中性粒细胞胞外诱捕网参与胃癌患者癌症相关血栓形成的发生。
Neutrophil extracellular traps participate in the development of cancer-associated thrombosis in patients with gastric cancer.
机构信息
Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
The Key Laboratory of Myocardial Ischemia, Harbin Medical University, Harbin 150001, Heilongjiang Province, China.
出版信息
World J Gastroenterol. 2022 Jul 14;28(26):3132-3149. doi: 10.3748/wjg.v28.i26.3132.
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) were observed by immunofluorescence staining. NET procoagulant activity (PCA) was determined by fibrin formation and thrombin-antithrombin complex (TAT) assays. Thrombosis 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. 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 and . NETs are potential therapeutic targets in the prevention and treatment of VTE in GC patients.
背景
静脉血栓栓塞症（VTE）的发展与胃癌（GC）患者的高死亡率相关。中性粒细胞胞外诱捕网（NETs）已被报道与一些疾病的血栓前状态相关，但在 GC 患者中很少有报道。
目的
研究 NETs 对 GC 患者癌相关血栓形成的影响。
方法
通过 ELISA、流式细胞术和免疫荧光染色分析患者血液和组织样本中的 NETs 水平。通过免疫荧光染色观察 NET 的生成以及血小板和内皮细胞（ECs）的过度凝血。通过纤维蛋白形成和凝血酶-抗凝血酶复合物（TAT）测定来确定 NET 促凝活性（PCA）。通过下腔静脉（IVC）狭窄诱导的小鼠模型来测量血栓形成。
结果
与健康个体相比，GC 患者的血液和组织样本中更有可能形成 NETs。研究表明，GC 细胞及其条件培养基，但不是胃黏膜上皮细胞，刺激中性粒细胞释放 NETs。此外，NETs 通过上调细胞上的磷脂酰丝氨酸和 P 选择素表达来诱导血小板的高凝状态。此外，NETs 刺激正常血小板在玻璃表面上的粘附。同样，NETs 通过下调细胞间紧密连接的表达但上调组织因子的表达来触发 ECs 向高凝表型的转化。用 NETs 处理正常血小板或 ECs 会增加血浆纤维蛋白形成和 TAT 复合物的水平。在 IVC 狭窄模型中，荷瘤小鼠形成血栓的能力更强，与对照组小鼠相比，NETs 在荷瘤小鼠的血栓中大量积累。值得注意的是，脱氧核糖核酸酶 I、活化蛋白 C 和西维来司他联合治疗可显著消除 NETs 的 PCA。
结论
GC 诱导的 NETs 强烈增加了 VTE 发展的风险。NETs 是预防和治疗 GC 患者 VTE 的潜在治疗靶点。
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