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Roles of glycosaminoglycans and glycanmimetics in tumor progression and metastasis

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Abstract

Various tumor cells exhibit structural alterations in the sulfated modifications to glycosaminoglycans (GAGs). The altered expression of chondroitin sulfate (CS) and heparan sulfate (HS) on the surfaces of tumor cells is known to play a key role in malignant transformation and tumor metastasis. The receptor molecule for the CS chains containing E-disaccharide units (CS-E) expressed on Lewis lung carcinoma (LLC) cells was recently revealed to be Receptor for Advanced Glycation End-products (RAGE). RAGE is also involved in the development of various pathological conditions including aging, infection, pulmonary fibrosis, diabetes, and Alzheimer’s disease, by binding to a wide range of ligands. RAGE binds strongly not only to CS-E, but also to HS-expressing LLC cells. Recombinant RAGE bound CS-E and HS with high affinity. Furthermore, in a mouse model, the colonization of the lungs by LLC cells was inhibited by intravenously injected CS-E, an anti-CS-E antibody, or an anti-RAGE antibody. These findings demonstrated that RAGE is at least one of the critical receptors for CS and HS chains expressed on the tumor cell surface and is involved in experimental lung metastasis, and also that CS/HS and RAGE are potential molecular targets for the treatment of pulmonary metastasis. We, hence, reviewed these findings and also several chemically synthesized small GAGmimetics that exhibit potent anti-metastatic and/or anti-tumor activities.

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Abbreviations

CS:

Chondroitin sulfate

DS:

Dermatan sulfate

HS:

Heparan sulfate

VEGF:

Vascular endothelial growth factor

FGF2:

Fibroblast growth factor-2

GAG:

Glycosaminoglycan

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Acknowledgments

This work was supported in part by Grants-in-Aid for Scientific Research (B) 23390016 20390019 (to K. S.) and a Grant-in-Aid for Challenging Exploratory Research 25670018 (to K. S.) from the Japan Society for the Promotion of Science (JSPS). This research was supported in part by the University Grants Commission (41-257-2012-SR), Vision Group Science and Technology, Department of Science and Technology (No. SR/FT/LS-142/2012) to Basappa. Basappa also thanks Karnataka University, INDIA for the PAVATE fellowship.

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Authors and Affiliations

  1. Laboratory of Chemical Biology, Department of Chemistry, Bangalore University, Palace Road, Bangalore, 560001, India

    Basappa

  2. Department of Chemistry, University of Mysore, Manasagangotri, Mysore, 560001, India

    Kanchugarakoppal S. Rangappa

  3. Research Group of Proteoglycan Signaling and Therapeutics, Hokkaido University Graduate School of Life Science, Frontier Research Center for Post-Genomic Science and Technology, West-11, North-21, Kita-ku, Sapporo, Hokkaido, 001-0021, Japan

    Kazuyuki Sugahara

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Correspondence to Kazuyuki Sugahara.

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Basappa, Rangappa, K.S. & Sugahara, K. Roles of glycosaminoglycans and glycanmimetics in tumor progression and metastasis. Glycoconj J 31, 461–467 (2014). https://doi.org/10.1007/s10719-014-9551-9

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  • DOI: https://doi.org/10.1007/s10719-014-9551-9

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