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Breast cancer cells mediate endothelial cell activation, promoting von Willebrand Factor release, tumour adhesion and transendothelial migration
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.
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.
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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.
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Date
2022
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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.