Tesakov Ivan, Korneichuk Anna D, Filkova Aleksandra A, Boldova Anna E, Deputatova Anna A, Kokhan Anatoly U, Korol Yuliya D, Mazova Kristina A, Pakina Viktoria A, Poleshko Anna G, Shumskiy Vladislav A, Blinova Ekaterina V, Blinov Dmitrii S, Shamova Ekaterina V, Panteleev Mikhail A, Sveshnikova Anastasia N
Dmitry Rogachev National Medical Research Center of Pediatric Hematology, Oncology, and Immunology, 1 Samory Mashela Str., 117997, Moscow, Russia.
Department of Oncology, Hematology, Immunology, and Rheumatology, University Hospital Tübingen, Tübingen, Germany.
J Mol Med (Berl). 2025 Aug 5. doi: 10.1007/s00109-025-02580-7.
Metastasis, a major complication in cancer, is known to depend on the interaction of tumor cells with platelets. However, anti-platelet therapy does not reliably increase survival rates. To address this, here we use light transmission aggregometry, flow cytometry, and confocal microscopy for characterization of human platelets interaction with six lines of tumor cell cultures. A murine model of Lewis carcinoma was used to test the effects of antiplatelet and anticoagulation therapy. Tumor-cell-induced platelet aggregation (TCIPA) correlated with the cell line invasive potential, required calcium and plasma proteins, and was only mildly suppressed by platelet inhibition. However, TCIPA was completely abolished by heparin, rivaroxaban, or dabigatran. For pre-fixed platelets, TCIPA was completely inhibited by the fibrin polymerization inhibitor GPRP. Tumor cells directly induced spatial fibrin polymerization in a factor X-dependent manner. Confocal microscopy confirmed platelet entrapment in the fibrin mesh formed around tumor cells. In the murine model of tumor cell injection, both anticoagulation and antiplatelet treatment reduced lung metastasis. These data suggest that formation of the fibrin mesh associated with a circulating tumor cell, with platelet entrapped in it (not necessarily in the activated state), could be an important early step in the metastasis development. KEY MESSAGES: Platelet-tumor cell heteroaggregates are stabilized by the fibrin network. Thrombin formation is induced by tumor cells, while platelet activation is less essential. Anticoagulant treatment prevents this interaction and may suppress metastasis.
转移是癌症的一种主要并发症，已知其取决于肿瘤细胞与血小板的相互作用。然而，抗血小板治疗并不能可靠地提高生存率。为了解决这个问题，我们在这里使用光透射聚集测定法、流式细胞术和共聚焦显微镜来表征人类血小板与六种肿瘤细胞培养系的相互作用。使用Lewis癌的小鼠模型来测试抗血小板和抗凝治疗的效果。肿瘤细胞诱导的血小板聚集（TCIPA）与细胞系的侵袭潜力相关，需要钙和血浆蛋白，并且仅被血小板抑制轻度抑制。然而，TCIPA被肝素、利伐沙班或达比加群完全消除。对于预固定的血小板，TCIPA被纤维蛋白聚合抑制剂GPRP完全抑制。肿瘤细胞以因子X依赖的方式直接诱导空间纤维蛋白聚合。共聚焦显微镜证实血小板被困在肿瘤细胞周围形成的纤维蛋白网中。在肿瘤细胞注射的小鼠模型中，抗凝和抗血小板治疗均减少了肺转移。这些数据表明，与循环肿瘤细胞相关的纤维蛋白网的形成，其中包裹着血小板（不一定处于活化状态），可能是转移发展的重要早期步骤。关键信息：血小板 - 肿瘤细胞异质聚集体由纤维蛋白网络稳定。肿瘤细胞诱导凝血酶形成，而血小板活化不太重要。抗凝治疗可防止这种相互作用并可能抑制转移。
