Department of Pharmacy, University Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Molecules. 2018 Oct 24;23(11):2753. doi: 10.3390/molecules23112753.
An intimate interplay with platelets is an initial key issue for tumor cells in terms of hematogenous metastasis. Tumor cells activate platelets by different pathways and receive, upon forming a platelet cloak, protection from immune surveillance and support in metastatic niche creation. Therapeutic intervention with this early interaction is promising to antagonize the whole metastatic cascade. Here we aimed to investigate the capability of low molecular weight heparin (LMWH), unfractionated heparin (UFH), and a non-anticoagulant heparin derivative or FXa inhibitor fondaparinux to interfere with platelet activation by tumor cells. Coagulation-dependent and independent pathways of platelet activation by three tumor cell lines, and interference therewith were analyzed by fluorigenic thrombin formation assay, platelet aggregometry, ATP and VEGF release and endothelial tube formation assay. LMWH and UFH were found to repress various routes of platelet activation, reflected by attenuated endothelial tube formation. This confirms the duality of anti-coagulative and anti-adhesive properties of heparin. While non-anticoagulative heparin (RO-heparin) depressed platelets' ATP and VEGF release by contact inhibition sufficiently, fondaparinux just attenuated tissue factor mediated thrombin generation. Concluding, these data suggest that LMWH as a guideline-based drug for anticoagulative strategies in oncology is promising to provide additional benefit for interference with metastatic activities.
肿瘤细胞发生血行转移初始的关键问题之一是与血小板的密切相互作用。肿瘤细胞通过不同途径激活血小板，形成血小板“外衣”后，获得免受免疫监视和支持转移灶形成的保护。通过这种早期相互作用进行治疗干预，有望拮抗整个转移级联反应。在这里，我们旨在研究低分子量肝素 (LMWH)、未分级肝素 (UFH) 以及非抗凝肝素衍生物或 FXa 抑制剂磺达肝素钠抑制肿瘤细胞激活血小板的能力。通过荧光法血栓形成测定、血小板聚集测定、ATP 和 VEGF 释放以及内皮管形成测定分析三种肿瘤细胞系的血小板激活的凝血依赖性和非依赖性途径及其干扰情况。LMWH 和 UFH 被发现抑制血小板的各种激活途径，这反映在减弱的内皮管形成上。这证实了肝素抗凝和抗黏附特性的双重性。而非抗凝肝素 (RO 肝素) 通过接触抑制充分抑制血小板的 ATP 和 VEGF 释放，而磺达肝素钠仅减弱组织因子介导的凝血酶生成。总之，这些数据表明，LMWH 作为肿瘤学抗凝策略的指南药物，有望为干预转移活动提供额外的益处。
