Electronic Thesis and Dissertation Repository

Thesis Format

Monograph

Degree

Master of Science

Program

Biochemistry

Supervisor

Boffa, Michael B.

Abstract

Metastasis and angiogenesis are hallmarks of aggressive cancers, both depending on degradation of extracellular matrix by proteases such as plasmin. Plasmin activation is inhibited by thrombin-activatable fibrinolysis inhibitor (TAFI)-mediated cleavage of terminal lysine residues on plasminogen receptors. Activation of TAFI is most effectively done in complex with thrombomodulin (TM). TM is known to have anti-cancer properties, but it is not known if this is due to TAFI activation or an alternative substrate protein C (PC). We hypothesize that specific promotion of TAFI activation with TM treatment will attenuate metastatic and angiogenic capabilities of tumour cells.

Melanoma and lung carcinoma cells were treated with either wild-type, TAFI-specific, or PC-specific TM. In vitro plasminogen activation, invasion, proteolysis, and tube formation assays were performed in each cell type and TAFI-specific TM was found to reduce metastatic and angiogenic potential. This suggests that TAFI activation accounts for the anti-metastatic and anti-angiogenic properties of TM.

Summary for Lay Audience

Metastasis is the spread of cancer cells from one location in the body to another and is the main cause of death for people with cancer. Angiogenesis is the formation of new blood vessels and is required to supply cancer cells with oxygen and nutrients so the cancer and grow and spread. Both metastasis and angiogenesis depend on the movement of either cancer cells or the cells that line blood vessels. For these cells to move through the body, they need to break down structural proteins that surround cells. Plasmin is a major enzyme used by cancer and blood vessels to break down these proteins. This process can be stopped by preventing the generation of plasmin using another protein called TAFI. However, TAFI first needs to be activated before plasmin generation can be stopped. This is most effectively done by another complex involving the protein thrombomodulin (TM). We think that promoting TAFI activation with TM will stop plasmin activation, and therefore, will prevent metastasis and angiogenesis.

Melanoma and lung cancer are two dangerous and common types of cancer that have much higher mortality rates when metastasis and angiogenesis occur. We used our TM treatment on these two types of cancer to see if different aspects of metastasis and angiogenesis could be prevented. As predicted, TM treatment was able to stop plasmin activation and prevent metastatic and angiogenic abilities of both melanoma and lung cancer. In the future, this could be used as a new cancer treatment strategy.

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