The thrombin–inflammation axis in cancer progression

Cantrell, Rachel; Palumbo, Joseph S.

doi:10.1016/s0049-3848(20)30408-4

Cited by 25 publications

(26 citation statements)

References 88 publications

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“…The coagulation cascade is a potent source of inflammation in the context of acute wound healing, and it may also have a role as a regulator of the TME [ 24 , 26 ]. We explored the possibility that tumors from TCGA, stratified according to their expression of F3 , might differ in their overall cellular composition.…”

Section: Resultsmentioning

confidence: 99%

“…The coagulation system has a potent effect on myeloid cells and initiates inflammation during the physiological healing process [ 24 ]. In the TME, coagulation might contribute to the recruitment of cells of the myeloid/lymphoid lineages and modulate their activation and function [ 25 , 26 ]. In the present study, we aimed to explore the regulation of the coagulome of OSCC and its link to the TME of these tumors.…”

Section: Introductionmentioning

confidence: 99%

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Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

Lottin

Soudet

Fercot

et al. 2022

Cancers

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Background: Hemostatic complications, ranging from thromboembolism to bleeding, are a significant source of morbidity and mortality in cancer patients. The tumor coagulome represents the multiple genes and proteins that locally contribute to the equilibrium between coagulation and fibrinolysis. We aimed to study the coagulome of Oral Squamous Cell Carcinoma (OSCC) and examine its link to the tumor microenvironment (TME). Methods: We used data from bulk tumor DNA/RNA-seq (The Cancer Genome Atlas), single-cell RNA-seq data and OSCC cells in culture. Results: Among all tumor types, OSCC was identified as the tumor with the highest mRNA expression levels of F3 (Tissue Factor, TF) and PLAU (urokinase type-plasminogen activator, uPA). Great inter- and intra-tumor heterogeneity were observed. Single-cell analyses showed the coexistence of subpopulations of pro-coagulant and pro-fibrinolytic cancer cells within individual tumors. Interestingly, OSCC with high F3 expressed higher levels of the key immune checkpoint molecules CD274/PD-L1, PDCD1LG2/PD-L2 and CD80, especially in tumor dendritic cells. In vitro studies confirmed the particularity of the OSCC coagulome and suggested that thrombin exerts indirect effects on OSCC cells. Conclusions: OSCC presents a specific coagulome. Further studies examining a possible negative modulation of the tumor’s adaptive immune response by the coagulation process are warranted.

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Section: Resultsmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

Lottin

Soudet

Fercot

et al. 2022

Cancers

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“…Thrombin has more than a dozen recognized substrates. 43,44 In addition to fibrin polymerization, thrombin can trigger platelet activation, initiate regulatory pathways that both promote and suppress coagulation, and activate factor XI, protein C, thrombin-activated fibrinolysis inhibitor, and three G protein-coupled protease activated receptors (PAR-1, PAR-3, and PAR-4). 45,46 Determining the fibrinogen-independent mechanisms coupling thrombin to colon cancer growth will also be an important future direction.…”

Section: Discussionmentioning

confidence: 99%

Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth

Sharma

Mureb

Murab

et al. 2021

Journal of Thrombosis and Haemostasis

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Background We previously showed that fibrinogen is a major determinant of the growth of a murine model of colorectal cancer (CRC). Objective Our aim was to define the mechanisms coupling fibrin(ogen) to CRC growth. Results CRC tumors transplanted into the dorsal subcutis of Fib− mice were less proliferative and demonstrated increased senescence relative to those grown in Fib+ mice. RNA‐seq analyses of Fib+ and Fib− tumors revealed 213 differentially regulated genes. One gene highly upregulated in tumors from Fib− mice was stratifin, encoding 14‐3‐3σ, a master regulator of proliferation/senescence. In a separate cohort, we observed significantly increased protein levels of 14‐3‐3σ and its upstream and downstream targets (i.e., p53 and p21) in tumors from Fib− mice. In vitro analyses demonstrated increased tumor cell proliferation in a fibrin printed three‐dimensional environment compared with controls, suggesting that fibrin(ogen) in the tumor microenvironment promotes tumor growth in this context via a tumor cell intrinsic mechanism. In vivo analyses showed diminished activation of focal adhesion kinase (FAK), a key negative regulator of p53, in Fib− tumors. Furthermore, nuclear magnetic resonance–based metabolomics demonstrated significantly reduced metabolic activity in tumors from Fib− relative to Fib+ mice. Together, these findings suggest that fibrin(ogen)‐mediated engagement of colon cancer cells activates FAK, which inhibits p53 and its downstream targets including 14‐3‐3σ and p21, thereby promoting cellular proliferation and preventing senescence. Conclusions These studies suggest that fibrin(ogen) is an important component of the colon cancer microenvironment and may be exploited as a potential therapeutic target.

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“…Moreover, research implicates components of the hemostatic system in the early neoplastic alterations pivotal for tumorigenesis and tumor growth [ 68 ]. Indeed, there exists a reciprocal interaction between cancer and components of the hemostatic system, by which cancer promotes thromboembolism, and the aberrant activity of components of the hemostatic system enhances cancer development, progression, and metastasis [ 69 ]. This is supported by studies providing evidence that chronic conventional anticoagulation is associated with a decreased incidence of certain cancers [ 70 , 71 ].…”

Section: Metabolic Syndrome Obesity Diabetes and Prostate Cancer: Sta...mentioning

confidence: 99%

Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue

AlZaim

Al-Saidi

Hammoud

et al. 2022

Cancers

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The increased global prevalence of metabolic disorders including obesity, insulin resistance, metabolic syndrome and diabetes is mirrored by an increased incidence of prostate cancer (PCa). Ample evidence suggests that these metabolic disorders, being characterized by adipose tissue (AT) expansion and inflammation, not only present as risk factors for the development of PCa, but also drive its increased aggressiveness, enhanced progression, and metastasis. Despite the emerging molecular mechanisms linking AT dysfunction to the various hallmarks of PCa, thromboinflammatory processes implicated in the crosstalk between these diseases have not been thoroughly investigated. This is of particular importance as both diseases present states of hypercoagulability. Accumulating evidence implicates tissue factor, thrombin, and active factor X as well as other players of the coagulation cascade in the pathophysiological processes driving cancer development and progression. In this regard, it becomes pivotal to elucidate the thromboinflammatory processes occurring in the periprostatic adipose tissue (PPAT), a fundamental microenvironmental niche of the prostate. Here, we highlight key findings linking thromboinflammation and the pleiotropic effects of coagulation factors and their inhibitors in metabolic diseases, PCa, and their crosstalk. We also propose several novel therapeutic targets and therapeutic interventions possibly modulating the interaction between these pathological states.

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The thrombin–inflammation axis in cancer progression

Cited by 25 publications

References 88 publications

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

Molecular Landscape of the Coagulome of Oral Squamous Cell Carcinoma

Fibrinogen activates focal adhesion kinase (FAK) promoting colorectal adenocarcinoma growth

Thromboinflammatory Processes at the Nexus of Metabolic Dysfunction and Prostate Cancer: The Emerging Role of Periprostatic Adipose Tissue

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