• AISI
• NHANES
• aggregate index of systemic inflammation
• female cancer
• mortality

• coagulation system
• immune cell death

• Extracellular Traps
• Neutrophils/enzymology
• Humans
• Animals
• Mice
• Receptor, PAR-2/genetics
• Receptor, PAR-2/metabolism
• Enzyme Activation
• Mice, Inbred C57BL
• Factor Xa/metabolism
• Blood Coagulation
• Proteolysis
• Mice, Knockout
• Male
• Female
• Gingipain Cysteine Endopeptidases/metabolism

• the National Science Centre of Poland, 2016/22/E/NZ6/00336

• Humans
• Extracellular Traps/metabolism
• Neoplasms/therapy
• Neoplasms/immunology
• Child
• Neutrophils/metabolism
• Prognosis

• PANoptosis
• colorectal cancer
• immune microenvironment
• tumor microenvironment
• tumor progression

• Humans
• Tumor Microenvironment/immunology
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Colorectal Neoplasms/etiology
• Animals
• Necroptosis/immunology
• Apoptosis/immunology
• Pyroptosis/immunology

• immune
• inflammation
• neuroblastoma
• neutrophil extracellular traps
• prognosis

• PD‐1
• liraglutide
• liver cancer
• lung cancer
• neutrophil extracellular traps

• Liraglutide/pharmacology
• Animals
• Extracellular Traps/drug effects
• Extracellular Traps/metabolism
• Mice
• Liver Neoplasms/drug therapy
• Liver Neoplasms/metabolism
• Liver Neoplasms/pathology
• Lung Neoplasms/drug therapy
• Lung Neoplasms/metabolism
• Lung Neoplasms/pathology
• Mice, Inbred C57BL
• Immune Checkpoint Inhibitors/pharmacology
• Neutrophils/drug effects
• Neutrophils/metabolism
• Tumor Microenvironment/drug effects
• Cell Line, Tumor
• Humans
• Carcinoma, Lewis Lung/drug therapy
• Carcinoma, Lewis Lung/pathology
• Carcinoma, Lewis Lung/metabolism
• Reactive Oxygen Species/metabolism

• QML20200311 Beijing Hospitals Authority Youth Program

• oral cancer
• cancer microenvironment

• no.82372997 National Natural Science Foundation of China (National Science Foundation of China)
• no. 82303307 National Natural Science Foundation of China (National Science Foundation of China)
• BK20230306 Natural Science Foundation of Jiangsu Province (Jiangsu Provincial Natural Science Foundation)

• Cancer
• Cardiovascular disease
• Neutrophil
• Neutrophil extracellular traps

• Humans
• Extracellular Traps
• Cardiovascular Diseases
• Neoplasms
• Animals

Colorectal cancer (CRC) is the most common digestive malignancy across the world. Its first-line treatments applied in the routine clinical setting include surgery, chemotherapy, radiotherapy, targeted therapy, and immunotherapy. However, resistance to therapy has been identified as the major clinical challenge that fails the treatment method, leading to recurrence and distant metastasis. An increasing number of studies have been attempting to explore the underlying mechanisms of the resistance of CRC cells to different therapies, which can be summarized into two aspects: (1) The intrinsic characters and adapted alterations of CRC cells before and during treatment that regulate the drug metabolism, drug transport, drug target, and the activation of signaling pathways; and (2) the suppressive features of the tumor microenvironment (TME). To combat the issue of therapeutic resistance, effective strategies are warranted with a focus on the restoration of CRC cells’ sensitivity to specific treatments as well as reprogramming impressive TME into stimulatory conditions. To date, nanotechnology seems promising with scope for improvement of drug mobility, treatment efficacy, and reduction of systemic toxicity. The instinctive advantages offered by nanomaterials enable the diversity of loading cargoes to increase drug concentration and targeting specificity, as well as offer a platform for trying the combination of different treatments to eventually prevent tumor recurrence, metastasis, and reversion of therapy resistance. The present review intends to summarize the known mechanisms of CRC resistance to chemotherapy, radiotherapy, immunotherapy, and targeted therapy, as well as the process of metastasis. We have also emphasized the recent application of nanomaterials in combating therapeutic resistance and preventing metastasis either by combining with other treatment approaches or alone. In summary, nanomedicine is an emerging technology with potential for CRC treatment; hence, efforts should be devoted to targeting cancer cells for the restoration of therapeutic sensitivity as well as reprogramming the TME. It is believed that the combined strategy will be beneficial to achieve synergistic outcomes contributing to control and management of CRC in the future.

