The Role of Tumor Microvesicles in Cancer-Associated Thrombosis Public Deposited

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  • March 19, 2019
Creator
  • Geddings, Julia
    • Affiliation: School of Medicine, Department of Pathology and Laboratory Medicine
Abstract
  • Cancer patients have a ~4 -fold increased risk of venous thromboembolism (VTE) compared with the general population, and cancer patients with VTE have reduced survival compared with non-VTE patients. Microvesicles (MVs), also known as microparticles (MPs), are small membrane vesicles that are constitutively released from tumors, and tumor cell-derived, tissue factor (TF)-positive (TF+) MVs may contribute to thrombosis in cancer patients. I tested the hypothesis that tumor cell-derived, TF+ TMVs activate platelets in vitro and in vivo, and this contributes to cancer-associated VTE. For this study I first had to establish a reproducible model of cancer-associated thrombosis. The in vivo model chosen for this purpose was the inferior vena cava (IVC) stenosis model in mice. This model was chosen because it mimics certain features of human deep vein thrombosis, including the triggering of thrombosis with minimal endothelial damage, maintenance of blood flow at the site of thrombosis, and chronic thrombus development that can be followed over time in vivo. The strengths and weaknesses of this model are summarized in chapter 2 of this dissertation. The IVC stenosis model of thrombosis was used to evaluate the role of TF+ TMVs in the enhancement of thrombosis. In the study included as chapter 3 in this dissertation, I found that TF+ TMVs isolated from two human pancreatic cell carcinoma cells lines activate isolated human platelets in a TF- and thrombin-dependent manner in vitro. TF+ TMV-mediated platelet activation was also inhibited by the ADP scavenger apyrase and the P2Y12 receptor inhibitor 2MesAMP. Further, TF+ TMVs enhanced thrombosis in two mouse models of venous thrombosis in a TF-dependent manner. TF+ TMV-enhanced thrombosis was reduced in Par4 deficient mice and in wild-type mice treated with the platelet inhibitor clopidogrel, suggesting that TF+ TMV-enhanced thrombosis in mice was, in part, dependent on platelets. These studies identify TF+ TMV-induced platelet activation as a possible mechanism of thrombosis in cancer and suggest that platelet inhibitors, such as aspirin and clopidogrel, may be considered for the prevention of VTE in high risk cancer patients.
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  • In Copyright
Advisor
  • Mackman, Nigel
  • Weissman, Bernard
  • Kasthuri, Raj
  • Homeister, Jonathon
  • Bergmeier, Wolfgang
  • Key, Nigel
Degree
  • Doctor of Philosophy
Degree granting institution
  • University of North Carolina at Chapel Hill Graduate School
Graduation year
  • 2015
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  • Chapel Hill, NC
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