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Doxorubicin Enhances Procoagulant Activity of Endothelial Cells after Exposure to Tumour Microparticles on Microfluidic Devices

Algarni, Abdulrahman; Greenman, John; Madden, Leigh A.

Authors

Abdulrahman Algarni



Abstract

The majority of cancer patients undergoing chemotherapy have a significantly increased risk of venous thromboembolism via a mechanism not yet fully elucidated but which most probably involves tumour microparticles (MP) combined with damaged/activated endothelium. Tumour cell lines (ES-2 and U87) were cultured as 3D spheroids and transferred to biochips connected through to a second chip precultured with an endothelial cell layer (human umbilical vein endothelial cells [HUVECs]). Media were introduced with and without doxorubicin (DOX) to the spheroids in parallel chips under constant flow conditions. Media samples collected pre- and post-flow through the biochip were analysed for tissue factor microparticles (TFMP) and procoagulant activity (PCA). HUVECs were also harvested and tested for PCA at a constant cell number. TFMP levels in media decreased after passing over HUVECs in both conditions over time and this was accompanied by a reduction in PCA (indicated by a slower coagulation time) of the media. The relationship between PCA and TFMP was correlated (r = −0.85) and consistent across experiments. Harvested HUVECs displayed increased PCA when exposed to tumour spheroid media containing TFMP, which was increased further after the addition of DOX, suggesting that the TFMP in the media had bound to HUVEC cell surfaces. The enhanced PCA of HUVECs associated with the DOX treatment was attributed to a loss of viability of these cells rather than additional MP binding. The data suggest that tumour MP interact with HUVECs through ligand-receptor binding. The model described is a robust and reproducible method to investigate cytotoxic agents on tumour spheroids and subsequent downstream interaction with endothelial cells.

Citation

Algarni, A., Greenman, J., & Madden, L. A. (2020). Doxorubicin Enhances Procoagulant Activity of Endothelial Cells after Exposure to Tumour Microparticles on Microfluidic Devices. Bloods, 1(1), 23-34. https://doi.org/10.3390/bloods1010006

Journal Article Type Article
Acceptance Date Jul 21, 2020
Online Publication Date Jul 23, 2020
Publication Date 2020-09
Deposit Date Jul 24, 2020
Publicly Available Date Jul 24, 2020
Journal Bloods
Electronic ISSN 2673-415X
Publisher MDPI
Peer Reviewed Peer Reviewed
Volume 1
Issue 1
Pages 23-34
DOI https://doi.org/10.3390/bloods1010006
Keywords Doxorubicin; Microparticles; Microfluidics; Endothelium
Public URL https://hull-repository.worktribe.com/output/3547038
Publisher URL https://www.mdpi.com/2673-415X/1/1/6

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Publisher Licence URL
http://creativecommons.org/licenses/by/4.0

Copyright Statement
©2020 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open accessarticle distributed under the terms and conditions of the Creative Commons Attribution(CC BY) license (http://creativecommons.org/licenses/by/4.0/).





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