Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response
Anticoagulation inhibits tumor cell-mediated release of platelet angiogenic proteins and diminishes platelet angiogenic response
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DOI：
10.1182/blood-2013-02-485011
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发表时间：
2014-01-02
期刊：
影响因子：
20.3
通讯作者：
Italiano, Joseph E., Jr.
中科院分区：
文献类型：
--
作者：
Battinelli, Elisabeth M.;Markens, Beth A.;Italiano, Joseph E., Jr.
血小板是在差异调节过程中分泌的血管生成蛋白的储存库。由于凝血的倾向，恶性肿瘤患者通常使用肝素产品进行抗凝治疗，这一产品通过一种未知的机制提供了生存益处。我们假设抗血栓药物改变了血小板血管生成调节蛋白的释放。我们的数据显示，暴露于肝素的血小板释放的血管内皮生长因子（VEGF）显着减少，以响应5 '-二磷酸腺苷或肿瘤细胞（MCF-7细胞），并表现出降低的血管生成潜力。这些血小板的释放物含有减少的促血管生成蛋白。新型抗凝剂磺达肝癸钠（Xa抑制剂）对血小板血管生成潜力具有类似的影响。由于这些抗凝剂减少凝血酶的产生，我们假设它们破坏了通过血小板蛋白酶激活受体1（PAR 1）受体的信号传导。加入PAR 1拮抗剂的血小板减少VEGF的释放和血管生成的潜力。在抗凝剂的存在下暴露于PAR 1激动剂挽救了血管生成潜力。体内研究表明，抗凝患者的血小板具有降低的VEGF释放和血管生成潜力。我们的数据表明，抗血栓药物增加癌症患者生存率和减少转移的机制是通过减弱血小板血管生成潜力。
Platelets are a reservoir for angiogenic proteins that are secreted in a differentially regulated process. Because of the propensity for clotting, patients with malignancy are often anticoagulated with heparin products, which paradoxically offer a survival benefit by an unknown mechanism. We hypothesized that antithrombotic agents alter the release of angiogenesis regulatory proteins from platelets. Our data revealed that platelets exposed to heparins released significantly decreased vascular endothelial growth factor (VEGF) in response to adenosine 5'-diphosphate or tumor cells (MCF-7 cells) and exhibited a decreased angiogenic potential. The releasate from these platelets contained decreased proangiogenic proteins. The novel anticoagulant fondaparinux (Xa inhibitor) demonstrated a similar impact on the platelet angiogenic potential. Because these anticoagulants decrease thrombin generation, we hypothesized that they disrupt signaling through the platelet protease-activated receptor 1 (PAR1) receptor. Addition of PAR1 antagonists to platelets decreased VEGF release and angiogenic potential. Exposure to a PAR1 agonist in the presence of anticoagulants rescued the angiogenic potential. In vivo studies demonstrated that platelets from anticoagulated patients had decreased VEGF release and angiogenic potential. Our data suggest that the mechanism by which antithrombotic agents increase survival and decrease metastasis in cancer patients is through attenuation of platelet angiogenic potential.