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Acta Pharmacol Sin. 2018 Aug;39(8):1326-1337. doi: 10.1038/aps.2017.189. Epub 2018 Feb 8.

CTC clusters induced by heparanase enhance breast cancer metastasis.

Author information

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.
3
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. xhuang@simm.ac.cn.
4
Division of Anti-tumor Pharmacology, State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai, 201203, China. jding@simm.ac.cn.

Abstract

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 clusters. We also suggest that targeting the function of heparanase in cancer cell dissemination might limit metastatic progression.

KEYWORDS:

CTC clusters; adhesion molecules; cell adhesion; heparanase; human breast cancer; metastasis; suspension culture method

PMID:
29417941
PMCID:
PMC6289387
[Available on 2019-08-01]
DOI:
10.1038/aps.2017.189
[Indexed for MEDLINE]

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