High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors
High-level secretion of tissue factor-rich extracellular vesicles from ovarian cancer cells mediated by filamin-A and protease-activated receptors
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DOI：
10.1160/th15-03-0213
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发表时间：
2016-02-01
影响因子：
6.7
通讯作者：
Miyagi, Yohei
中科院分区：
文献类型：
--
作者：
Koizume, Shiro;Ito, Shin;Miyagi, Yohei
血栓栓塞事件在卵巢癌患者中经常发生。组织因子（TF）通常在肿瘤中过表达，包括卵巢透明细胞癌（CCC），这是一种预后不良的亚型。细胞表面上的TF-凝血因子VII（fVII）复合物激活下游凝血机制。此外，癌细胞分泌细胞外囊泡（EV），其充当TF的载体。因此，我们研究了不同组织学亚型的卵巢癌细胞产生的EV的特征。CCC细胞在EV内分泌高水平的TF，而高TF表达的乳腺癌细胞系MDA-MB-231脱落较少的TF阳性EV。我们还发现，CCC肿瘤与缺氧组织区域合成TF和fVII在体内，使这些肿瘤的异种移植小鼠的血液与MDA-MB-231肿瘤的小鼠相比，血液高凝。TF向EV的掺入和暴露于缺氧的CCC细胞的EV的分泌都依赖于肌动蛋白结合蛋白filamin-A（filA）。此外，这些EV的产生依赖于细胞表面上不同的蛋白酶激活受体（PAR）。这些结果表明CCC细胞可以产生大量依赖于filA和PAR的TF阳性EV。这种现象可能是卵巢癌患者静脉血栓栓塞发生率增加的机制。
Thromboembolic events occur frequently in ovarian cancer patients. Tissue factor (TF) is often overexpressed in tumours, including ovarian clear-cell carcinoma (CCC), a subtype with a generally poor prognosis. TF-coagulation factor VII (fVII) complexes on the cell surface activate downstream coagulation mechanisms. Moreover, cancer cells secrete extracellular vesicles (EVs), which act as vehicles for TF. We therefore examined the characteristics of EVs produced by ovarian cancer cells of various histological subtypes. CCC cells secreted high levels of TF within EVs, while the high-TF expressing breast cancer cell line MDA-MB-231 shed fewer TF-positive EVs. We also found that CCC tumours with hypoxic tissue areas synthesised TF and fVII in vivo, rendering the blood of xenograft mice bearing these tumours hypercoagulable compared with mice bearing MDA-MB-231 tumours. Incorporation of TF into EVs and secretion of EVs from CCC cells exposed to hypoxia were both dependent on the actin-binding protein, filamin-A (filA). Furthermore, production of these EVs was dependent on different protease-activated receptors (PARs) on the cell surface. These results show that CCC cells could produce large numbers of TF-positive EVs dependent upon filA and PARs. This phenomenon may be the mechanism underlying the increased incidence of venous thromboembolism in ovarian cancer patients.