Glycobiology Advance Access originally published online on March 17, 2009
Glycobiology 2009 19(7):735-742; doi:10.1093/glycob/cwp041
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Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells
3 Graduate School of Life Science, Hokkaido University, Sapporo, Japan
4 Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University, Graduate School of Medicine, Suita, Japan
5 Vascular Mapping Center, Burnham Institute for Medical Research UCSB, University of California, Santa Barbara, CA, USA
6 Medical Center for Translational Research, Osaka University Hospital, Suita, Japan
7 Department of Biochemistry, Nijmegen Centre for Molecular Life Sciences, Radboud University Nijmegen Medical Centre, Nijmegen, The Netherlands
8 Department of Chemistry, Bangalore University, Bangalore, India
1 To whom correspondence should be addressed: Tel: +81-(11)-706-9055; Fax: +81-(11)-706-9055; e-mail: tjohej{at}sci.hokudai.ac.jp and k-sugar{at}sci.hokudai.ac.jp
Received on December 26, 2008; revised on March 10, 2009; 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 in the liver in mice was effectively inhibited by the preadministration of CS-E (rich in E-unit) or the preincubation 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 anticancer molecules.
Key words: chondroitin sulfate / glycosaminoglycan / osteosarcoma / sulfation / tumor
2 These authors contributed equally to this work.