<scp>NETosis</scp>: Sculpting tumor metastasis and immunotherapy

Hu, Yanyan; Wang, Houhong; Liu, Yang

doi:10.1111/imr.13277

Cited by 10 publications

(6 citation statements)

References 183 publications

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“…Since elevated serum levels of NETs have been found in almost all cancers, NETs are considered potential therapeutic targets and prognostic markers. In conclusion, NETosis plays a vital role in cancer initiation, progression, metastasis, chemoresistance, and prognosis, making it a possible therapeutic approach to treat various cancers, including hematological malignancies (14,19,20).…”

Section: The Role Of the Tumor-associated Neutrophils And Netosis On ...mentioning

confidence: 99%

The impact of NETosis on hematological malignancies as a promising therapeutic target

Aydemir

2024

Front. Hematol.

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NETosis is a regulated cell death pathway primarily used by neutrophils to eliminate abnormal cells and pathogens, including bacteria, protozoa, fungi, and viruses, via neutrophil extracellular traps (NETs) production (1). Extracellular trap (ET) structure consists of DNA, chromatin, histones, granules, cytosolic and antimicrobial proteins produced against pathogens that can be formed by neutrophils (NETs), macrophages (METs), eosinophils (EETs), mast cells (MCETs), and basophils (BETs) involved in the antimicrobial response, thrombosis, diabetes, sepsis, immune regulation, cardiac function, cancer progression, metastasis, and chemoresistance (2). NETs are the first discovered ones released by activated neutrophils, comprising 50-70% of all white blood cells, and considered the first line of defense against pathogens, inflammation, cancer cells, and environmental exposures. Neutrophils regulate innate and adaptive immune systems, where activated neutrophils eliminate abnormal cells and pathogens via three major pathways: NETosis via NET formation, phagocytosis, and the release of cytotoxic enzymes called degranulation (3, 4).NETosis was first described by Takoma et al. in 1996 (2) and characterized in detail by Brinkman et al. in 2004 (3). NETosis is triggered via various signals and pathways including elevated intracellular calcium levels via b2 integrin, increased reactive oxygen species (ROS) levels, membrane surface receptors such as CD18, toll-like receptor 1 (TLR1), phorbol myristate acetate (PMA), nucleotide oligomerization domain (NOD)-like receptor 2, intracellular signaling cascades including SYK-PI3K-mTorc2 AND Raf-MEK-ERK-MAP kinase, cytokines and chemokines (IL-1, IL-18, TNF), changes in the pH, presence of bacterial toxins and proteins such as lipopolysaccharides (LPS) (5). NETosis is categorized into suicidal and vital NETosis depending on whether neutrophil integrity and function are preserved. Vital NETosis is independent of NADPH oxidase (NOX), in which neutrophils remain vital and take approximately 30 minutes. It is triggered by complement proteins, pathogens, and activated platelets via activation of TLR-2, TLR-4, and complement receptor 3 (CR3) that leads to activation of peptidyl arginine deiminase-4 (PAD4) enzyme involved in the chromatin decondensation (6). After activation, PAD4 enters the nucleus, triggering citrullinated H3 (CitH3) to activate chromatin decondensation. CitH3 is a biomarker associated with NETosis, NET production, venous thromboembolism, and

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Section: The Role Of the Tumor-associated Neutrophils And Netosis On ...mentioning

confidence: 99%

The impact of NETosis on hematological malignancies as a promising therapeutic target

Aydemir

2024

Front. Hematol.

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“…However, as with many physiological processes, there's a double‐edged sword to NETosis 14 . In recent years, a growing body of research has started to unveil the multifaceted roles of NETosis, especially its implications in non‐infectious diseases 15 . Among these, its association with cancer has generated significant interest.…”

Section: Introductionmentioning

confidence: 99%

“… 14 In recent years, a growing body of research has started to unveil the multifaceted roles of NETosis, especially its implications in non‐infectious diseases. 15 Among these, its association with cancer has generated significant interest. While on one hand, NETs might play a protective role by trapping circulating tumour cells, and preventing their metastasis, they have also been implicated in fostering tumour progression.…”

Section: Introductionmentioning

confidence: 99%

Prognostic impact and immunotherapeutic implications of NETosis‐related gene signature in gastric cancer patients

Xiang,

Wei,

et al. 2023

J Cellular Molecular Medi

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The role of NETosis and its related molecules remains unclear in gastric cancer. The data used in this study was directly downloaded from the Cancer Genome Atlas (TCGA) database. All analysis and plots are completed in R software using diverse R packages. In our study, we collected the list of NETosis‐related genes from previous publications. Based on the list and expression profile of gastric cancer patients from the TCGA database, we identified the NETosis‐related genes significantly correlated with patients survival. Then, CLEC6A, BST1 and TLR7 were identified through LASSO regression and multivariate Cox regression analysis for prognosis model construction. This prognosis model showed great predictive efficiency in both training and validation cohorts. We noticed that the high‐risk patients might have a worse survival performance. Next, we explored the biological enrichment difference between high‐ and low‐risk patients and found that many carcinogenic pathways were upregulated in the high‐risk patients. Meanwhile, we investigated the genomic instability, mutation burden and immune microenvironment difference between high‐ and low‐risk patients. Moreover, we noticed that low‐risk patients were more sensitive to immunotherapy (85.95% vs. 56.22%). High‐risk patients were more sensitive to some small molecules compounds like camptothecin_1003, cisplatin_1005, cytarabine_1006, nutlin‐3a (−)_1047, gemcitabine_1190, WZ4003_1614, selumetinib_1736 and mitoxantrone_1810. In summary, our study comprehensively explored the role of NETosis‐related genes in gastric cancer, which can provide direction for relevant studies.

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“…Specifically, it appears that dying neutrophil granulocytes produce so-called neutrophil extracellular traps (NETs) that shield cancer cells from cytotoxic immunity, hence impairing their clearance. 20 Moreover, dying neutrophils can stimulate unwarranted inflammatory and autoimmune responses. 21 Altogether, this volume of Immunological Reviews illustrates to which extent different cell stress and death modalities affecting malignant cells, pathogen-infected cells, or immune cells can elicit innate and cognate immune responses with vast consequences for wholebody physiology.…”

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confidence: 99%

“…However, cell death affecting immune cells may play down such a desirable immunosurveillance. Specifically, it appears that dying neutrophil granulocytes produce so‐called neutrophil extracellular traps (NETs) that shield cancer cells from cytotoxic immunity, hence impairing their clearance 20 . Moreover, dying neutrophils can stimulate unwarranted inflammatory and autoimmune responses 21 …”

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confidence: 99%