• Colorectal cancer
• Therapeutic resistance
• Nanotechnology
• Drug delivery system
• Combined treatment

• Humans
• Drug Resistance, Neoplasm
• Nanotechnology
• Drug Delivery Systems
• Immunotherapy
• Colorectal Neoplasms/drug therapy
• Tumor Microenvironment

• Cyclooxygenase-2 (COX-2)
• gastric cancer
• metastasis
• neutrophil extracellular traps (NETs)
• toll-like receptor 2 (TLR 2)

• cancer
• citrullination
• digestive system
• inflammation
• peptidylarginine deiminase

• CiteSpace
• Nets
• VOSviewer
• neutrophil
• visual analysis

Extracellular traps (ETs) and tumor-infiltrating immune cells play crucial roles in tumor progression. However, little is known about the clinical significance of tumor-infiltrating neutrophils and macrophages and the related ETs in pancreatic ductal adenocarcinoma (PDAC). This study investigates the associations between neutrophil or macrophage infiltration or ET formation and the clinicopathological features, molecular characteristics, immune checkpoint molecules, clinical outcomes, and response to adjuvant chemotherapy (ACT) in PDAC. We performed multiplex immunofluorescence staining to detect ET formation by neutrophils or macrophages using tissue microarrays obtained from 205 patients, and analyzed the immunohistochemistry data for PD-L1, PD-L2, B7-H3, and B7-H4. The ET expression rates in macrophages and neutrophils were 23.9% and 45.4%, respectively. Patients with a high density of neutrophils or positive expression of neutrophil ETs exhibited poorer progression-free survival (PFS) and disease-specific survival (DSS), whereas macrophage ETs were not related to PFS and DSS. Neutrophil infiltration and ET formation were identified as independent prognostic predictors of DSS using univariate and multivariate Cox analyses. Patients with PDAC with lower neutrophil infiltration or negative staining for neutrophil ETs are more likely to benefit from ACT. Patients with PDAC were more accurately stratified based on the infiltration of neutrophils and presence of neutrophil ETs, and patients with low neutrophil infiltration and negative staining for neutrophil ETs showed the best survival. Patients with positive neutrophil ETs demonstrated inferior DSS compared to those with negative neutrophil ETs in the PD-L1 tumor proportion score (TPS) < 1% and PD-L1 IC < 1% subgroups. However, the positive expression of neutrophil ETs was not related to DSS in the PD-L1 TPS ≥ 1% or PD-L1 IC ≥ 1% subgroup. Our findings emphasize the potential of neutrophil infiltration and ETs as prognostic markers that could guide the formulation of more effective personalized treatments for PDAC.

• Humans
• B7-H1 Antigen/metabolism
• Extracellular Traps/metabolism
• Biomarkers, Tumor/metabolism
• Carcinoma, Pancreatic Ductal/pathology
• Pancreatic Neoplasms/pathology

• Chinese Academy of Medical Sciences Initiative for Innovative Medicine
• National Natural Science Foundation of China

NETs are chromatin-derived webs extruded from neutrophils as a result of either infection or sterile stimulation using chemicals, cytokines, or microbes. In addition to the classical role that NETs play in innate immunity against infection and injuries, NETs have been implicated extensively in cancer progression, metastatic dissemination, and therapy resistance. The purpose of this review is to describe recent investigations into NETs and the roles they play in tumor biology and to explore their potential as therapeutic targets in cancer treatment.

• Chromatin
• Extracellular Traps
• Humans
• Immunity, Innate
• Neoplasms
• Neutrophils

MicroRNA (miRNA) regulates gene expression posttranscriptionally, and some of them function in tumor suppression and can be used in drug development. As a result, identifying and screening miRNAs that suppress tumors would be a significant addition to tumor treatment.

In this study, we analyzed the miRNA expression profile of colorectal cancer (CRC), constructed a negative regulatory network of the miRNA-target genes, and identified miR-4469 as one of the key tumor suppressors miRNAs. We analyzed the expression and survival of miR-4469 in pan-cancer, experimentally verified the expression level of miR-4469 in CRC cells and the effect on CRC cell proliferation and migration. We screened miR-4469 target genes for enrichment analysis and immune cell infiltration analysis and validated target gene expression to clarify the regulatory mechanisms involved in miR-4469.

miR-4469 was more highly expressed in normal colorectum tissues compared to CRC tissues and correlated with survival time in patients with multiple cancers. It was shown that miR-4469 was highly expressed in normal colon cells and miR-4469 expression could inhibit the proliferation and migration of CRC cells. In addition, studies on the mechanism showed that miR-4469 function is mainly related to the regulation of inflammatory cell infiltration, and the key target genes of miR-4469 in this process are SLC2A3, FGR, PLEKHO2, and MYO1F.

miR-4469 is a tumor suppressor in CRC, and its regulatory mechanism mainly affects the infiltration of inflammatory cells in the cancer tissue.

