Oligosaccharides from fucosylated glycosaminoglycan prevent breast cancer metastasis in mice by inhibiting heparanase activity and angiogenesis. (April 2021)

• Record Type: Journal Article
• Authors: Zhou, Lutan; Yin, Ronghua; Gao, Na; Sun, Huifang; Chen, Dingyuan; Cai, Ying; Ren, Lin; Yang, Lian; Zuo, Zhili; Zhang, Hongbin; Zhao, Jinhua
• Is Part Of: Pharmacological research. Volume 166(2021)
• Publication Date: 2021-04
• Subjects: BM basement membrane -- CAM chick chorioallantoic membrane -- dHG a depolymerized nHG -- ECM extracellular matrix -- FGF fibroblast growth factor -- HGF hepatocyte growth factor -- HS heparan sulfate -- HSPG heparan sulfate proteoglycans -- HUVECs human umbilical vein endothelial cells -- iXase intrinsic Xase -- KGF keratinocyte growth factor -- HTRF homogeneous time-resolved fluorescence -- LMWH low molecular weight heparin -- LUC-4T1 luciferase-labeled 4T1 mammary carcinoma cells -- nHG native fucosylated glycosaminoglycan -- PDB protein data bank -- TGF-β transforming growth factor β -- UFH unfractionated heparin -- VEGF vascular endothelial growth factor -- VTE venous thromboembolism; Oligosaccharides -- Heparanase -- Angiogenesis -- Metastasis; Pharmacology -- Periodicals; Pharmacology -- Periodicals; Research -- Periodicals; Médicaments -- Recherche -- Périodiques; Pharmacologie -- Périodiques; 615.105
• DOI: 10.1016/j.phrs.2021.105527
• Languages: English
• ISSNs: 1043-6618

Abstract

Abstract: 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 cucumber Holothuria fuscopunctata and 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. Graphical Abstract: ga1 Highlights: Fucosylated GAG and its derivatives are discovered as heparanase inhibitors. Oligosaccharides originated from FG inhibit cell migration and invasion in vitro . The oligosaccharides inhibit tube formation and angiogenesis. The oligosaccharides suppress tumor cell metastasis in mice.