Antithrombin is an important inhibitor of the coagulation cascade, but it can also serve as an anti-inflammatory, antiangiogenic, antiviral, and antiapoptotic protein. A role for antithrombin in modulating tumor cell invasion and migration has been demonstrated here. U87-MG, A549, and HT29 cell surfaces. A central loop and heparin-binding domain are required for the inhibitory process to occur, and antithrombin must be activated by heparin. This study has revealed a novel mechanism of inhibition for enteropeptidase, cleavage of antithrombin, in turn, has resulted in a molecule with antiangiogenic properties that reduces the formation of vascular endothelium. Heparin and antithrombin were added to U87MG and A549 cells to inhibit motility and invasion in wound healing assays, as well as the destruction of matrix gelatin by invadopodia. RNA interference experiments showed that enteropeptidase controlled these processes. The enteropeptidase and antithrombin were colocalized in vivo when carcinoma cells were grafted into nude mice.
Lastly, HT29 cells induced in vivo experimental metastasis was reduced by heparin treatment. However, there is some evidence linking proteolytic cascades to tumor development, not antithrombin itself. Tumors grow and metastasize through a combination of proteolytic activities combined with intracellular and intercellular signaling events, for example, to invade surrounding tissues and spread to distant sites. Tumor cells use deregulated proteases to disrupt and remodel intercellular connections and interactions with the extracellular matrix. There arseveralof enzymes that are deregulated during the growth and progression of tumors, including members of the serine protease superfamily known as Type II transmembrane serine proteases (TTSP). Matriptase, TMPRSS3, TMPRSS4, matriptase2, and TMPRSS2 are differentially expressed in squamous cell carcinoma gene 1 (DESC1) 11. Enteropeptidase is regulated by this enzyme. We investigate the effects of antithrombin on the migration, invasion, and angiogenesis of tumor cells in this study. Antithrombin does not inhibit enteropeptidase in vivo. A mouse model of metastasis was also examined in which heparin was treated in vivo.