Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels

Liu, Xiaobo; Wang, Yuanyuan; Bauer, Alexander; Kirschfink, Michael; Ding, Peipei; Gebhardt, Christoffer; Borsig, Lubor; Tüting, Thomas; Renné, Thomas; Häffner, Karsten; Hu, Weiguo; Schneider, Stefan W.; Gorzelanny, Christian

doi:10.1073/pnas.2122716119

Cited by 22 publications

(13 citation statements)

References 77 publications

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“…The arachidonic acid pathway is a metabolic process that plays a key role in carcinogenesis, and its enzymes are emerging as novel targets for cancer prevention and therapy ( Yarla et al, 2016 ). Simultaneously weakening the complement system and the coagulation cascade seems to be a prudent treatment for cancer patients ( Liu et al, 2022b ). The pyrimidine pathway contributes to cancer mechanisms ( Weber, 1983 ).…”

Section: Discussionmentioning

confidence: 99%

Clinical relevance of RNA editing profiles in lung adenocarcinoma

Shi

Chen²,

Wang³

et al. 2023

Front. Genet.

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Background: Lung adenocarcinoma (LUAD) is the most frequently occurring lung cancer worldwide, with increasing death rates. It belongs to the non-small cell lung cancer (NSCLC) type and has a strong association with previous smoking history. Growing evidence has demonstrated the significance of adenosine-to-inosine RNA editing (ATIRE) dysregulation in cancer. The aim of the present study was to evaluate ATIRE events that might be clinically useful or tumorigenic.Methods: To explore survival-related ATIRE events in LUAD, its ATIRE profiles, gene expression data, and corresponding patients’ clinical information were downloaded from the Cancer Genome Atlas (TCGA) and the synapse database. We evaluated 10441 ATIRE in 440 LUAD patients from the TCGA database. ATIRE profiles were merged with TCGA survival data. We selected prognostic ATIRE sites, using a univariate Cox analysis (p < 0.001). Cox proportional hazards regression and lasso regression analysis were used to determine survival-related ATIRE sites, create risk ratings for those sites, and build a prognostic model and a nomogram for assessing overall survival (OS). Six ATIRE sites were used in the prognostic model construction and patients were randomly divided into a validation cohort (n = 176) and a training cohort (n = 264). The “Pheatmap” program was used to create risk curves that included risk score, survival time, and expression of ATIRE sites. We also determined the clinical prediction model’s discrimination. The decision curve analysis and the 1-, 2-, and 3-year corrective curves were simultaneously used to evaluate the nomogram. We also evaluated the relationship between the amount of ATIRE sites and host gene expression and the impact of ATIRE expression on transcriptome expression.Results: The pyroglutamyl-peptidase I (PGPEP1) chr19:18476416A > I, ankyrin repeat domain 36B pseudogene 1 (ANKRD36BP1) (dist = 3,795), T-box transcription factor (TBX19) (dist = 29815) chr1:168220463A > I, Syntrophin Beta 2 (SNTB2) chr16:69338598A > I, hook microtubule-tethering protein 3 (HOOK3) chr8:42883441A > I, NADH dehydrogenase flavoprotein 3 (NDUFV3) chr21:44329452A > I, and FK506-binding protein 11 (FKBP11) chr12:49316769A > I were used in the prognostic model construction. High levels of risk score were significantly associated with worse OS and progression-free survival. Tumour stage and risk score were related to OS in LUAD patients. The predictors were among the prognostic nomogram model’s risk score, age, gender, and tumor stage. The calibration plot and C-index (0.718) demonstrated the significant accuracy of nomogram’s predictions. ATIRE level was markedly elevated in tumor tissues and was highly variable between patients.Conclusion: Events involving ATIRE in LUAD were highly functional and clinically relevant. The RNA editing-based model provides a solid framework for further investigation of the functions of RNA editing in non-coding areas and may be used as a unique method for predicting LUAD survival.

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Section: Discussionmentioning

confidence: 99%

Clinical relevance of RNA editing profiles in lung adenocarcinoma

Shi

Chen²,

Wang³

et al. 2023

Front. Genet.

