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Article

Factor VIIa Regulates the Level of Cell-Surface Tissue Factor through Separate but Cooperative Mechanisms

1
Biomedical Section, University of Hull, Cottingham Road, Hull HU6 7RX, UK
2
Department of Medical Laboratories, College of Applied Medical Sciences, Majmaah University, P.O. Box 66, Majmaah 11952, Saudi Arabia
3
Einthoven Laboratory for Vascular and Regenerative Medicine, Department of Internal Medicine, Division of Thrombosis and Hemostasis, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands
4
Division of Cancer-Hull York Medical School, University of Hull, Cottingham Road, Hull HU6 7RX, UK
*
Author to whom correspondence should be addressed.
Academic Editor: Florian Langer
Cancers 2021, 13(15), 3718; https://doi.org/10.3390/cancers13153718
Received: 15 June 2021 / Revised: 18 July 2021 / Accepted: 21 July 2021 / Published: 23 July 2021
Under normal conditions, blood coagulation is suppressed to prevent thrombosis. However, during inflammatory conditions such as injury or disease conditions, the protein “tissue factor (TF)” is expressed on the surface of the cells and is also released into the bloodstream within cell-derived vesicles called “microvesicles”. TF appears first at the site of trauma which makes TF suitable for determining the extent of damage and instructing cells to proliferate and repair, or if severely damaged, to die. The relationship between cancer and thrombosis was reported in the early part of the 19th century. Cancer cells and particularly those with aggressive tendencies have the ability to produce, and then optimise the amount of TF on the cell, in order to maximise the pro-survival and proliferative properties of this protein. This study has demonstrated some of the mechanisms by which cells control excessive amounts of TF, to levels ideal for tumour survival and growth.
Procoagulant activity of tissue factor (TF) in response to injury or inflammation is accompanied with cellular signals which determine the fate of cells. However, to prevent excessive signalling, TF is rapidly dissipated through release into microvesicles, and/or endocytosis. To elucidate the mechanism by which TF signalling may become moderated on the surface of cells, the associations of TF, fVII/fVIIa, PAR2 and caveolin-1 on MDA-MB-231, BxPC-3 and 786-O cells were examined and compared to that in cells lacking either fVII/fVIIa or TF. Furthermore, the localisation of labelled-recombinant TF with cholesterol-rich lipid rafts was explored on the surface of primary human blood dermal endothelial cells (HDBEC). Finally, by disrupting the caveolae on the surface of HDBEC, the outcome on TF-mediated signalling was examined. The association between TF and PAR2 was found to be dependent on the presence of fVIIa. Interestingly, the presence of TF was not pre-requisite for the association between fVII/fVIIa and PAR2 but was significantly enhanced by TF, which was also essential for the proliferative signal. Supplementation of HDBEC with exogenous TF resulted in early release of fVII/fVIIa from caveolae, followed by re-sequestration of TF-fVIIa. Addition of labelled-TF resulted in the accumulation within caveolin-1-containing cholesterol-rich regions and was also accompanied with the increased assimilation of cell-surface fVIIa. Disruption of the caveolae/rafts in HDBEC using MβCD enhanced the TF-mediated cellular signalling. Our data supports a hypothesis that cells respond to the exposure to TF by moderating the signalling activities as well as the procoagulant activity of TF, through incorporation into the caveolae/lipid rafts. View Full-Text
Keywords: tissue factor; factor VIIa; protease-activated receptor-2; caveolae; cholesterol-rich microdomins; cell signalling tissue factor; factor VIIa; protease-activated receptor-2; caveolae; cholesterol-rich microdomins; cell signalling
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MDPI and ACS Style

Madkhali, Y.; Rondon, A.M.R.; Featherby, S.; Maraveyas, A.; Greenman, J.; Ettelaie, C. Factor VIIa Regulates the Level of Cell-Surface Tissue Factor through Separate but Cooperative Mechanisms. Cancers 2021, 13, 3718. https://doi.org/10.3390/cancers13153718

AMA Style

Madkhali Y, Rondon AMR, Featherby S, Maraveyas A, Greenman J, Ettelaie C. Factor VIIa Regulates the Level of Cell-Surface Tissue Factor through Separate but Cooperative Mechanisms. Cancers. 2021; 13(15):3718. https://doi.org/10.3390/cancers13153718

Chicago/Turabian Style

Madkhali, Yahya, Araci M.R. Rondon, Sophie Featherby, Anthony Maraveyas, John Greenman, and Camille Ettelaie. 2021. "Factor VIIa Regulates the Level of Cell-Surface Tissue Factor through Separate but Cooperative Mechanisms" Cancers 13, no. 15: 3718. https://doi.org/10.3390/cancers13153718

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