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J. Biol. Chem., Vol. 283, Issue 49, 34294-34304, December 5, 2008

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Involvement of Highly Sulfated Chondroitin Sulfate in the Metastasis of the Lewis Lung Carcinoma Cells^*

Fuchuan Li¹², Gerdy B. ten Dam^¶13, Sengottuvelan Murugan², Shuhei Yamada, Taishi Hashiguchi, Shuji Mizumoto, Kayoko Oguri^||, Minoru Okayama^**, Toin H. van Kuppevelt^¶, and Kazuyuki Sugahara⁴

From the Graduate School of Life Science, Hokkaido University, Sapporo 001-0021, Japan, the Department of Biochemistry, Kobe Pharmaceutical University, Kobe 658-8558, Japan, the ^||Clinical Research Center, National Hospital Organization Nagoya Medical Center, Nagoya 460-0001, Japan, the ^**Department of Biotechnology, Faculty of Engineering, Kyoto Sangyo University, Kyoto 603-8555, Japan, and the ^¶Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands

The altered expression of cell surface chondroitin sulfate (CS) and dermatan sulfate (DS) in cancer cells has been demonstrated to play a key role in malignant transformation and tumor metastasis. However, the functional highly sulfated structures in CS/DS chains and their involvement in the process have not been well documented. In the present study, a structural analysis of CS/DS from two mouse Lewis lung carcinoma (3LL)-derived cell lines with different metastatic potentials revealed a higher proportion of ^4,5HexUA-GalNAc(4,6-O-disulfate) generated from E-units (GlcUA-GalNAc(4, 6-O-disulfate)) in highly metastatic LM66-H11 cells than in low metastatic P29 cells, although much less CS/DS is expressed by LM66-H11 than P29 cells. This key finding prompted us to study the role of CS-E-like structures in experimental lung metastasis. The metastasis of LM66-H11 cells to lungs was effectively inhibited by enzymatic removal of tumor cell surface CS or by preadministration of CS-E rich in E-units in a dose-dependent manner. In addition, immunocytochemical analysis showed that LM66-H11 rather than P29 cells expressed more strongly the CS-E epitope, which was specifically recognized by the phage display antibody GD3G7. More importantly, this antibody and a CS-E decasaccharide fraction, the minimal structure recognized by GD3G7, strongly inhibited the metastasis of LM66-H11 cells probably by modifying the proliferative and invading behavior of the metastatic tumor cells. These results suggest that the E-unit-containing epitopes are involved in the metastatic process and a potential target for the diagnosis and treatment of malignant tumors.

Received for publication, August 5, 2008 , and in revised form, October 8, 2008.

^* This work was supported in part by Grant-in-aid 16390026 from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (MEXT), funds from the New Energy and Industrial Technology Development Organization (to K. S.) and the Core Research for Evolutional Science and Technology Program of the Japan Science and Technology Agency, Human Frontier Science Program Grants RGP62/2004 (to T. H. V. K.) and RGP18/2005 (to K. S.), Dutch Cancer Society Grant 2008-4058 (to G. T. D.), the "Academic Frontier" Project for Private Universities matching funds subsidy (to M. O.), and in part by Grant-in Aid for Scientific Research on Priority Areas 17046028 (to K. O.). The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked "advertisement" in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.

The on-line version of this article (available at http://www.jbc.org) contains supplemental Fig. S1.

¹ These authors contributed equally to this work.

² Supported by a postdoctoral fellowship from the Japan Society for the Promotion of Science.

³ To whom correspondence may be addressed. Present address: Dept. of Biochemistry, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, 6500 HB Nijmegen, The Netherlands. Tel.: 31-24-3610759/14270; Fax: 31-24-3540339; E-mail: g.tendam{at}ncmls.ru.nl.

⁴ To whom correspondence may be addressed: Laboratory of Proteoglycan Signaling and Therapeutics, Graduate School of Life Science, Hokkaido University, Frontier Research Center for Post-Genomic Science and Technology, Nishi 11, Kita 21, Kita-ku, Sapporo, Hokkaido 001-0021, Japan. Tel.: 81-11-706-9054; Fax: 81-11-706-9056; E-mail: k-sugar{at}sci.hokudai.ac.jp.

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