Date of Award

2016

Degree Type

Dissertation

Degree Name

Ph.D.

Department

Chemistry and Biochemistry

First Advisor

Boffa, Michael

Keywords

Angiogenesis, Cancer, Metastasis, Plasminogen, TAFI, Thrombomodulin

Rights

CC BY-NC-ND 4.0

Abstract

Cancer metastasis is an important process in cancer progression. This process is facilitated by proteases that promote degradation of the extracellular matrix, cell migration and cell invasion. Angiogenesis is important to the metastatic process and also involves extracellular matrix degradation, endothelial cell migration and invasion. Proteases such as plasmin and matrix metalloproteinases are responsible for degradation of the extracellular matrix, facilitating cancer cell invasion and subsequent metastasis. These proteases are also important in promoting tumour angiogenesis. Therefore, developing methods to target these proteases may effectively inhibit cancer metastasis and tumour angiogenesis. TAFI is a plasma zymogen initially known for its role in attenuating fibrinolysis. TAFIa is formed through cleavage by thrombin, plasmin or, by thrombin in complex with thrombomodulin. TAFIa is a carboxypeptidase, cleaving carboxyl terminal lysine residues from plasminogen binding sites on cell surface receptors, which are important in accelerating plasminogen activation to plasmin. We have demonstrated that TAFIa is able to inhibit metastatic behaviours, including breast cancer cell invasion, migration and collagen degradation. We have shown that TAFIa inhibits these metastatic behaviours through attenuation of plasminogen activation to plasmin. Additionally, we have demonstrated that TAFIa also acts as an anti-angiogenic factor, inhibiting endothelial cell invasion, migration, tube formation and collagen degradation. We have also shown that these effects are mediated by the ability of TAFIa to inhibit plasminogen activation on the endothelial cell surface. Taken together these results indicate that TAFIa is an anti-metastatic and anti-angiogenic factor that may represent a novel therapeutic strategy to target cancer metastasis.

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