Published online Jul 14, 2022. doi: 10.3748/wjg.v28.i26.3132
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
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.
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.
The present study aimed to investigate the effect of NETs on the development of cancer-associated thrombosis in GC patients.
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).
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.
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.
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.