key words: chondroitin sulfate / glycosaminoglycan / tumor / osteosarcoma / sulfation
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