Sugahara Kazuki N, Hirata Takako, Tanaka Toshiyuki, Ogino Shinji, Takeda Mitsuhiro, Terasawa Hiroaki, Shimada Ichio, Tamura Jun-ichi, ten Dam Gerdy B, van Kuppevelt Toin H, Miyasaka Masayuki
Laboratory of Immunodynamics, Department of Microbiology and Immunology, Osaka University Graduate School of Medicine, Suita, Japan.
Cancer Res. 2008 Sep 1;68(17):7191-9. doi: 10.1158/0008-5472.CAN-07-6198.
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.
在肿瘤细胞侵袭过程中，某些细胞外基质（ECM）成分，如透明质酸（HA）会被降解为小分子寡糖，这些寡糖可在患者体内检测到。我们之前报道过，此类HA寡糖可诱导肿瘤细胞中一种ECM结合分子CD44的蛋白水解切割，并以CD44依赖的方式促进肿瘤细胞迁移。在此，我们报道肿瘤ECM的另一种成分硫酸软骨素E（CSE）在降解为寡糖时，能强烈增强CD44的切割及肿瘤细胞的运动能力。在胰腺导管腺癌中检测到了CSE及其降解产物。在表达CD44的胰腺肿瘤细胞中，降解形式的CSE而非完整的CSE增强了CD44的切割；对这种低分子量CSE（LMW-CSE）进行酶消化可消除这种增强作用。在所检测的LMW-CSE制剂中，3-kDa CSE诱导CD44切割的能力最强。核磁共振分析表明，3-kDa-CSE与CD44结合，阻断这种结合可消除CD44切割诱导作用。LMW-CSE还能诱导肿瘤细胞中显著的丝状伪足形成和细胞骨架变化；阻断LMW-CSE与CD44的结合也可消除这些作用。化学合成的CSE六糖也以CD44依赖的方式增强了CD44切割和肿瘤细胞运动能力。我们得出结论，CSE的降解形式通过与肿瘤细胞CD44相互作用来调节细胞黏附和迁移，这表明与CD44相互作用的肿瘤相关ECM的降解产物在CD44介导的肿瘤进展中起重要作用。
