Clinical & Experimental Metastasis

, Volume 34, Issue 2, pp 155–169 | Cite as

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

  • Zainab A. Bazzi
  • Jennifer Balun
  • Dora Cavallo-Medved
  • Lisa A. Porter
  • Michael B. BoffaEmail author
Research Paper


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.


TAFI Angiogenesis Breast cancer Plasminogen Endothelial cells 



Basement membrane extract


Conditioned media


ε-aminocaproic acid


Extracellular matrix


Human umbilical vein endothelial cells


Matrix metalloproteinases


Plasminogen activation system


Potato tuber carboxypeptidase inhibitor


Thrombin-activatable fibrinolysis inhibitor


Activated thrombin-activatable fibrinolysis inhibitor




Tissue-type plasminogen activator


Urokinase plasminogen activator


Urokinase plasminogen activator receptor


Vascular endothelial growth factor



This work was funded by a Seeds4Hope grant from the Windsor Essex Cancer Centre Foundation.

Supplementary material

10585_2017_9837_MOESM1_ESM.pdf (324 kb)
Supplementary material 1 (PDF 324 KB)


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Copyright information

© Springer Science+Business Media Dordrecht 2017

Authors and Affiliations

  1. 1.Department of Chemistry and BiochemistryUniversity of WindsorWindsorCanada
  2. 2.Department of Biochemistry, Room 4245A Robarts Research InstituteUniversity of Western OntarioLondonCanada
  3. 3.Department of Biological SciencesUniversity of WindsorWindsorCanada

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