Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

Grilz, Ella; Mauracher, Lisa-Marie; Posch, Florian; Königsbrügge, Oliver; Zöchbauer‐Müller, Sabine; Marosi, Christine; Lang, Irene; Pabinger, Ingrid; Ay, Cihan

doi:10.1111/bjh.15906

Cited by 95 publications

(59 citation statements)

References 62 publications

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“…Citrullinated histone H 3 and histone-DNA complex are parts of neutrophil extracellular traps (NETs), released from acute inflammation and neutrophil apoptosis and necrosis. These NETs are formed after citrullination of histones by activation of protein arginine deiminase 4, which has been associated with thrombosis in patients with cancers [ 40 , 41 ]. Leukocytes are known to release nuclear contents that form these extracellular traps, which are mainly composed of the histone-DNA complex [ 42 ].…”

Section: Discussionmentioning

confidence: 99%

Identification of Biomarkers in Patients with Thrombotic Thrombocytopenic Purpura Presenting with Large and Small Ischemic Stroke

Lin

Memon

Sui

et al. 2021

Cerebrovasc Dis Extra

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Background: Thrombotic thrombocytopenic purpura (TTP) is a rare blood disorder resulting in organ damage including ischemic strokes. We sought to characterize the neuroimaging patterns of stroke in a large cohort of patients with immune-mediated TTP (iTTP) and determined their associations with clinical and laboratory parameters and outcomes. Methods: We analyzed the Alabama TTP Registry who had laboratory confirmation of acute iTTP. We reviewed the neuroimaging patterns of those with ischemic stroke on MRI, clinical information, and laboratory results. Small ischemic strokes were ≤20 mm in their maximum diameter in the axial plane. Large ischemic strokes were >20 mm. Student t test, Mann-Whitney U test, and χ2 test were all used for data analysis. Results: Of 108 iTTP patients, 21 had ischemic stroke on neuroimaging. The median platelet count in these patients was 12 × 109/L (interquartile range, IQR, 8.8–21 × 109/L), plasma ADAMTS13 activity 1.8 U/dL (IQR 0–4.5 U/dL), and the mean plasma level of anti-ADAMTS13 IgG was 6,595.8 U/mL (SD 3,448.9 U/mL). Comparison between patients with large ischemic strokes (n = 10) and small ischemic strokes (n = 11) revealed that patients with small stroke were older (p = 0.043) and had higher plasma levels of citrullinated histone 3 (p = 0.006) and histone/DNA complex (p = 0.014) than those with large strokes. There were no significant differences between 2 stroke groups in mortality or exacerbation. Conclusions: iTTP patients can present with large ischemic strokes and are usually younger. Further research should be performed in assessing different etiologies of iTTP-associated stroke based on neutrophil extracellular trap formation biomarkers (e.g., histone markers) seen in small ischemic stroke.

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Section: Discussionmentioning

confidence: 99%

Identification of Biomarkers in Patients with Thrombotic Thrombocytopenic Purpura Presenting with Large and Small Ischemic Stroke

Lin

Memon

Sui

et al. 2021

Cerebrovasc Dis Extra

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“…Although there are caveats with associating NETs and human disease, the sheer number of recent findings in this area underscores the importance of strictly regulated neutrophil activation and turnover (safe removal) to health and homeostasis. For example, NETs have been associated with multiple types of cancer and cancer metastasis 39 , 40 , including breast cancer 41 , hepatocellular carcinoma 42 , lung cancer 43 , ovarian cancer 44 , oral squamous cell carcinoma 45 , pancreatic cancer 46 , and thyroid cancer 47 . NETs have been implicated in autoimmune disorders such as lupus erythematosus 48 – 51 and in the development of thrombosis 52 – 54 and can contribute to the severity of sepsis 55 , 56 .…”

