Selective Activation of Thrombin Activatable Fibrinolysis Inhibitor (TAFI) Attenuates Metastatic and Angiogenic Capabilities of Melanoma and Lung Carcinoma in vitro
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.