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“…Elevated NETs are present in many lung diseases including Cystic Fibrosis (CF), non-CF bronchiectasis, asthma and COPD (27)(28)(29)(30). We and others have demonstrated that NETs can disrupt barrier function of the epithelium and endothelium, a key mechanism of NET-induced pathogenesis in the lung (10,31). NETs are complex structures with over 100 proteins, many of which are immunomodulatory, so defining NET concentrations is challenging.…”

Section: Discussionmentioning

confidence: 99%

Heterogeneity in Neutrophil Extracellular Traps from Healthy Human Subjects

Collins,

Imbrogno,

Kopras

et al. 2023

Preprint

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Neutrophil Extracellular Traps (NETs), a key component of early defense against microbial infection, are also associated with tissue injury. NET composition has been reported to vary with some disease states, but the composition and variability of NETs across many healthy subjects provides a critical comparison that has not been well investigated. We evaluated NETs from twelve healthy subjects of varying ages isolated from multiple blood draws over a three and one half-year period to delineate the variability in extracellular DNA, protein, enzymatic activities, and susceptibility to protease inhibitors. We calculated correlations for NET constituents and loss of human bronchial epithelial barrier integrity, measured by transepithelial electrical resistance, after NET exposure. We found that although there was some variability within the same subject over time, the mean numbers of neutrophils, protein, LDH, serine protease activities, and cytokines IL-8, IL-1RA, and G-CSF in isolated NETs were consistent across subjects. Total DNA and double stranded DNA content in NETs were different across donors. NETs had little or no TNFα, IL-17A, or GM-CSF. NET DNA concentration correlated with increased NET neutrophil elastase activity and higher NET IL-1RA concentrations. NET serine protease activity varied considerably within the same donor from day-to-day. Mean response to protease inhibitors was significantly different across donors. NET DNA concentration correlated best with reductions in barrier integrity of human bronchial epithelia. Defining NET concentration by DNA content correlates with other NET components and reductions in NET-driven epithelial barrier dysfunction, suggesting DNA is a reasonable surrogate measurement for these complex structures in healthy subjects.

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“…Cancer endothelium functions as a starting point of the complement cascade. C5a promotes to recruit neutrophils 89 . After contacting with the vascular endothelium, neutrophils are activated via complement membrane attack complexes (MACs), with subsequent generation of NETs.…”

Section: Netosis In Cancer Metastasismentioning

confidence: 99%

“…C5a promotes to recruit neutrophils. 89 After contacting with the vascular endothelium, neutrophils are activated via complement membrane attack complexes (MACs), with subsequent generation of NETs. Behind the wall of blood vessels, NETs open the endothelial barriers, with enhancement in vascular leakage, resulting in the access of cancer cells to the circulating system and systemic dissemination.…”

Section: Extravasationmentioning

confidence: 99%

NETosis: Sculpting tumor metastasis and immunotherapy

Hu,

Wang,

Liu

2023

Immunological Reviews

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SummaryThe process of neutrophil extracellular traps (NETs) formation, called NETosis, is a peculiar death modality of neutrophils, which was first observed as an immune response against bacterial infection. However, recent work has revealed the unique biology of NETosis in facilitating tumor metastatic process. Neutrophil extracellular traps released by the tumor microenvironment (TME) shield tumor cells from cytotoxic immunity, leading to impaired tumor clearance. Besides, tumor cells tapped by NETs enable to travel through vessels and subsequently seed distant organs. Targeted ablation of NETosis has been proven to be beneficial in potentiating the efficacy of cancer immunotherapy in the metastatic settings. This review outlines the impact of NETosis at almost all stages of tumor metastasis. Furthermore, understanding the multifaceted interplay between NETosis and the TME components is crucial for supporting the rational development of highly effective combination immunotherapeutic strategies with anti‐NETosis for patients with metastatic disease.

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Neutrophils activated by membrane attack complexes increase the permeability of melanoma blood vessels

Cited by 22 publications

References 77 publications

Clinical relevance of RNA editing profiles in lung adenocarcinoma

Clinical relevance of RNA editing profiles in lung adenocarcinoma

Heterogeneity in Neutrophil Extracellular Traps from Healthy Human Subjects

NETosis: Sculpting tumor metastasis and immunotherapy

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