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Chondroitin Sulfate E Fragments Enhance CD44 Cleavage and CD44-Dependent Motility in Tumor Cells

¹ Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine and ² The 21st Century COE Program, Research Institute for Microbial Diseases, Osaka University, Osaka, Japan; ³ The Laboratory of Physical Chemistry, Graduate School of Pharmaceutical Science, University of Tokyo, Tokyo, Japan; ⁴ Department of Regional Environment, Faculty of Regional Sciences, Tottori University, Tottori, Japan; and ⁵ Department of Biochemistry, Nijmegen Center for Molecular Life Sciences, Radboud University Nijmegen Medical Center, Nijmegen, the Netherlands

Requests for reprints: Masayuki Miyasaka, Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine C8, 2-2, Yamada-oka, Suita 565-0871, Japan. Phone: 81-6-6879-3972; Fax: 81-6-6879-3979; E-mail: mmiyasak{at}orgctl.med.osaka-u.ac.jp.

Key Words: Chondroitin Sulfate E fragments • CD44 • cleavage • tumor cell • migration

During tumor cell invasion, certain extracellular matrix (ECM) components such as hyaluronan (HA) are degraded into small oligosaccharides, which are detected in patients. We previously reported that such HA oligosaccharides induce the proteolytic cleavage of an ECM-binding molecule CD44 from tumor cells and promote tumor cell migration in a CD44-dependent manner. Here, we report that chondroitin sulfate E (CSE), another component of the tumor ECM, strongly enhances CD44 cleavage and tumor cell motility when degraded into oligosaccharides. CSE and its degradation products were detected in pancreatic ductal adenocarcinoma. In CD44-expressing pancreatic tumor cells, degraded forms of CSE but not intact CSE enhanced CD44 cleavage; enzymatic digestion of such low-molecular weight CSE (LMW-CSE) abrogated this enhancement. Among the LMW-CSE preparations examined, 3-kDa CSE most potently induced CD44 cleavage. Nuclear magnetic resonance analysis showed that the 3-kDa-CSE bound to CD44, and that blocking such binding abrogated the CD44 cleavage induction. LMW-CSE also induced prominent filopodia formation and cytoskeletal changes in tumor cells; these effects were also abrogated by blocking the LMW-CSE binding to CD44. Chemically synthesized CSE hexasaccharides also enhanced the CD44 cleavage and tumor cell motility in a CD44-dependent manner. We conclude that the degraded forms of CSE modulate cell adhesion and migration by interacting with tumor-cell CD44, suggesting that the degradation products of tumor-associated ECMs that interact with CD44 play a significant role in CD44-mediated tumor progression. [Cancer Res 2008;68(17):7191–9]

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