CTC clusters induced by heparanase enhance breast cancer metastasis  

作　　者：Rong-rui WEI Dan-ni SUN Hong YANG Juan YAN Xiong ZHANG Xing-ling ZHENG Xu-hong FU Mei-yu GENG Xun HUANG Jian DING 

机构地区：[1]Department of New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China [2]Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China

出　　处：《Acta Pharmacologica Sinica》2018年第8期1326-1337,共12页中国药理学报（英文版）

基　　金：This work was supported by the National Natural Science Foundation of China （No 81302791）, the Youth Innovation Promotion Association CAS, the Strategic Priority Research Program of the Chinese Academy of Sciences （No XDA12020326） and the Shanghai Talent Development Funds （No 201663）, all awarded to Xun HUANG.

摘　　要：Aggregated metastatic cancer cells, referred to as circulating tumor cell （CTC） clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase （HPSE）. Heparanase induced FAK- and ICAM-l-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.Aggregated metastatic cancer cells, referred to as circulating tumor cell （CTC） clusters, are present in the blood of cancer patients and contribute to cancer metastasis. However, the origin of CTC clusters, especially intravascular aggregates, remains unknown. Here, we employ suspension culture methods to mimic CTC cluster formation in the circulation of breast cancer patients. CTC clusters generated using these methods exhibited an increased metastatic potential that was defined by the overexpression of heparanase （HPSE）. Heparanase induced FAK- and ICAM-l-dependent cell adhesion, which promoted intravascular cell aggregation. Moreover, knockdown of heparanase or inhibition of its activity with JG6, a heparanase inhibitor, was sufficient to block the formation of cell clusters and suppress breast cancer metastasis. Our data reveal that heparanase-mediated cell adhesion is critical for metastasis mediated by intravascular CTC clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

关 键 词：human breast cancer CTC clusters HEPARANASE METASTASIS cell adhesion adhesion molecules suspension culture method 

分 类 号：TP316[自动化与计算机技术—计算机软件与理论] S682.33[自动化与计算机技术—计算机科学与技术]