Polyphosphate expression by cancer cell extracellular vesicles mediates binding of factor XII and contact activation.
Polyphosphate expression by cancer cell extracellular vesicles mediates binding of factor XII and contact activation.
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癌细胞胞外囊泡表达多磷酸介导因子XII的结合和接触活化。
DOI：
10.1182/bloodadvances.2021005116
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发表时间：
2021-11-23
期刊：
影响因子：
7.5
通讯作者：
McCrae KR
中科院分区：
文献类型：
--
作者：
Shim YJ;Chatterjee V;Swaidani S;Alluri RK;Kundu S;Merkulova A;Angelini D;You D;Whitney SA;Feener EP;Barnard J;Schmaier AH;Khorana AA;McCrae KR
在许多癌症患者中观察到HK裂开，表明接触系统激活。来自癌细胞系或癌症患者的EV表达多磷酸盐，结合并激活FXII，并且是促血栓形成的。细胞外囊泡（EV）参与多种生物学过程，包括细胞内通讯、核酸转运和血管功能调节。EV水平在癌症中升高，研究表明EV可能通过组织因子的表达刺激癌症患者的血栓形成。然而，有限的数据还表明EV通过将因子XII（FXII）活化为FXIIa而参与凝血接触途径的活化。为了更好地定义EV启动接触激活的能力，我们比较了源自不同癌细胞系的EV激活FXII的能力。来自所有细胞系的EV激活FXII，其中来自胰腺癌和肺癌细胞系的EV表现出最有效的活性。与FXII的激活一致，EV诱导高分子量激肽原（HK）裂解为裂解的激肽原。我们还观察到来自癌症患者的EV刺激FXII活化和HK裂解。为了确定EV激活FXII的机制，用小牛肠碱性磷酸酶或大肠杆菌外聚磷酸酶处理EV以降解多磷酸盐;这种处理阻断了FXII与EV的结合以及EV介导FXII激活的能力。在体内，EV在野生型小鼠中诱导肺血栓形成，并通过FXII、HK或前激肽释放酶的缺乏提供保护。此外，用小牛肠碱性磷酸酶预处理EV可抑制其促血栓形成作用。这些结果表明，多磷酸盐介导的EV和EV相关的多磷酸盐的接触因子的结合可能有助于EV在癌症中的促血栓形成作用。
Cleaved HK is observed in many patients with cancer, suggesting activation of the contact system. EVs from cancer cell lines or patients with cancer express polyphosphate, bind and activate FXII, and are prothrombotic. Extracellular vesicles (EV) have been implicated in diverse biological processes, including intracellular communication, transport of nucleic acids, and regulation of vascular function. Levels of EVs are elevated in cancer, and studies suggest that EV may stimulate thrombosis in patients with cancer through expression of tissue factor. However, limited data also implicate EV in the activation of the contact pathway of coagulation through activation of factor XII (FXII) to FXIIa. To better define the ability of EV to initiate contact activation, we compared the ability of EV derived from different cancer cell lines to activate FXII. EV from all cell lines activated FXII, with those derived from pancreatic and lung cancer cell lines demonstrating the most potent activity. Concordant with the activation of FXII, EV induced the cleavage of high molecular weight kininogen (HK) to cleaved kininogen. We also observed that EVs from patients with cancer stimulated FXII activation and HK cleavage. To define the mechanisms of FXII activation by EV, EV were treated with calf intestinal alkaline phosphatase or Escherichia coli exopolyphosphatase to degrade polyphosphate; this treatment blocked binding of FXII to EVs and the ability of EV to mediate FXII activation. In vivo, EV induced pulmonary thrombosis in wild-type mice, with protection conferred by a deficiency in FXII, HK, or prekallikrein. Moreover, pretreatment of EVs with calf intestinal alkaline phosphatase inhibited their prothrombotic effect. These results indicate that polyphosphate mediates the binding of contact factors to EV and that EV-associated polyphosphate may contribute to the prothrombotic effects of EV in cancer.
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DOI：
10.1126/science.aau6977
发表时间：
2020-02-07
期刊：
Science (New York, N.Y.)
影响因子：
--
作者：
Kalluri R;LeBleu VS
通讯作者：
LeBleu VS
DOI：
10.1016/j.trsl.2020.06.012
发表时间：
2020-11
期刊：
Translational research : the journal of laboratory and clinical medicine
影响因子：
--
作者：
Kim AS;Khorana AA;McCrae KR
通讯作者：
McCrae KR
影响因子：
16.6
作者：
Labberton, Linda;Kenne, Ellinor;Renne, Thomas
通讯作者：
Renne, Thomas
影响因子：
56.9
作者：
DVORAK, HF;QUAY, SC;CARVALHO, AC
通讯作者：
CARVALHO, AC
影响因子：
2.7
作者：
Aschar-Sobbi, Roozbeh;Abramov, Andrey Y.;Pavlov, Evgeny
通讯作者：
Pavlov, Evgeny