Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells
Involvement of chondroitin sulfate E in the liver tumor focal formation of murine osteosarcoma cells
复制标题
DOI：
10.1093/glycob/cwp041
复制
发表时间：
2009-07-01
期刊：
影响因子：
4.3
通讯作者：
Sugahara, Kazuyuki
中科院分区：
文献类型：
--
作者：
Basappa;Murugan, Sengottuvelan;Sugahara, Kazuyuki
细胞表面硫酸乙酰肝素在调节肿瘤细胞的转移行为中起着关键作用，而硫酸软骨素/硫酸皮肤素（CS/DS）在这方面的作用却知之甚少。在这里，我们的特点CS/DS链从鼠骨肉瘤细胞系LM8G7，形成肿瘤结节在肝脏。CS/DS链的结构分析显示，LM8G7中GlcUA β 1 - 3GalNAc（4，6-O-二硫酸盐）（E单位）的比例（12%）高于其亲本细胞系LM8（6%），后者很少在肝脏中形成肿瘤。用E-单位特异性抗体GD3G7进行免疫染色，证实LM8G7中表位的表达高于LM8细胞。通过预先给予CS-E（富含E-单位）或将抗体GD3G7与肿瘤细胞预孵育，可有效抑制小鼠肝脏中LM8G7细胞的肿瘤灶形成。CS-E或GD3G7在体外抑制LM8G7细胞与层粘连蛋白包被的板的粘附。此外，CS-E或抗体的加入也降低了LM8G7细胞的体外侵袭能力。此外，CS-E或抗体剂量依赖性地抑制LM8G7细胞的增殖。CS-E和GD3G7还显著降低了LM8G7细胞与VEGF的体外结合。因此，本研究揭示了高度硫酸化的CS/DS结构在骨肉瘤细胞的肝脏定植中的意义，并且还为基于GAG的抗癌分子的开发提供了框架。
Cell surface heparan sulfate plays a critical role in regulating the metastatic behavior of tumor cells, whereas the role of chondroitin sulfate/dermatan sulfate (CS/DS) has been little understood in this context. Here, we characterized CS/DS chains from the murine osteosarcoma cell line LM8G7, which forms tumor nodules in liver. Structural analysis of the CS/DS chains showed a higher proportion of GlcUA beta 1-3GalNAc(4,6-O-disulfate) (E-units) in LM8G7 (12%) than in its parental cell line LM8 (6%), which rarely forms tumors in the liver. Immunostaining with GD3G7, an antibody specific to E-units, confirmed the higher expression of the epitope in LM8G7 than LM8 cells. The tumor focal formation of LM8G7 cells in the liver in mice was effectively inhibited by the preadministration of CS-E (rich in E-unit) or the preincubation of the antibody GD3G7 with the tumor cells. CS-E or GD3G7 inhibited the adhesion of LM8G7 cells to a laminin-coated plate in vitro. In addition, the invasive ability of LM8G7 cells in vitro was also reduced by the addition of CS-E or the antibody. Further, CS-E or the antibody inhibited the proliferation of LM8G7 cells dose dependently. The binding of LM8G7 cells to VEGF in vitro was also significantly reduced by CS-E and GD3G7. Thus, the present study reveals the significance of highly sulfated CS/DS structures in the liver colonization of osteosarcoma cells and also provides a framework for the development of GAG-based anticancer molecules.