2024 年第 3 期 第 19 卷

细胞外组蛋白与膀胱癌相关血栓形成的研究进展

Research progress of extracellular histones and bladder cancer-related thrombosis

作者：张行军王锦锐车宪平

英文作者：Zhang Xingjun Wang Jinrui Che Xianping

单位：海南医学院第二附属医院泌尿外科一区，海口570311

英文单位：The First Ward of Department of Urology the Second Affiliated Hospital of Hainan Medical University Haikou 570311 China

关键词：膀胱癌；细胞外组蛋白；血栓

英文关键词：Bladdercancer;Extracellularhistone;Thrombus

• 摘要：

• 膀胱恶性肿瘤的患者都处于高凝状态。然而，肿瘤引起这种高凝状态的机制尚不完全清楚。本文综述了现有的人类和动物研究细胞外组蛋白和癌症相关血栓形成的文献。肽基精氨酸脱亚胺酶4（PAD4）对组蛋白的瓜氨酸化被认为是导致中性粒细胞释放细胞外组蛋白的关键途径之一。膀胱癌细胞可以通过释放可溶性介质（如白细胞介素8）和激活血小板来促进中性粒细胞释放细胞外组蛋白。外源性DNA酶已被证明可以在体外降解细胞外组蛋白并减少血栓形成。目前临床上还未使用PAD4抑制剂，但动物模型提示了其有效的结果和安全性。动物实验结果表明，一些被批准用于其他适应证的疗法，如白细胞介素1受体阻断剂和Janus蛋白酪氨酸激酶抑制剂，可能减轻细胞外组蛋白在癌症中的形成或其促血栓作用。抑制细胞外组蛋白的形成是否也能减少癌症相关的血栓形成在临床上还未确定。

• Patients with bladder malignancies are in a hypercoagulable state. However, the mechanism by which tumors cause this hypercoagulable state is not fully understood. This article reviews the existing literature on human and animal studies of extracellular histones and cancer-related thrombosis. Citrullination of histone proteins by peptidylarginine deiminase 4 (PAD4) is considered to be one of the key pathways leading to the release of extracellular histones by neutrophils. Bladder cancer cells can promote the release of extracellular histones by neutrophils through the release of soluble mediators such as interleukin-8 and activation of platelets. Exogenous dnase has been shown to degrade extracellular histones and reduce thrombosis in vitro. PAD4 inhibitors are not currently in clinical use, but animal models suggest effective results and safety. Results  from studies in animals suggest that some therapies approved for other indications, such as interleukin-1 receptor blockers and Janus protein tyrosine kinase inhibitors, may attenuate the formation of extracellular histones or their prothrombotic effects in cancer. Whether inhibition of extracellular histone formation also reduces cancer-associated thrombosis is clinically uncertain.