Chondroitin sulfate E fragments enhance CD44 cleavage and CD44-dependent motility in tumor cells
Chondroitin sulfate E fragments enhance CD44 cleavage and CD44-dependent motility in tumor cells
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DOI：
10.1158/0008-5472.can-07-6198
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发表时间：
2008-09-01
期刊：
影响因子：
11.2
通讯作者：
Miyasaka, Masayuki
中科院分区：
文献类型：
--
作者：
Sugahara, Kazuki N.;Hirata, Takako;Miyasaka, Masayuki
在肿瘤细胞侵袭过程中，某些细胞外基质（ECM）组分（如透明质酸（HA））降解为小寡糖，在患者体内检测到。我们以前报道过，这种HA寡糖诱导ECM结合分子CD 44从肿瘤细胞中蛋白水解裂解，并以CD 44依赖性方式促进肿瘤细胞迁移。在这里，我们报告硫酸软骨素E（CSE），肿瘤ECM的另一种成分，强烈增强CD 44裂解和肿瘤细胞运动时降解成寡糖。胰腺导管腺癌中检测到CSE及其降解产物。在表达CD 44的胰腺肿瘤细胞中，降解形式的CSE而不是完整的CSE增强了CD 44裂解;这种低分子量CSE（LMW-CSE）的酶消化消除了这种增强。在检查的LMW-CSE制剂中，3-kDa CSE最有效地诱导CD 44裂解。核磁共振分析表明3-kDa-CSE与CD 44结合，而CD 44与CSE结合。阻断这种结合消除了CD 44切割诱导。LMW-CSE还在肿瘤细胞中诱导显著的丝状伪足形成和细胞骨架变化;这些作用也通过阻断LMW-CSE与CD 44的结合而消除。化学合成的CSE六糖也以CD 44依赖性方式增强CD 44切割和肿瘤细胞运动性。我们得出结论，CSE的降解形式通过与肿瘤细胞CD 44相互作用来调节细胞粘附和迁移，这表明与CD 44相互作用的肿瘤相关ECM的降解产物在CD 44介导的肿瘤进展中起重要作用。
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.