Abstract
Induction of thrombosis in tumor vasculature represents an appealing strategy for combating cancer. Herein, we combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel bi-functional fusion protein consisting of truncated coagulase (tCoa) bearing an RGD motif on its C-terminus for cancer therapy. We demonstrated that free coagulase failed to elicit any significant thrombotic activity. Conversely, RGD delivery of coagulase retained coagulase activity and afforded favorable interaction of fusion proteins with prothrombin and αvβ3 endothelial cell receptors, as verified by in silico, in vitro, and in vivo experiments. Although free coagulase elicited robust coagulase activity in vitro, only targeted coagulase (tCoa-RGD) was capable of producing extensive thrombosis, and subsequent infarction and massive necrosis of CT26 mouse colon, 4T1 mouse mammary and SKOV3 human ovarian tumors in mice. Additionally, systemic injections of lower doses of tCoa-RGD produced striking tumor growth inhibition of CT26, 4T1 and SKOV3 solid tumors in animals. Altogether, the nontoxic nature, unique shortcut mechanism, minimal effective dose, wide therapeutic window, efficient induction of thrombosis, local effects and susceptibility of human blood to coagulase suggest tCoa-RGD fusion proteins as a novel and promising anticancer therapy for human trials.
Highlights
Myocardial/brain infarctions are the leading causes of death around the globe
Induction of tumor vascular infarction by truncated form of human tissue factor (tTF) fusion proteins leads to the significant regression of malignant tumors, and could even bear curative potential as single therapies[13], complete elimination of tumors often fails due to induction of incomplete thrombosis and the systemic toxicity that is reported for tTF fusion proteins at the higher doses[14]
We combined unique intrinsic coagulation properties of staphylocoagulase with new acquired functional potentials introduced by genetic engineering, to generate a novel fusion protein consisting of truncated coagulase bearing an RGD motif on its C-terminus, to induce selective infarction of tumor-feeding blood vessels for cancer therapy
Summary
Myocardial/brain infarctions are the leading causes of death around the globe. A sole blood clot is enough to cause congestion of a single vessel, and further deplete cells of oxygen and nutrients. The binding of the tCoa-RGD-prothrombin complex with targeted surface receptors of tumor endothelial cells was studied with docking and simulation.
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