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Full Length Article
Breast cancer cell-induced platelet activation is compounded by tamoxifen T and anastrozole in vitro
a School of Anatomical Sciences, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193 Johannesburg, South Africa
b Department of Internal Medicine, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, 7 York Road, Parktown, 2193 Johannesburg, South Africa
c Department of Molecular Medicine and Haematology, School of Pathology, Faculty of Health Sciences, University of the Witwatersrand, National Health Laboratory Services (NHLS), 7 York Road, Parktown, 2193 Johannesburg, South Africa
Platelet-tumour cell interaction is implicated in the initiation of breast cancer-associated thrombosis, with hormone-therapy (Tamoxifen/Anastrozole), increasing this risk. However, recent in vitro research indicates that Tamoxifen inhibits platelet activation, while the eﬀects of Anastrozole on platelet activation are not well characterised. This study investigated platelet activation caused by Tamoxifen or Anastrozole-treated breast cancer 1971007-91-6 in vitro.
MCF7 and T47D cells were pre-treated with Tamoxifen or Anastrozole to mimic the eﬀects of the drugs in vivo, and co-cultured with whole blood. Platelet activation was determined using flow cytometry. Platelet (CD41a+CD62P+) was determined using an interval gating strategy. Platelet morphology was visualised using scanning electron microscopy.
Our results support clinical findings, showing that hormone-therapy is associated with platelet activation. Tamoxifen-treated MCF7 cells increased P-selectin expression, with ultrastructural analysis showing fully spread platelets. Conversely, Tamoxifen-treated T47D cells decreased P-selectin expression with platelets showing signs of early aggregation. Anastrozole pre-treatment decreased P-selectin expression, with treated MCF7 cells in-ducing platelet membrane folds and lamellipodia extension, and treated T47D cells inducing platelet aggregation and fibrin network formation indicating hypercoagulation.
The findings support clinical studies. Hormone-therapy augments tumour cell-induced platelet activation, which may be linked to cell phenotype. This may have clinical implications for treatment strategies.
Breast cancer is one of the most commonly diagnosed cancers in women worldwide, with an increasing incidence in third-world coun-tries . Increasing evidence points towards an association between tumour progression and platelet function [2,3]. Within the tumour microenvironment, leaky blood vessels allow for engagement between platelets and tumour cells, with platelets postulated to facilitate tumour cell intravasation . In the circulatory system tumour cell-induced platelet aggregation confers protection against immunosurveillance [5,6], and high velocity shear forces . Additionally, the release of platelet-stored growth factors, allows for extravasation and coloniza-tion of secondary sites . Tumour cells facilitate this dynamic cross-talk with platelets by activating procoagulation mechanisms via the secretion of tumour-associated tissue factor, thrombin or adenosine
diphosphate (ADP) [7,8]. Upon activation, platelets undergo rapid changes in morphology [9,10]. Early platelet activation includes re-traction of granular contents into the centre of the platelet with the widening of the open canalicular system (OCS), forming pseudopodia extending into lamellipodia and filipodia [9,11]. This is followed by further extension and final release of granular contents from the OCS facilitating further adhesion and aggregation, prior to the final or spread phase [9,10]. α-Granular contents include membrane proteins (e.g. GPIb complex, GPIIb/IIIa, P-selectin), coagulation factors (e.g. Factors V, XI; fibrinogen, von Willebrand factor), growth factors and chemokines. These components are also stored within microparticles [12–14] and released during the activation process. These constituents mediate a range of functions [15,16] which ultimately facilitate tumour progression while contributing to hypercoagualation .