Thrombin inhibition and cisplatin block tumor progression in ovarian cancer by alleviating the immunosuppressive microenvironment.

Eric T Alexander,Allyson R Minton,Joanne Van Ryn,Susan K Gilmour,Molly C Peters

doi:10.18632/oncotarget.13300

Eric T Alexander, Allyson R Minton + Show 3 more

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https://doi.org/10.18632/oncotarget.13300

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Abstract

Cancer is often associated with an increased risk of thrombotic complications which can be aggravated by treatment with chemotherapeutics such as cisplatin. Multiple lines of evidence suggest that thrombin activity promotes tumor growth and metastasis. We examined the effect of co-treatment with dabigatran etexilate, a direct thrombin inhibitor, and cisplatin using the murine ID8 ovarian cancer model. Mice receiving co-treatment with both dabigatran etexilate and low dose cisplatin had significantly smaller tumors, developed less ascites and had lower levels of circulating activated platelets and tissue factor (TF) positive microparticles than those treated with dabigatran etexilate or cisplatin alone. Co-treatment with dabigatran etexilate and cisplatin significantly decreased the number of Gr1+/CD11b+ myeloid derived suppresser cells and CD11b+/CD11c+ dendritic cells in the ascites of ID8 tumor-bearing mice. Co-treatment also significantly reduced levels of pro-tumorigenic cytokines including TGF-β, VEGF, IL-6, IL-10, and MCP-1 in the ascites while increasing IFN-γ production by CD8+ effector T cells in the tumor ascites. These results demonstrate that co-treatment with dabigatran etexilate significantly augments the anti-tumor activity of cisplatin in ovarian tumor progression by alleviating the immunosuppressive microenvironment, suggesting that thrombin may be a potential therapeutic target for treatment of ovarian cancer.

Highlights

The association between thrombosis and cancer dates back to 1865 when Armand Trousseau observed that patients who presented with idiopathic venous thromboembolism frequently had an underlying cancer
Because cancer often induces a pro-thrombotic state that is exacerbated by chemotherapeutic agents, we evaluated the effect of thrombin inhibition with dabigatran etexilate in conjunction with low dose chemotherapeutic treatment using the ID8-luc ovarian cancer model
Treatment with either low dose cisplatin treatment or dabigatran etexilate alone modestly reduced ID8 tumor growth compared to vehicle treatment as measured by bioluminescence (Figure 1B and 1C)

Summary

Introduction

The association between thrombosis and cancer dates back to 1865 when Armand Trousseau observed that patients who presented with idiopathic venous thromboembolism frequently had an underlying cancer. The mechanisms are not clearly understood, chemotherapeutic agents have pro-thrombotic side effects associated with platelet activation, increased cellular exposure of phosphatidylserine (PS) and elevation of tissue factor (TF)-positive microparticles [4, 5]. The critical role of thrombin in promoting tumor growth reflects its many functions, including fibrin formation [6], platelet activation [7], activation of PAR signaling [8] and the proteolytic breakdown of extracellular matrix. Thrombin generation promotes metastasis through fibrin deposition, platelet activation and via PAR-1 signaling [10]. Thrombin is an effective promoter of angiogenesis by both clotting-dependent mechanisms, via platelet activation and fibrin deposition, and clotting-independent mechanisms mediated by PAR activation. Www.impactjournals.com/oncotarget fibrin formation and platelet-derived TGF-β can inhibit natural killer cell activity, helping the tumor evade host immunosurveillance [13, 14]

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