Immunomodulatory role of thrombin in cancer progression

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 recep...

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Bibliographic Details
Published in:Molecular carcinogenesis 2022-06, Vol.61 (6), p.527-536
Main Authors: Alexander, Eric T., Gilmour, Susan K.
Format: Article
Language:English
Subjects:
Cancer
Chemotherapy
Effector cells
Fibrin
Hemostasis
Immune response
Immunomodulation
Immunoregulation
immunosuppression
Immunosurveillance
Inflammation
Interleukin 6
Lymphocytes T
Macrophages
Metastases
Monocyte chemoattractant protein
Monocytes
Natural killer cells
Thrombin
thrombin inhibitor
Tumor cells
Tumor microenvironment
Tumor-infiltrating lymphocytes
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Summary: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.
ISSN:0899-1987
1098-2744
DOI:10.1002/mc.23398