Oncotarget

Research Papers:

Activated platelets inhibit hepatocellular carcinoma cell differentiation and promote tumor progression via platelet-tumor cell binding

Rongfeng Zhang, Huishu Guo, Jingchao Xu, Bing Li, Yue-Jian Liu, Cheng Cheng, Chunyan Zhou, Yongfu Zhao and Yang Liu _

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Oncotarget. 2016; 7:60609-60622. https://doi.org/10.18632/oncotarget.11300

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Abstract

Rongfeng Zhang1,*, Huishu Guo2,*, Jingchao Xu3, Bing Li4, Yue-Jian Liu2, Cheng Cheng5, Chunyan Zhou6, Yongfu Zhao3, Yang Liu1

1Institute of Heart and Vascular Diseases, First Affiliated Hospital of Dalian Medical University, Dalian, China

2Department of Central Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China

3Department of General Surgery, Second Affiliated Hospital of Dalian Medical University, Dalian, China

4Department of Clinical Laboratory, First Affiliated Hospital of Dalian Medical University, Dalian, China

5Translational Research on Neurological Diseases Center, First Affiliated Hospital of Dalian Medical University, Dalian, China

6Department of Clinical Pharmacy, First Affiliated Hospital of Dalian Medical University, Dalian, China

*These authors have contributed equally to this work

Correspondence to:

Yang Liu, email: liuyang19831119@163.com

Yongfu Zhao, email: dl.zyf67@163.com

Keywords: platelet, clopidogrel, tumor differentiation, hepatocellular carcinoma, TCF4

Received: January 17, 2016     Accepted: July 26, 2016     Published: August 16, 2016

ABSTRACT

Lack of differentiation in hepatocellular carcinoma (HCC) is associated with increased circulating platelet size. We measured platelet activation and plasma adenosine diphosphate (ADP) levels in HCC patients based on differentiation status. Local platelet accumulation and platelet-hepatoma cell binding were measured using immunohistochemistry (IHC) or flow cytometry. Using a xenograft assay in NON/SCID mice, we tested the effects of the anti-platelet drug clopidogrel on platelet activation, platelet infiltration, platelet-tumor cell binding and tumor cell differentiation. HCC patients with poor differentiation status displayed elevated platelet activation and higher ADP levels. Platelets accumulated within poorly differentiated tissues and localized at hepatoma cell membranes. Platelet-tumor cell binding was existed in carcinoma tissues, largely mediated by P-selectin on platelets. NOD/SCID mice with xenograft tumors also exhibited increased platelet activation and platelet-tumor cell binding. Clopidogrel therapy triggered hepatoma cell differentiation by attenuating platelet activation and platelet-tumor cell binding. TCF4 knockdown promoted HepG-2 cell differentiation and inhibited tumor formation, and TCF4 could be the potential downstream target for clopidogrel therapy.


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