Section: Nets and Human Diseasementioning

confidence: 99%

Phagocytosis and neutrophil extracellular traps

DeLeo¹,

Allen²

2020

Fac Rev

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Neutrophils are recruited rapidly to sites of infection in response to host- and/or microbe-derived proinflammatory molecules. At such sites, neutrophils phagocytose microbes and are activated to produce superoxide and other reactive oxygen species (ROS). In addition, neutrophils contain stores of antimicrobial peptides and enzymes that work in concert with ROS to kill ingested microbes. Neutrophils can also release chromosomal DNA bound with antimicrobial peptides and enzymes to form web-like structures known as extracellular traps. Neutrophil extracellular traps (NETs) have been reported to ensnare and kill microbes and are commonly considered to be an important component of innate host defense. Notably, the formation of NETs is most often reported as a cytolytic process. Whereas intraphagosomal killing of microbes sequesters cytotoxic antimicrobial molecules that would otherwise damage host tissues, the formation of NETs and associated extracellular release of these molecules can contribute to host tissue destruction and disease. Here we compare and contrast phagocytosis and NETs in host defense, with emphasis on recent studies of NETs that ultimately underscore the importance of phagocytosis as the primary means by which neutrophils eliminate microbes.

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“…The degradation or inhibition of NETs by DNAse-1 or neutrophil elastase (NE) inhibitor has been demonstrated to prevent metastasis in a murine cecal ligation and puncture model ( 15 ). Citrullinated histone H3 (cit-h3; a NETs activation marker) is detectable in the plasma of patients with advanced cancer, and can serve as a distinct prognostic marker that is associated with a poor clinical outcome in numerous types of tumor ( 16 ). After deposition of NETs was found to be significant in malignant tumors, it was also identified that NETs increase the risk of thrombosis in patients with cancer, which may be associated with a poor prognosis ( 17 , 18 ).…”

Section: Introductionmentioning

confidence: 99%

Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial‑mesenchymal transition

Zhu

Zou

Yang³

et al. 2021

Int J Mol Med

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The risks of tumor recurrence following the successful resection of the primary tumor have been known for decades; however, the precise mechanisms underlying treatment failures remain unknown. The formation of neutrophil extracellular traps (NETs) has increasingly been demonstrated to be associated with thrombi formation in cancer patients, as well as with the development and metastasis of cancer. The present study demonstrated that the level of peripheral blood NETs in patients with gastric cancer (Gc) was associated with tumor progression, and patients with stage III/IV disease exhibited significant differences compared with the healthy controls and patients with stage I/II disease, which may be associated with an increased risk of metastasis. In addition, plasma from patients with stage III/IV Gc was more prone to stimulate neutrophils to form NETs; thus, it was hypothesized that the formation of NETs may be affected by the tumor microenvironment. A higher deposition of NETs in Gc tissues compared with normal resection margins was also identified. In vitro, following treatment with phorbol myristate acetate, which promotes the formation of NETs, or with dNAse-1/GSK-484, which inhibits the formation of NETs, it was found that the tumor migratory ability was altered; however, no significant changes were observed in cell proliferation and cell cycle progression. Epithelial-mesenchymal transition (EMT) is a key event associated with dissemination and metastasis in Gc pathogenesis. Finally, the present study demonstrated that NETs promote a more aggressive mesenchymal phenotype and promote the progression of Gc in vitro and in vivo. On the whole, to the best of our knowledge, the present study reports a previously unknown role of NETs in the regulation of Gc, which is associated with EMT and migration. Therefore, targeting NETs may prove to be therapeutically beneficial.

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Citrullinated histone H3, a biomarker for neutrophil extracellular trap formation, predicts the risk of mortality in patients with cancer

Cited by 95 publications

References 62 publications

Identification of Biomarkers in Patients with Thrombotic Thrombocytopenic Purpura Presenting with Large and Small Ischemic Stroke

Identification of Biomarkers in Patients with Thrombotic Thrombocytopenic Purpura Presenting with Large and Small Ischemic Stroke

Phagocytosis and neutrophil extracellular traps

Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial‑mesenchymal transition

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