Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis
Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis
复制标题
来自岩藻糖基化糖胺聚糖的寡糖通过抑制乙酰肝素酶活性和血管生成来预防小鼠乳腺癌转移
DOI：
10.1016/j.phrs.2021.105527
复制
发表时间：
2021
影响因子：
9.3
通讯作者：
Jinhua Zhao
中科院分区：
文献类型：
--
作者：
Lutan Zhou;Ronghua Yin;Na Gao;Huifang Sun;Dingyuan Chen;Ying Cai;Lin Ren;Lian Yang;Zhili Zuo;Hongbin Zhang;Jinhua Zhao
肿瘤细胞的侵袭和转移是恶性疾病的标志，也是需要克服的最大障碍。乙酰肝素酶介导的硫酸乙酰肝素（HS）降解是肿瘤血管生成和转移的关键过程，因此，乙酰肝素酶成为肿瘤研究的一个有吸引力的靶点。本文报道了一种从海参中提取的天然岩藻糖基化糖胺聚糖（nHG）和一种解聚的nHG（dHG）及其所含的寡糖（hs 17、hs 14、hs 11、hs 8和hs 5）作为乙酰肝素酶抑制剂的研究结果。nHG及其衍生物具有与乙酰肝素酶直接结合的能力，导致乙酰肝素酶活性的显著抑制。此外，它们对乙酰肝素酶的表观结合亲和力与它们的抑制作用相当，其抑制作用随着链长的增加而沿着升高，类似于肝素的作用。此外，寡糖抑制4T1乳腺癌细胞和人脐静脉内皮细胞（HUVECs）的迁移和侵袭，还抑制Matrigel基质中的管形成和鸡绒毛尿囊膜（CAM）测定中的血管生成。在转移性小鼠模型中，寡糖对4T1乳腺癌细胞表现出实际的抗转移作用。根据已报道的dHG及其寡糖的抗凝活性和低出血倾向，使用寡糖可能对有血栓形成倾向的肿瘤患者产生更好的效果。
The invasion and metastasis of tumor cells are the hallmarks of malignant diseases and the greatest obstacle to overcome. Heparanase-mediated degradation of heparan sulfate (HS) is the critical process for tumor angiogenesis and metastasis, therefore, heparanase become an attractive target for cancer research. Herein, we reported a native fucosylated glycosaminoglycan (nHG) extracted from sea cucumberHolothuria fuscopunctataand a depolymerized nHG (dHG) and its contained oligosaccharides (hs17, hs14, hs11, hs8 and hs5), acting as heparanase inhibitors. nHG and its derivatives have the ability to bind with heparanase directly, leading to significant inhibition of heparanase activity. Moreover, their apparent binding affinity to heparanase was comparable to their inhibitory effect, which was elevated along with the increase of chain length, similar to the effect of heparins. In addition, oligosaccharides inhibited the migration and invasion of 4T1 mammary carcinoma cells and human umbilical vein endothelial cells (HUVECs) and also suppressed tube formation in Matrigel matrix and angiogenesis in the chick chorioallantoic membrane (CAM) assay. In the metastatic mouse model, oligosaccharides exhibited practical antimetastatic effects on 4T1 mammary carcinoma cells. According to the reported anticoagulant activity and the low bleeding tendency of dHG and its oligosaccharides, the use of the oligosaccharides may lead to better effects on tumor patients with thrombosis tendency.