Inhibition of platelet activation prevents the P‐selectin and integrin‐dependent accumulation of cancer cell microparticles and reduces tumor growth and metastasis in vivo

• Published in: International journal of cancer Vol. 136; no. 2; pp. 462 - 475
• Main Authors: Mezouar, Soraya, Darbousset, Roxane, Dignat‐George, Françoise, Panicot‐Dubois, Laurence, Dubois, Christophe
• Format: Journal Article
• Language: English
• Published: United States Wiley Subscription Services, Inc 15.01.2015; Wiley
• Subjects: Animals; Blood Coagulation; Blotting, Western; Cancer; Cell-Derived Microparticles - metabolism; Disease Models, Animal; Flow Cytometry; Fluorescent Antibody Technique; Integrins - metabolism; Life Sciences; Medical research; Medication; Metastasis; Mice; Mice, Inbred C57BL; microparticles; Neoplasm Metastasis; P-Selectin - metabolism; Pancreatic cancer; Pancreatic Neoplasms - complications; Pancreatic Neoplasms - pathology; Pancreatic Neoplasms - prevention & control; Pharmaceutical sciences; Platelet Activation; Platelet Aggregation Inhibitors - therapeutic use; platelets; Prescription drugs; Real-Time Polymerase Chain Reaction; Reverse Transcriptase Polymerase Chain Reaction; RNA, Messenger - genetics; Thromboplastin - antagonists & inhibitors; Thromboplastin - metabolism; Thrombosis; Thrombosis - etiology; Thrombosis - pathology; Thrombosis - prevention & control; Ticlopidine - analogs & derivatives; Ticlopidine - therapeutic use; tissue factor; Tumor Cells, Cultured; microparticles; pancreatic cancer; thrombosis; tissue factor; platelets
• ISSN: 0020-7136; 1097-0215
• DOI: 10.1002/ijc.28997

Venous thromboembolism constitutes one of the main causes of death during the progression of a cancer. We previously demonstrated that tissue factor (TF)‐bearing cancer cell‐derived microparticles accumulate at the site of injury in mice developing a pancreatic cancer. The presence of these microparticles at the site of thrombosis correlates with the size of the platelet‐rich thrombus. The objective of this study was to determine the involvement of TF expressed by cancer cell‐derived microparticles on thrombosis associated with cancer. We observed that pancreatic cancer cell derived microparticles expressed TF, its inhibitor tissue factor pathway inhibitor (TFPI) as well as the integrins αvβ1 and αvβ3. In mice bearing a tumor under‐expressing TF, a significant decrease in circulating TF activity associated with an increase bleeding time and a 100‐fold diminished fibrin generation and platelet accumulation at the site of injury were observed. This was mainly due to the interaction of circulating cancer cell‐derived microparticles expressing TFPI with activated platelets and fibrinogen. In an ectopic model of cancer, treatment of mice with Clopidogrel, an anti‐platelet drug, decreased the size of the tumors and restored hemostasis by preventing the accumulation of cancer cell‐derived microparticles at the site of thrombosis. In a syngeneic orthotopic model of pancreatic cancer Clopidogrel also significantly inhibited the development of metastases. Together, these results indicate that an anti‐platelet strategy may efficiently treat thrombosis associated with cancer and reduce the progression of pancreatic cancer in mice. What's new? Tissue factor (TF) plays a key role in coagulation and is capable of activating inflammatory and angiogenic responses, potentially facilitating the progression of cancer. As a result, anticoagulant or antiplatelet drugs could be effective means of prevention for tumor progression and metastasis. Here, pancreatic cancer cell‐derived microparticles were found to express TF and its inhibitor TFPI. The microparticles interacted with platelets, with effects on bleeding and platelet accumulation, in mice. In cancer mouse models, treatment with the antiplatelet drug clopidogrel restored hemostasis, resulted in decreased tumor size, and prevented the development of metastases.