CTC clusters induced by heparanase enhance breast cancer metastasis

Authors: Rong-rui WEI1, Dan-ni SUN2, Hong YANG2, Juan YAN2, Xiong ZHANG2, Xing-ling ZHENG2, Xu-hong FU2, Mei-yu GENG2, Xun HUANG2, Jian DING2
1 Department of New Drug Screening Center, China Pharmaceutical University, Nanjing 210009, China
2 2Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China
Corresponding to: Xun HUANG:, Jian DING:,
DOI: 10.1038/aps.2017.189
Received: 18 August 2017
Accepted: 26 November 2017
Advance online: 8 February 2018


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-1-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
Keywords: human breast cancer; CTC clusters; heparanase; metastasis; cell adhesion; adhesion molecules; suspension culture method