Venous thromboembolism (VTE) is a clinical term which refers to the development of deep vein thrombosis and pulmonary embolism. Pancreatic cancer patients have a high rate of VTE but the mechanism of VTE initiation and propagation has not been fully elucidated. The development of this condition in pancreatic cancer patients has been shown to be associated with many negative patient outcomes including increased mortality. Microparticles (MPs) are small membrane vesicles that are released by many cell types, including cancer cells. Importantly, these MPs contain the procoagulant protein tissue factor. We and others have shown that pancreatic tumors release tissue factor-positive MPs into the circulation in mouse models and in patients. I hypothesize that tumor-derived MPs (TMPs) trigger venous thrombosis by delivering tissue factor to the vessel wall via specific ligand-receptor interactions. I will examine the roles of P-selectin and E-selectin on the endothelial cel surface, and PS bridging proteins in the circulation in this process both in vivo and in vitro.
In Specific Aim 1 I will evaluate the contribution of P-selectin, E-selectin, and PS bridging proteins to the binding of pancreatic TMPs to activated endothelial cells in vitro. I will do this by determining the effect of blocking P-selectin, E-selectin, and PS on the surface of activated primary endothelial cells with well- characterized neutralizing monoclonal antibodies or small molecule inhibitors on the binding of labeled MPs.
In Specific Aim 2 I will determine the role of different ligand-receptor interactions in the binding of pancreatic TMPs to activated endothelium and subsequent thrombosis in mice. The docking of labeled pancreatic TMPs to sites of laser-activated venule endothelium will be visualized by intravital microscopy. An inferior vena cava stenosis model of venous thrombosis will be used since it mimics many of the features of DVT in humans. The identification of specific ligand-receptor interactions involved in the docking of pancreatic TMPs to the activated endothelium may lead to the development of novel drugs for preventing cancer-induced VTE.
The development of venous thrombosis in pancreatic cancer patients is a common occurrence. When pancreatic cancer patients develop these thrombi, it can have a hugely negative impact on their quality of life and shorten their lifespan. Current preventative treatments for this condition are sorely lacking. In this study we will determine the role of tumor derived microparticles in the initiation of venous thrombosis in pancreatic cancer patients. These studies should lead to the development of new anticoagulant drugs which could be safer for use in pancreatic cancer patients for the prevention of venous thrombosis than the currently available therapies.
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|Hisada, Y; Geddings, J E; Ay, C et al. (2015) Venous thrombosis and cancer: from mouse models to clinical trials. J Thromb Haemost 13:1372-82|
|Geddings, Julia E; Mackman, Nigel (2014) Comment on "tissue factor expressed by microparticles is associated with mortality but not with thrombosis in cancer patients". Thromb Haemost 111:180-1|
|Geddings, Julia E; Mackman, Nigel (2014) New players in haemostasis and thrombosis. Thromb Haemost 111:570-4|
|Geddings, J; Aleman, M M; Wolberg, A et al. (2014) Strengths and weaknesses of a new mouse model of thrombosis induced by inferior vena cava stenosis: communication from the SSC of the ISTH. J Thromb Haemost 12:571-3|
|Geddings, Julia E; Mackman, Nigel (2013) Tumor-derived tissue factor-positive microparticles and venous thrombosis in cancer patients. Blood 122:1873-80|