Abstract
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.
Highlights
Among all common human malignancies, patients suffering from pancreatic cancer have the highest risk of clinically apparent venous thromboembolism in the first year after cancer diagnosis [1,2]
A combination of P-selectin blockade and inhibition of the plasmatic coagulation cascade seems likely for synergistic activity in attenuating platelet aggregation by both tumor cell lines. These findings indicate that tissue factor (TF) expression on pancreatic cancer cells and the subsequent generation of thrombin contribute to a procoagulant cellular phenotype
The close interaction tumor cells and is platelet well-known andmechanism for consisting of P-selectin and thrombin generation induced by AsPC-1 and Capan-2 panpancreatic cancer patients a highly relevant fact that determines their coagulation status
Summary
Among all common human malignancies, patients suffering from pancreatic cancer have the highest risk of clinically apparent venous thromboembolism in the first year after cancer diagnosis [1,2]. Several risk factors have been identified to be associated with hypercoagulability, classified as patient-, tumor- or treatment-related factors. In the case of pancreatic cancer, the tumor localization and stage of the disease, a probable metastatic burden, mucin secretion by the cancer cells, chemotherapeutic treatment, surgical interventions, or obesity, among other factors can shift the hemostatic equilibrium to a pre- or even thrombotic state [3,4,5]. While the clinical observations and identified risk factors are relatively clear and unambiguous, the molecular mechanisms contributing to a status of increased coagulation are only partially understood. Platelet aggregation induced by cancer cells is regarded as a key factor and initiator of the hypercoagulable state in malignancies. Platelets contribute to cancer progression by numerous mechanisms and have a pivotal impact on the protumorigenic capacity
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