Breast cancer cells mediate endothelial cell activation, promoting von Willebrand Factor release, tumour adhesion and transendothelial migration
AuthorsDhami, S. P. S.
Byrne, C. M.
Kirwan, Cliona C
O'Donnell, J. S.
O'Sullivan, J. M.
AffiliationIrish Centre for Vascular Biology, School of Pharmacy and Biomolecular Sciences, Royal College of Surgeons in Ireland, Dublin, Ireland
MetadataShow full item record
AbstractBackground: 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.
CitationDhami 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.
JournalJournal of Thrombosis and Haemastasis
- Heparins that block VEGF-A-mediated von Willebrand factor fiber generation are potent inhibitors of hematogenous but not lymphatic metastasis.
- Authors: Goertz L, Schneider SW, Desch A, Mayer FT, Koett J, Nowak K, Karampinis I, Bohlmann MK, Umansky V, Bauer AT
- Issue date: 2016 Oct 18
- von Willebrand factor fibers promote cancer-associated platelet aggregation in malignant melanoma of mice and humans.
- Authors: Bauer AT, Suckau J, Frank K, Desch A, Goertz L, Wagner AH, Hecker M, Goerge T, Umansky L, Beckhove P, Utikal J, Gorzelanny C, Diaz-Valdes N, Umansky V, Schneider SW
- Issue date: 2015 May 14
- Von Willebrand factor and cancer; metastasis and coagulopathies.
- Authors: Patmore S, Dhami SPS, O'Sullivan JM
- Issue date: 2020 Oct
- Osteoprotegerin modulates platelet adhesion to von Willebrand factor during release from endothelial cells.
- Authors: Wohner N, Sebastian S, Muczynski V, Huskens D, de Laat B, de Groot PG, Lenting PJ
- Issue date: 2022 Mar
- Circulating Angiogenic Mediators in Patients with Moderate and Severe von Willebrand Disease: A Multicentre Cross-Sectional Study.
- Authors: Groeneveld DJ, Sanders YV, Adelmeijer J, Mauser-Bunschoten EP, van der Bom JG, Cnossen MH, Fijnvandraat K, Laros-van Gorkom BAP, Meijer K, Lisman T, Eikenboom J, Leebeek FWG
- Issue date: 2018 Jan