• Colorectal cancer
• Neutrophil
• Tumor suppressor
• miR-4469

Neutrophil extracellular traps (NETs) are extracellular reticular fibrillar structures composed of DNA, histones, granulins and cytoplasmic proteins that are delivered externally by neutrophils in response to stimulation with various types of microorganisms, cytokines and host molecules, etc. NET formation has been extensively demonstrated to trap, immobilize, inactivate and kill invading microorganisms and acts as a form of innate response against pathogenic invasion. However, NETs are a double-edged sword. In the event of imbalance between NET formation and clearance, excessive NETs not only directly inflict tissue lesions, but also recruit pro-inflammatory cells or proteins that promote the release of inflammatory factors and magnify the inflammatory response further, driving the progression of many human diseases. The deleterious effects of excessive release of NETs on gut diseases are particularly crucial as NETs are more likely to be disrupted by neutrophils infiltrating the intestinal epithelium during intestinal disorders, leading to intestinal injury, and in addition, NETs and their relevant molecules are capable of directly triggering the death of intestinal epithelial cells. Within this context, a large number of NETs have been reported in several intestinal diseases, including intestinal infections, inflammatory bowel disease, intestinal ischemia–reperfusion injury, sepsis, necrotizing enterocolitis, and colorectal cancer. Therefore, the formation of NET would have to be strictly monitored to prevent their mediated tissue damage. In this review, we summarize the latest knowledge on the formation mechanisms of NETs and their pathophysiological roles in a variety of intestinal diseases, with the aim of providing an essential directional guidance and theoretical basis for clinical interventions in the exploration of mechanisms underlying NETs and targeted therapies.

• Colitis
• Colorectal neoplasms
• Infection
• Inflammation
• Intestinal diseases
• Neutrophil extracellular traps
• Neutrophils
• Therapeutics

Neutrophil extracellular traps (NETs), products of neutrophil death when exposed to certain stimuli, were first proposed as a type of response to bacterial infection in infectious diseases. Since then, extensive studies have discovered its involvement in other non-infectious inflammatory diseases including thromboembolism, autoimmune diseases, and cancer. Colorectal cancer (CRC) is one of the most common malignancies in the world. NET formation is closely associated with tumorigenesis, progression, and metastasis in CRC. Therefore, the application of NETs in clinical practice as diagnostic biomarkers, therapeutic targets, and prognostic predictors has a promising prospect. In addition, therapeutics targeting NETs are significantly efficient in halting tumor progression in preclinical cancer models, which further indicates its potential clinical utility in cancer treatment. This review focuses on the stimuli of NETosis, its pro-tumorigenic activity, and prospective clinical utility primarily in but not limited to CRC.

Surgery is unanimously regarded as the primary strategy to cure solid tumors in the early stages but is not always used in advanced cases. However, tumor surgery must be carefully considered because the risk of metastasis could be increased by the surgical procedure. Tumor surgery may result in a deep wound, which induces many biological responses favoring tumor metastasis. In particular, NETosis, which is the process of forming neutrophil extracellular traps (NETs), has received attention as a risk factor for surgery-induced metastasis. To reduce cancer mortality, researchers have made efforts to prevent secondary metastasis after resection of the primary tumor. From this point of view, a better understanding of surgery-induced metastasis might provide new strategies for more effective and safer surgical approaches. In this paper, recent insights into the surgical effects on metastasis will be reviewed. Moreover, in-depth opinions about the effects of NETs on metastasis will be discussed.

Therapies that limit the formation of web-like structures formed by white cells known as neutrophils may lower the risk of cancer spread (metastasis) following surgical tumor removal. Removing solid tumors remains a key cancer treatment, but in some cases surgery itself increases the risk of metastasis. Jong-Wan Park at Seoul National University, South Korea, and co-workers reviewed current understanding of metastasis following surgery. Surgical removal destroys the architecture supporting cancer cells but this can release tumor cells into blood vessels. The stress of deep wounds also affects immune responses, most notably neutrophil extracellular traps (NETs), web-like structures formed by neutrophils to trap and kill pathogens. NETs have previously been implicated in metastasis. In a post-surgical environment enriched in neutrophils and pro-inflammatory cytokines, NET formation may help cancer cells thrive, promoting metastasis.

