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    Breast cancer cells mediate endothelial cell activation, promoting von Willebrand Factor release, tumour adhesion and transendothelial migration

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    Authors
    Dhami, S. P. S.
    Patmore, S.
    Comerford, C.
    Byrne, C. M.
    Cavanagh, B.
    Castle, John
    Kirwan, Cliona C
    Kenny, M.
    Schoen, I.
    O'Donnell, J. S.
    O'Sullivan, J. M.
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    Affiliation
    Irish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
    Issue Date
    2022
    
    Metadata
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    Abstract
    Background: Breast cancer results in a 3-4 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. Tumour 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 tumour metastasis. Objective: To investigate the role of VWF in breast cancer metastasis and examine the effect of LMWH in modulating EC activation and breast tumour transmigration. Methods: VWF levels were measured by ELISA. Primary EC were used to assess tumour induced activation, angiogenesis, tumour adhesion and transendothelial migration. Results and conclusion: Patients with metastatic breast cancer have markedly elevated plasma VWF:Ag levels which also correlate with poorer survival. MDA-MB-231 and MCF-7 breast cancer cells induce secretion of VWF, angiopoietin-2 and osteoprotegerin from EC 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 tumour cells also contributes to a pro-angiogenic effect on EC. VWF multimers secreted from EC, in response to tumour-VEGF-A, mediate adhesion of breast tumour cells along the endothelium. LMWH inhibits VWF-breast tumour adhesion and transendothelial migration. Our findings highlight the significant crosstalk between tumour cells and the endothelium including increased VWF secretion which may contribute to tumour metastasis.
    Citation
    Dhami SPS, Patmore S, Comerford C, Byrne CM, Cavanagh B, Castle J, et al. Breast cancer cells mediate endothelial cell activation, promoting von Willebrand factor release, tumor adhesion, and transendothelial migration. Journal of Thrombosis and Haemostasis. Wiley; 2022.
    Journal
    Journal of Thrombosis and Haemastasis
    URI
    http://hdl.handle.net/10541/625382
    DOI
    10.1111/jth.15794
    PubMed ID
    35722954
    Additional Links
    https://dx.doi.org/10.1111/jth.15794
    Type
    Article
    Language
    en
    ae974a485f413a2113503eed53cd6c53
    10.1111/jth.15794
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