期刊
AMERICAN JOURNAL OF PHYSIOLOGY-CELL PHYSIOLOGY
卷 316, 期 2, 页码 C264-C273出版社
AMER PHYSIOLOGICAL SOC
DOI: 10.1152/ajpcell.00367.2018
关键词
aspirin; cancer; coagulation; platelets; PAR4; thrombosis
资金
- National Institutes of Health [R01HL101972, R01GM116184, R01HL133923, F31HL13623001, R03HD096173]
- Altarum Institute
- OHSU/OSU Cancer Prevention and Control Initiative
- Knight Cancer Institute (CEDAR)
- VA Employee Education System
- VA Office of Academic Affiliations
- VA Office of Research and Development
- National Cancer Institute's Center for Strategic Scientific Initiatives
- Department of Veterans Affairs, Veterans Health Administration, Office of Research and Development, Health Services Research and Development
Cancer-associated thrombosis is a common first presenting sign of malignancy and is currently the second leading cause of death in cancer patients after their malignancy. However. the molecular mechanisms underlying cancer-associated thrombosis remain undefined. In this study, we aimed to develop a better understanding of how cancer cells affect the coagulation cascade and platelet activation to induce a prothrombotic phenotype. Our results show that colon cancer cells trigger platelet activation in a manner dependent on cancer cell tissue factor (TF) expression. thrombin generation, activation of the protease-activated receptor 4 (PAR4) on platelets and consequent release of ADP and thromboxane A2. Platelet-colon cancer cell interactions potentiated the release of platelet-derived extracellular vesicles (EVs) rather than cancer cell-derived EVs. Our data show that single colon cancer cells were capable of recruiting and activating platelets and generating fibrin in plasma under shear flow. Finally. in a retrospective analysis of colon cancer patients, we found that the number of venous thromboembolism events was 4.5 times higher in colon cancer patients than in a control population. In conclusion, our data suggest that platelet-cancer cell interactions and perhaps platelet procoagulant EVs may contribute to the prothrombotic phenotype of colon cancer patients. Our work may provide rationale for targeting platelet-cancer cell interactions with PAR4 antagonists together with aspirin and/or ADP receptor antagonists as a potential intervention to limit cancer-associated thrombosis, balancing safety with efficacy.
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