生物谷Bioon.com 讯 癌症是危害人类健康的主要因素之一。其中肝细胞癌（HCC）死亡率在第二位，每年约有60万患者死于肝癌，而且发病率仍在飙升。以抑制肿瘤血管生成而间接抑制肿瘤生长不失为一种优选方法，但是由于机体对抗血管生成抑制剂的耐药性，寻找高效、低毒的抗血管抑制剂是癌症治疗的热点之一。
中国科学院上海药物研究所糖生物学及糖化学实验室丁侃课题组对多糖的抗肿瘤作用机制进行了研究。该课题组从中药天麻中提取、纯化修饰得到多糖化合物WSS25，发现该多糖化合物通过靶向骨形成蛋白BMP2及其受体，阻断BMP/SMAD/ID1信号通路对抗血管生成进而在体内发挥肝癌细胞瘤生长的抑制作用。研究论文于8月2日在线发表在美国《生物化学杂志》(Journal of Biological Chemistry)。
在肝癌细胞中高表达的I型脱氧核糖核酸结合抑制蛋白（Id1）促进血管生成而被认定为很好的抗肿瘤血管生成新靶点。硫酸肝素蛋白聚糖（HS）通过阻止硫酸肝素-蛋白反应从而抑制血管生成。HS模拟物WSS25抑制血管生成，同时完全阻断了Id1的表达，也阻断了BMP/Smad/Id1信号通路的表达。石英微天平分析表明WSS25与BMP2及其受体强烈结合。从而有效抑制肝癌细胞在裸鼠身上移植瘤的生长。因此，WSS25是具有良好开发前景的血管生成抑制剂，机制的研究也为靶向性多糖癌症治疗新药研究奠定了基础。
该项目主要由邱宏博士完成。研究工作得到了国家科技部、国家自然科学基金委及中国科学院的资助。（生物谷Bioon.com）
生物谷近期特别推荐会议：
2010细胞治疗研究进展与临床应用前沿研讨会 www.Cell-therapies.net 2010年9月23日-25日天津召开
第一届肿瘤基础和转化医学国际研讨会 www.cancerasia.org 2010年10月12日-10月15日上海召开
凝聚社会力量 共抗癌症--生物谷专访中山大学肿瘤防治中心钱朝南研究员
生物谷推荐英文摘要：
JBC doi: 10.1074/jbc.M110.105544
WSS25 inhibits growth of xenografted hepatocellular cancer cells in nude mice by disrupting angiogenesis via blocking BMP/SMAD/ID1 signaling
Hong Qiu1, Bo Yang2, Zhi Chao Pei1, Zhang Zhang1 and Kan Ding1,*
The highly expressed Id1 (inhibitor of DNA binding/differentiation) protein promotes angiogenesis in HCC and is a well-established target for anti-angiogenesis therapeutic strategies. Heparan sulphate (HS) mimetics such as PI-88 can abrogate HS-protein interactions to inhibit angiogenesis. Id1 is the direct downstream effector of BMPs (Bone morphogenetic proteins), which are angiogenic and HS binding proteins. Thus, targeting BMPs by HS mimetics may inhibit angiogenesis via attenuating Id1 expression. We report here that a HS mimetic WSS25 potently inhibited the tube formation of HMEC-1 cells on Matrigel and their migration. Meanwhile, WSS25 (25 μg/mL) nearly completely blocked Id1 expression in the HMEC-1 cells as demonstrated by oligo-angiogenesis microarray analysis and further confirmed by RT-PCR and Western blotting. The BMP/Smad/Id1 signaling was also blocked by WSS25 treatment in the HMEC-1 cells. Importantly, Id1 knock-down in HMEC-1 cells caused the disruption of their tube formation on Matrigel. By employing quartz crystal microbalance (QCM) analysis, we found that WSS25 strongly bound to BMP2. Moreover, WSS25 impaired BMP2 induced tube formation of HMEC-1 cells on Matrigel and angiogenesis in Matrigel transplanted into C57BL6 mice. Furthermore, WSS25 (100 mg/kg) abrogated the growth of HCC cells xenografted in male nude mice. Immunohistochemical analysis showed that both the expression of Id1 and the endothelial cell marker CD31 were lower in the WSS25 treated tumor tissue than in the control. Therefore, WSS25 is a potential drug candidate for HCC therapy as a tumor angiogenesis inhibitor.
1 Shanghai Institute of Materia Medica, Chinese Academy of Sciences, China;
2 College of Pharmaceutical Sciences, Zhejiang University, China
