Pharmaceutical Institute, University of Bonn, An der Immenburg 4, 53121 Bonn, Germany.
Int J Mol Sci. 2021 Mar 24;22(7):3323. doi: 10.3390/ijms22073323.
Pancreatic cancer patients have an elevated risk of suffering from venous thrombosis. Among several risk factors that contribute to hypercoagulability of this malignancy, platelets possess a key role in the initiation of clot formation. Although single mechanisms of platelet activation are well-known in principle, combinations thereof and their potential synergy to mediate platelet activation is, in the case of pancreatic cancer, far from being clear. Applying an inhibitor screening approach using light transmission aggregometry, dense granule release, and thrombin formation assays, we provide evidence that a combination of tissue factor-induced thrombin formation by cancer cells and their platelet P-selectin binding is responsible for AsPC-1 and Capan-2 pancreatic cancer cell-mediated platelet activation. While the blockade of one of these pathways leads to a pronounced inhibition of platelet aggregation and dense granule release, the simultaneous blockade of both pathways is inevitable to prevent platelet aggregation completely and minimize ATP release. In contrast, MIA PaCa-2 pancreatic cancer cells express reduced levels of tissue factor and P-selectin ligands and thus turn out to be poor platelet activators. Consequently, a simultaneous blockade of thrombin and P-selectin binding seems to be a powerful approach, as mediated by heparin to crucially reduce the hypercoagulable state of pancreatic cancer patients.
胰腺癌患者易患静脉血栓形成。在导致这种恶性肿瘤高凝状态的几个危险因素中，血小板在血栓形成的启动中起着关键作用。尽管血小板激活的单一机制在原则上是众所周知的，但在胰腺癌的情况下，这些机制的组合及其潜在的协同作用来介导血小板激活还远未清楚。应用使用透光比浊法、致密颗粒释放和凝血酶形成测定的抑制剂筛选方法，我们提供的证据表明，癌细胞诱导的组织因子诱导的凝血酶形成与癌细胞的血小板 P-选择素结合相结合，导致了 AsPC-1 和 Capan-2 胰腺癌细胞介导的血小板激活。虽然阻断其中一种途径会导致血小板聚集和致密颗粒释放明显抑制，但同时阻断这两种途径是防止血小板聚集完全和最小化 ATP 释放所必需的。相比之下，MIA PaCa-2 胰腺癌细胞表达的组织因子和 P-选择素配体水平降低，因此表现为较差的血小板激活剂。因此，通过肝素同时阻断凝血酶和 P-选择素结合似乎是一种有效的方法，可以显著降低胰腺癌患者的高凝状态。
