Basic Study
Copyright ©The Author(s) 2022. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Jul 14, 2022; 28(26): 3132-3149
Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3132
Neutrophil extracellular traps participate in the development of cancer-associated thrombosis in patients with gastric cancer
Jia-Cheng Li, Xiao-Ming Zou, Shi-Feng Yang, Jia-Qi Jin, Lei Zhu, Chang-Jian Li, Hao Yang, An-Ge Zhang, Tian-Qi Zhao, Chong-Yan Chen
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 by National 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
Abstract
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 are rarely reported in GC patients.

AIM

To investigate the effect of NETs on the development of cancer-associated thrombosis in GC patients.

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 procoagulant activity (PCA) was determined by fibrin formation and thrombin–antithrombin complex (TAT) assays. Thrombosis in vivo was measured in a murine model induced by flow stenosis in the inferior vena cava (IVC).

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, stimulated NET release from neutrophils. In addition, NETs induced a hypercoagulable state of platelets by upregulating the expression of phosphatidylserine and P-selectin on the cells. Furthermore, NETs stimulated the adhesion of normal platelets on glass surfaces. Similarly, NETs triggered the conversion of ECs to hypercoagulable phenotypes by downregulating the expression of their intercellular tight junctions but upregulating that of tissue factor. Treatment of normal platelets or ECs with NETs augmented the level of plasma fibrin formation and the TAT complex. In the models 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 I, activated protein C, and sivelestat markedly abolished the PCA of NETs.

CONCLUSION

GC-induced NETs strongly increased 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.

Keywords: Neutrophil extracellular traps, Gastric cancer, Platelet, Endothelial cells, Venous thromboembolism

Core tip: We found that gastric cancer (GC)-induced neutrophil extracellular traps (NETs) strongly increase the risk of venous thromboembolism (VTE) development in GC patients. NETs are potential therapeutic targets in the prevention and treatment of VTE in GC patients.