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Clin Exp Metastasis. 2017 Feb;34(2):155-169. doi: 10.1007/s10585-017-9837-y. Epub 2017 Jan 25.

Activated thrombin-activatable fibrinolysis inhibitor attenuates the angiogenic potential of endothelial cells: potential relevance to the breast tumour microenvironment.

Author information

1
Department of Chemistry and Biochemistry, University of Windsor, Windsor, ON, Canada.
2
Department of Biochemistry, Room 4245A Robarts Research Institute, University of Western Ontario, 1151 Richmond Street North, London, ON, N5B 3P7, Canada.
3
Department of Biological Sciences, University of Windsor, Windsor, ON, Canada.
4
Department of Biochemistry, Room 4245A Robarts Research Institute, University of Western Ontario, 1151 Richmond Street North, London, ON, N5B 3P7, Canada. mboffa@uwo.ca.

Abstract

Thrombin-activatable fibrinolysis inhibitor (TAFI) is a basic carboxypeptidase zymogen present in blood plasma. Proteolytic activation of TAFI by thrombin, thrombin in complex with the endothelial cell cofactor thrombomodulin, or plasmin results in an enzyme (TAFIa) that removes carboxyl-terminal lysine residues from protein and peptide substrates, including cell-surface plasminogen receptors. TAFIa is therefore capable of inhibiting plasminogen activation in the pericellular milieu. Since plasminogen activation has been linked to angiogenesis, TAFIa could therefore have anti-angiogenic properties, and indeed TAFIa has been shown to inhibit endothelial tube formation in a fibrin matrix. In this study, the TAFI pathway was manipulated by providing exogenous TAFI or TAFIa or by adding a potent and specific inhibitor of TAFIa. We found that TAFIa elicited a series of anti-angiogenic responses by endothelial cells, including decreased endothelial cell proliferation, cell invasion, cell migration, tube formation, and collagen degradation. Moreover, TAFIa decreased tube formation and proteolysis in endothelial cell culture grown alone and in co-culture with breast cancer cell lines. In accordance with these findings, inhibition of TAFIa increased secretion of matrix metalloprotease proenzymes by endothelial and breast cancer cells. Finally, treatment of endothelial cells with TAFIa significantly inhibited plasminogen activation. Taken together our results suggest a novel role for TAFI in inhibiting tumour angiogenic behaviors in breast cancer.

KEYWORDS:

Angiogenesis; Breast cancer; Endothelial cells; Plasminogen; TAFI

PMID:
28124276
DOI:
10.1007/s10585-017-9837-y
[Indexed for MEDLINE]

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