Li JC, Zou XM, Yang SF, Jin JQ, Zhu L, Li CJ, Yang H, Zhang AG, Zhao TQ, Chen CY. Neutrophil extracellular traps participate in the development of cancer-associated thrombosis in patients with gastric cancer. World J Gastroenterol 2022; 28(26): 3132-3149 [PMID: 36051331 DOI: 10.3748/wjg.v28.i26.3132]
Corresponding Author of This Article
Xiao-Ming Zou, MD, PhD, Chief Doctor, Professor, Surgeon, Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, Heilongjiang Province, China. zou4930@163.com
Research Domain of This Article
Oncology
Article-Type of This Article
Basic Study
Open-Access Policy of This Article
This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Jia-Cheng Li, Xiao-Ming Zou, Shi-Feng Yang, Lei Zhu, Chang-Jian Li, Hao Yang, An-Ge Zhang, Tian-Qi Zhao, Chong-Yan Chen, Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Jia-Cheng Li, Shi-Feng Yang, Jia-Qi Jin, Lei Zhu, Hao Yang, An-Ge Zhang, The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Jia-Qi Jin, Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China
Author contributions: Zou XM and Li JC designed the study, completed the experiments, and drafted the manuscript; Yang SF, Zhao TQ, and Jin JQ collected the patient clinical data and performed part of the experiments; Zhu L, Li CJ, and Chen CY participated in the animal experiments; Yang H and Zhang AG performed the statistical analysis; all authors have read and approved the final manuscript.
Supported byNational Natural Science Foundation of China, No. 81672355.
Institutional review board statement: The study was reviewed and approved by the ethics committee of the Second Affiliated Hospital of Harbin Medical University (No. KY2016-032).
Institutional animal care and use committee statement: All animal experiments in this study were approved by the ethics committee of the Second Affiliated Hospital of Harbin Medical University (No. KY2016-032).
Conflict-of-interest statement: The authors declare no conflict of interest for this manuscript.
Data sharing statement: No additional data are available.
ARRIVE guidelines statement: The authors have read the ARRIVE guidelines, and the manuscript was prepared and revised according to the ARRIVE guidelines.
Open-Access: This article is an open-access article that was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution NonCommercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: https://creativecommons.org/Licenses/by-nc/4.0/
Corresponding author: Xiao-Ming Zou, MD, PhD, Chief Doctor, Professor, Surgeon, Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, No. 246 Xuefu Road, Nangang District, Harbin 150001, Heilongjiang Province, China. zou4930@163.com
Received: October 19, 2021 Peer-review started: October 19, 2021 First decision: January 11, 2022 Revised: January 20, 2022 Accepted: March 16, 2022 Article in press: March 16, 2022 Published online: July 14, 2022 Processing time: 266 Days and 21.2 Hours
ARTICLE HIGHLIGHTS
Research background
The development of venous thromboembolism (VTE) is associated with high mortality among gastric cancer (GC) patients. Neutrophil extracellular traps (NETs) have been reported to correlate with the prothrombotic state in some diseases, but it was rarely reported in GC patients.
Research motivation
Cancer cells exert a procoagulant activity (PCA) in their microenvironment, which is related to activation of the coagulation system. However, the molecular mechanism underlying PCA in GC patients is poorly understood.
Research objectives
The present study aimed to investigate the effect of NETs on the development of cancer-associated thrombosis in GC patients.
Research methods
The levels of NETs in blood and tissue samples of patients were analyzed by ELISA, flow cytometry, and immunofluorescence staining. NET generation and hypercoagulation of platelets and endothelial cells (ECs) in vitro were observed by immunofluorescence staining. NET PCA was determined by fibrin formation and thrombin–antithrombin complex assays. Thrombosis in vivo was measured in a murine model induced by flow stenosis in the inferior vena cava (IVC).
Research results
NETs were likely to form in blood and tissue samples of GC patients compared with healthy individuals. In vitro studies showed that GC cells and their conditioned medium, but not gastric mucosal epithelial cells, can stimulate NET release from neutrophils. Furthermore, NETs induced hypercoagulable state of platelets and ECs. In a model of IVC stenosis, tumor-bearing mice showed a stronger ability to form thrombi, and NETs abundantly accumulated in the thrombi of tumor-bearing mice compared with control mice. Notably, the combination of deoxyribonuclease, activated protein C, and sivelestat markedly abolished the PCA of NETs.
Research conclusions
Our findings demonstrate that GC-induced NETs strongly increase the risk of VTE development both in vitro and in vivo. NETs are potential therapeutic targets in the prevention and treatment of VTE in GC patients.
Research perspectives
The treatment strategies can consider the combination of traditional anticoagulant drugs and NETs inhibiting drugs, so as to reduce the risk of cancer associated thrombosis in patients with GC and improve the clinical treatment effect.
