ORCID Profile
0000-0003-0309-3313
Current Organisations
University of Dublin Trinity College
,
Royal College of Surgeons in Ireland
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Publisher: Elsevier BV
Date: 07-2021
DOI: 10.1002/RTH2.12532
Publisher: Elsevier BV
Date: 10-2022
DOI: 10.1111/JTH.15794
Abstract: Breast cancer results in a three- to four-fold increased risk of venous thromboembolism (VTE), which is associated with reduced patient survival. Despite this, the mechanisms underpinning breast cancer-associated thrombosis remain poorly defined. Tumor cells can trigger endothelial cell (EC) activation resulting in increased von Willebrand factor (VWF) secretion. Importantly, elevated plasma VWF levels constitute an independent biomarker for VTE risk. Moreover, in a model of melanoma, treatment with low molecular weight heparin (LMWH) negatively regulated VWF secretion and attenuated tumor metastasis. To investigate the role of VWF in breast cancer metastasis and examine the effect of LMWH in modulating EC activation and breast tumor transmigration. von Willebrand factor levels were measured by ELISA. Primary ECs were used to assess tumor-induced activation, angiogenesis, tumor adhesion, and transendothelial migration. Patients with metastatic breast cancer have markedly elevated plasma VWF:Ag levels that also correlate with poorer survival. MDA-MB-231 and MCF-7 breast cancer cells induce secretion of VWF, angiopoietin-2, and osteoprotegerin from ECs, which is further enhanced by the presence of platelets. Vascular endothelial growth factor-A (VEGF-A) plays an important role in modulating breast cancer-induced VWF release. Moreover, VEGF-A from breast tumor cells also contributes to a pro-angiogenic effect on ECs. VWF multimers secreted from ECs, in response to tumor-VEGF-A, mediate adhesion of breast tumor cells along the endothelium. LMWH inhibits VWF-breast tumor adhesion and transendothelial migration. Our findings highlight the significant crosstalk between tumor cells and the endothelium including increased VWF secretion which may contribute to tumor metastasis.
Publisher: Elsevier BV
Date: 04-2021
DOI: 10.1111/JTH.15267
Publisher: American Society of Hematology
Date: 18-02-2010
DOI: 10.1182/BLOOD-2009-07-235150
Abstract: During Plasmodium falciparum malaria infections, von Willebrand factor (VWF) levels are elevated, postmortem studies show platelets colocalized with sequestered infected erythrocytes (IEs) at brain microvascular sites, whereas in vitro studies have demonstrated platelet-mediated IE adhesion to tumor necrosis factor-activated brain endothelium via a bridging mechanism. This current study demonstrates how all these observations could be linked through a completely novel mechanism whereby IEs adhere via platelet decorated ultra-large VWF strings on activated endothelium. Using an in vitro laminar flow model, we have demonstrated tethering and firm adhesion of IEs to the endothelium specifically at sites of platelet accumulation. We also show that an IE pro-adhesive state, capable of supporting high levels of binding within minutes of induction, can be removed through the action of the VWF protease ADAMTS-13 (a disintegrin and metalloproteinase with a thrombospondin type 1 motif, member 13). We propose that this new mechanism contributes to sequestration both independently of and in concert with current adhesion mechanisms.
Publisher: Public Library of Science (PLoS)
Date: 20-03-2009
No related grants have been discovered for James O'Donnell.