Immunomodulatory role of thrombin in cancer progression

Abstract

Coagulation proteases and the generation of thrombin are increased in tumors. In addition, chemotherapeutic agents commonly used to treat malignant cancers can exacerbate cancer‐associated thromboses. Thrombin can modify tumor cell behavior directly through the activation of protease‐activated receptors (PAR) or indirectly by generating fibrin matrices. In addition to its role in generating fibrin to promote hemostasis, thrombin acts directly on multiple effector cells of the immune system impacting both acute and chronic inflammatory processes. Thrombin‐mediated release of interleukin‐6, tumor necrosis factor‐α, and monocyte chemoattractant protein‐1 leads to the accumulation of multiple tumor‐infiltrating immunosuppressive cell populations including myeloid derived suppresser cells, M2‐like macrophages, and T regulatory cells. Ablation of PAR‐1 from the tumor microenvironment, but not the tumor, has been shown to dramatically reduce tumor growth and metastasis in multiple tumor models. Thrombin‐activated platelets release immunosuppressive cytokines including transforming growth factor‐β that can inhibit natural killer cell activity, helping tumor cells to evade host immunosurveillance. Taken together, there is strong evidence that thrombin influences cancer progression via multiple mechanisms, including the tumor immune response, with thrombin emerging as a target for novel therapeutic strategies for cancer.

Inhibitory Effect of Recombinant Tyrosine-sulfated Madanin-1, a Thrombin Inhibitor, on the behavior of MDA-MB-231 and SKOV3 Cells in vitro

“…Cancer has many mechanisms that even induce thrombin production 23 , e.g., broblast and epithelial expression of thrombin are signi cantly increased in invasive breast cancer 24 . Thrombin activates signaling pathways, including the phosphatidylinositol 3-kinase (PI3K) and mitogenactivated protein kinase (MAPK) cascade via the PAR-1 receptor 25 ; and stimulation of PAR-1 receptors on tumor cells and stromal cells mediates diverse effects, including cancer progression, in ammation, and immunosuppression 26,27 . Moreover, Zhong et al 28 reported that thrombin treatment of SKOV3 cells not only increased invasion but also upregulated PAR-1.…”

The prognostic role of coagulation markers in the progression and metastasis of laryngeal squamous cell carcinoma

“…It has been reported that Fib can reduce the sensitivity of tumor cells to chemotherapy, protect tumor cells, and thus promote their proliferation and metastasis [ 12 , 45 ]. Despite recent reports on the application of anticoagulant therapy using heparin or low molecular weight heparin in LSCC patients with high Fib, its efficacy for LSCC has not been established [ 46 – 48 ]. Therefore, in LSCC patients with high Fib, anticoagulant therapy may also be considered, with the re-evaluation of the chemotherapy sensitivity.…”

Baicalein promotes KDM4E to induce BICD1 and inhibit triple‐negative breast cancer progression by blocking PAR1 signaling

“…BICD1 has been reported to inhibit protease‐activated receptor‐1 (PAR1, also termed thrombin receptor) signaling by interactions with the cytoplasmic 8th helix of PAR1, and BICD1 was revealed as an effective suppressor of PAR1‐induced proliferation of BRCA cells 10 . Considering that thrombin has been linked to earlier events in cancer pathogenesis 11 and ablation of PAR1 from the tumor microenvironment dramatically reduced tumor growth and metastasis in multiple tumor models, 12 the purpose of the present study was to ascertain whether the antitumor properties of baicalein in BC are related to the KDM4E/BICD1/PAR1 axis.…”