Role of thrombin as a tumor growth factor

Karpatkin, Simon

doi:10.4161/cc.9.4.10729

Cited by 48 publications

(40 citation statements)

References 27 publications

(31 reference statements)

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“…Previous in vitro studies suggested that activation of tumor cell–associated PAR-1 promotes colon cancer proliferation and invasion (42, 43). Although this view is consistent with the data presented here, these studies also reveal that stromal cell–associated PAR-1 promotes colon cancer growth.…”

Section: Discussionmentioning

confidence: 98%

Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen

et al. 2015

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Thrombin-mediated proteolysis is a major determinant of metastasis, but is not universally important for primary tumor growth. Here, we report that colorectal adenocarcinoma represents one important exception whereby thrombin-mediated functions support both primary tumor growth and metastasis. In contrast with studies of multiple nongastrointestinal cancers, we found that the growth of primary tumors formed by murine and human colon cancer cells was reduced in mice by genetic or pharmacologic reduction of circulating prothrombin. Reduced prothrombin expression was associated with lower mitotic indices and invasion of surrounding tissue. Mechanistic investigations revealed that thrombin-driven colonic adenocarcinoma growth relied upon at least two targets of thrombin-mediated proteolysis, protease-activated receptor-1 (PAR-1) expressed by stromal cells and the extracellular matrix protein, fibrinogen. Colonic adenocarcinoma growth was reduced in PAR-1–deficient mice, implicating stromal cell-associated PAR-1 as one thrombin target important for tumor outgrowth. Furthermore, tumor growth was dramatically impeded in fibrinogen-deficient mice, offering the first direct evidence of a critical functional role for fibrinogen in malignant tumor growth. Tumors harvested from fibrinogen-deficient mice displayed a relative reduction in cell proliferative indices, as well as increased tumor necrosis and decreased tumor vascular density. Collectively, our findings established a functional role for thrombin and its targets PAR-1 and fibrinogen in the pathogenesis of colonic adenocarcinoma, supporting tumor growth as well as local invasion and metastasis.

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Section: Discussionmentioning

confidence: 98%

Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen

et al. 2015

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“…NETs are procoagulant 26 and could therefore promote tumor growth through local thrombin generation. 27 The NETting process could also have a predominant role in the generation of a beneficial extracellular matrix by delivering proteinases and could also favor the release of inflammatory and angiogenic factors. For example, NETs have been shown to contain and activate matrix metalloproteinases, 28 preserve the enzymatic activity of elastase 29 and recruit platelets, 30 important cells for angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

Priming of neutrophils toward NETosis promotes tumor growth

et al. 2016

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Neutrophils play a major role in cancer biology and both pro-and antitumoral functions of tumorinfiltrating neutrophils have been described. We have shown that tumors, by releasing G-CSF into the bloodstream, prime circulating neutrophils to form neutrophil extracellular traps (NETs) and we have detected the presence of NETs within the tumor microenvironment. Here, we report, using PAD4-deficient mice with a defect in neutrophil chromatin decondensation and NET formation, that the priming of neutrophils toward NETosis favors tumor growth. Interestingly, in a tumor model that does not release G-CSF and in which neutrophils are not primed for NETosis, PAD4-deficiency did not reduce tumor growth. However, supplying exogenous G-CSF to the wild-type (WT) host promoted intratumoral NETosis and tumor growth. Taken together, our results suggest that the priming of neutrophils for NETosis by the tumor or its environment leads to the accumulation of intratumoral NETs and a growth advantage to the tumor. Our work unveiled a pro-tumoral role for NETs which strengthens their potential as a new target in the fight against cancer.

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“…The thrombin receptor is expressed on many tumor cell lines and on breast tumor biopsy specimens (Ruf et al, 2010). In addition to the mitogenic effects on fibroblast, smooth muscle cells and endothelial cells, thrombin also exerts direct effects on cancer cells (Green and Karpatkin, 2010). It is also worth noting that thrombin is the key legend of PAR firing inflammation and cell migration (Eroglu et al, 2012).…”

Section: Iv-c Thrombinmentioning

confidence: 99%

Platelets, Coagulation and Cancer: Multifaceted Interactions

Goubran

Burnouf²

2012

American Medical Journal

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Approach: Literature review of the multifaceted interactions between platelets, coagulation and cancer. Results: Over the years, the links existing between cancer development, progression and occurrence of metastasis on one side and coagulation on the other have become obvious. Tumors seems to activate platelets whereas, platelets, on the other hand, through their capacity to activate and release soluble factors and microparticles, interact with tumor cells and influence immune regulation. They appear to be key regulators of many cancer events. Furthermore, coagulation with its different facets also interplays and significantly crosstalks with malignancy. The objectives of this article are to review the mechanisms through which cancer interacts with platelets and the coagulation, triggering thrombosis and the role played by platelets and coagulation factors in the regulation of cancer and to underline the perspectives that are now open in the development of novel diagnostic tools and new cancer treatment strategies. Conclusion/Recommendations: Challenging issues and unresolved questions still need to be addressed to understand the complexity existing between coagulation factors and platelet components and the different stages of cancer progression. Recent discoveries are leading clinicians to consider new therapeutic applications of anticoagulant therapies or new drugs targeting specific platelet functions in cancer patients' management. Furthermore, markers of coagulation and platelet activity may prove to serve as biomarkers for dormant tumors.

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Role of thrombin as a tumor growth factor

Cited by 48 publications

References 27 publications

Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen

Colon Cancer Growth and Dissemination Relies upon Thrombin, Stromal PAR-1, and Fibrinogen

Priming of neutrophils toward NETosis promotes tumor growth

Platelets, Coagulation and Cancer: Multifaceted Interactions

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