肿瘤表面拥有一层厚厚的“糖衣盔甲”，如何在化疗时，让药物顺利通过这一屏障？上海交通大学附属第六人民医院检验科主任高锋教授课题组潜心攻关10余年，利用生化手段，在基础研究中将“糖外衣”分解片段，并最终击碎肿瘤“糖衣盔甲”。
此项“以毒攻毒”的研究成果发表在国际生物化学刊物《journal of biological chemistry (JBC)》(2012年12月刊)上。专家认为，该研究为肿瘤化疗提供了有力的理论证据，同时也有望开辟肿瘤靶向治疗的新路径。
据高锋教授介绍，人体细胞表面有无数的分子环绕着，医学上统称为细胞外基质成分。肿瘤发生时，这些分子会发生成分改变，其中有部分肿瘤如乳腺癌、结肠癌、头颈部癌等的细胞表面会出现膜受体重新分布、膜受体被诱导而局部聚集成簇的现象。由此肿瘤表面形成了一层厚厚的“糖衣盔甲”，化疗时，这也是导致疗效不佳的一个重要因素。
透明质酸是细胞外最多的糖分子，它与细胞的连接首先要通过受体CD44相互作用，在细胞外形成富含水的微环境。这个微环境就好比给细胞穿上了衬衣，而当乳腺癌形成时，这件衬衣变成了厚厚的羽绒服并把肿瘤保护起来。多年来，国内外的科学家们一直试图找到破解保护衣的手段，以期在化疗时，能够让药物有效地进入肿瘤细胞里面。
“能不能利用不会被分解的分子取代HA消化酶和抗体呢？”在这个思路的引导下，课题组于2008年瞄准了HA本身的分解片段，即透明质酸寡分子（oHA）。在导师高锋教授的指导下，杨翠霞博士及课题组进行了三个阶段的研究，最后应用纳米手段将药物连接到oHA上，并伪装形成肿瘤细胞的“盟友”，潜入肿瘤表面，有效攻击“糖衣盔甲”，并在动物体内对照组得到验证，结果表明该方法使化疗药物治疗肿瘤模型的疗效提高了50%。
The High and Low Molecular Weight Forms of Hyaluronan Have Distinct Effects on CD44 Clustering.
Cuixia Yang,Manlin Cao,Hua Liu,Yiqing He,Jing Xu,Yan Du,Yiwen Liu,Wenjuan Wang,Lian Cui,Jiajie Hu and Feng Gao
Abstract：CD44 is a major cell surface receptor for the glycosaminoglycan hyaluronan (HA). Native high molecular weight hyaluronan (nHA) and oligosaccharides of hyaluronan (oHA) provoke distinct biological effects upon binding to CD44. Despite the importance of such interactions, however, the feature of binding with CD44 at the cell surface and the molecular basis for functional distinction between different sizes of HA is still unclear. In this study we investigated the effects of high and low molecular weight hyaluronan on CD44 clustering.For the first time, we provided direct evidence for a strong relationship between HA size and CD44 clustering in vivo. In CD44-transfected COS-7 cells, we showed that exogenous nHA stimulated CD44 clustering, which was disrupted by oHA. Moreover, naturally expressed CD44 was distributed into clusters due to abundantly expressed nHA in HK-2 cells (human renal proximal tubule cells) and BT549 cells (human breast cancer cell line) without exogenous stimulation. Our results suggest that native HA binding to CD44 selectively induces CD44 clustering, which could be inhibited by oHA. Finally, we demonstrated that HA regulates cell adhesion in a manner specifically dependent on its size.
文献链接：The High and Low Molecular Weight Forms of Hyaluronan Have Distinct Effects on CD44 Clustering.
