展开的蛋白质反应将ER压力与癌症相关的血栓形成联系起来
Oluwatoyosi Muse1, Rushad Patell1, Christian G Peters1
1Division of Hemostasis and Thrombosis, Department of Medicine, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, Massachusetts, USA.
JCI insight
|August 31, 2023
概括
癌细胞中的未折叠蛋白质反应 (UPR) 激活增强了前血栓外细胞囊泡的释放. 这种ER压力机制提供了癌症和血栓形成之间的联系,提供了新的治疗点.
科学领域:
- 在瘤学瘤学.
- 血液学 血液学 血液学
- 细胞生物学 细胞生物学
背景情况:
- 血栓形成是晚期癌症的常见并发症.
- 癌症与血栓形成的确切细胞机制尚不清楚.
- 展开的蛋白质反应 (UPR) 是一个内质网膜 (ER) 应激途径,与晚期癌症有关.
研究的目的:
- 调查UPR在癌症相关血栓形成中的作用.
- 阐明癌症促进血栓形成的细胞机制.
- 确定预防与癌症相关的静脉血栓栓塞的潜在治疗点.
主要方法:
- 来自癌症患者血的蛋白质组分析.
- 评估癌细胞上浮体中的前凝剂活性.
- 研究UPR诱导和抑制对细胞外囊泡释放的影响.
- 使用siRNA介导的淘汰和UPR通路的药理学抗剂.
- 检查囊泡性贩运在组织因子输送中的作用.
主要成果:
- 血中升高的UPR标志物与癌症患者的静脉血栓栓塞相关.
- 诱导UPR增强了癌细胞中的血凝剂释放,由IRE1α和PERK介导.
- UPR激活刺激了组织因子 (TF) 的细胞表面局部化.
- 携带TF的细胞外囊泡 (EVTF) 的释放取决于UPR和囊泡贩运途径.
结论:
- UPR激活通过增加原血栓性EVTFs的释放来促进癌症中的血栓形成.
- 这项研究确立了ER压力与癌症相关的血栓形成之间的机制联系.
- 准UPR和膀性贩运途径可能为管理癌症血栓形成提供新的策略.
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