A Combined Activity of Thrombin and P-Selectin Is Essential for Platelet Activation by Pancreatic Cancer Cells.

Publisher: MDPI Country of Publication: Switzerland NLM ID: 101092791 Publication Model: Electronic Cited Medium: Internet ISSN: 1422-0067 (Electronic) Linking ISSN: 14220067 NLM ISO Abbreviation: Int J Mol Sci Subsets: MEDLINE

Original Publication: Basel, Switzerland : MDPI, [2000-

Platelet Activation*; P-Selectin/*chemistry ; Pancreatic Neoplasms/*metabolism ; Thrombin/*chemistry ; Venous Thrombosis/*metabolism; Blood Platelets/metabolism ; Cell Line, Tumor ; Humans ; Ligands ; Platelet Adhesiveness ; Platelet Aggregation ; Risk Factors ; Thrombophilia ; Thromboplastin/metabolism ; Venous Thrombosis/complications ; Pancreatic Neoplasms

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.

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not applicable Kirstin Diehl Foundation, Neuwied, Germany

Keywords: P-selectin; dense granule release; hypercoagulability; pancreatic cancer; platelet aggregation; platelets; thrombin; tissue factor

0 (Ligands)
0 (P-Selectin)
0 (SELP protein, human)
9035-58-9 (Thromboplastin)
EC 3.4.21.5 (Thrombin)

Date Created: 20210403 Date Completed: 20210609 Latest Revision: 20231213

20231215

PMC8037188

10.3390/ijms22073323

33805059