Background: Neutrophil extracellular traps (NETs) play an important role in the occurrence, metastasis and immune escape of cancers. This study aimed to investigate NET-related genes, their clinical prognostic value and their correlation with immunotherapy and anticancer drugs in patients with head and neck squamous cell carcinoma (HNSCC).

Methods: Differentially expressed NET-related genes in HNSCC were identified based on multiple public databases. To improve the clinical practicability and avoid overfitting, univariable, least absolute shrinkage and selection operator (LASSO) and multivariable Cox algorithms were used to construct a prognostic risk model. A nomogram was further used to explore the clinical value of the model. Internal and external validation were conducted to test the model. Furthermore, the immune microenvironment, immunophenoscore (IPS) and sensitivity to anticancer drugs in HNSCC patients with different prognostic risks were explored.

Results: Six NET-related genes were screened to construct the risk model. In the training cohort, Kaplan–Meier (K-M) analysis showed that the overall survival (OS) of low-risk HNSCC patients was significantly better than that of high-risk HNSCC patients (p < 0.001). The nomogram also showed a promising prognostic value with a better C-index (0.726 vs 0.640) and area under the curve (AUC) (0.743 vs 0.706 at 3 years, 0.743 vs 0.645 at 5 years) than those in previous studies. Calibration plots and decision curve analysis (DCA) also showed the satisfactory predictive capacity of the nomogram. Internal and external validation further strengthened the credibility of the clinical prognostic model. The level of tumor mutational burden (TMB) in the high-risk group was significantly higher than that in the low-risk group (p = 0.017), and the TMB was positively correlated with the risk score (R = 0.11; p = 0.019). Moreover, the difference in immune infiltration was significant in HNSCC patients with different risks (p < 0.05). Furthermore, the IPS analysis indicated that anti-PD-1 (p < 0.001), anti-CTLA4 (p < 0.001) or combining immunotherapies (p < 0.001) were more beneficial for low-risk HNSCC patients. The response to anticancer drugs was also closely correlated with the expression of NET-related genes (p < 0.001).

Conclusion: This study identified a novel prognostic model that might be beneficial to develop personalized treatment for HNSCC patients.

• Opioids
• enterococcus
• inflammation
• lactobacillus
• lamina propria
• microbial dysbiosis
• neutrophils
• tight junction

• Animals
• Mice
• Neutrophil Infiltration
• Dysbiosis/chemically induced
• Morphine
• Analgesics, Opioid
• RNA, Ribosomal, 16S/genetics
• Gastrointestinal Microbiome
• Microbiota
• Opioid-Related Disorders

• R01 DA012104 NIDA NIH HHS
• R01 DA034582 NIDA NIH HHS
• R01 DA043252 NIDA NIH HHS
• R01 DA044582 NIDA NIH HHS
• R01 DK117576 NIDDK NIH HHS
• R01 DA050542 NIDA NIH HHS
• R01 DA022935 NIDA NIH HHS
• R01 DA031202 NIDA NIH HHS
• T32 DA045734 NIDA NIH HHS
• R01 DA047089 NIDA NIH HHS

Characterized as a complex of extracellular DNA fibers and granule proteins, neutrophil extracellular traps (NETs) are generated specifically by neutrophils which play a critical role in host defense and immune regulation. NETs have been initially found crucial for neutrophil anti-microbial function. Recent studies suggest that NETs are involved in tumorigenesis and cancer progression. However, the function of NETs in cancer remains unclear, which might be due to the variation of research models and the heterogeneity of cancers. Although most of malignant tumors have similar biological behaviors, significant differences indeed exist in various systems. Malignant tumors of the digestive system cause the most incidence and mortality of cancer worldwide. In this review, we would focus on research developments on NETs in digestive cancers to provide insights on their role in digestive cancer progression and future research directions.

• cancer
• digestive system
• immunity
• neutrophil extracellular trap
• targeted therapy

• Anti-tumor
• NETosis
• Neutrophil activation
• Neutrophil membrane
• PMN-MDSCs
• Pro-tumor

• Cancer
• Neutrophil extracellular traps
• Signal pathway
• Tumor microenvironment

Many gut disease etiologies are attributed to the presence of robust inflammatory cell recruitment. The recruitment of neutrophils plays a vital role in inflammatory infiltration. Neutrophils have various antimicrobial effector mechanisms, including phagocytosis, oxidative burst, and degranulation. It is suggested that neutrophils could release neutrophil extracellular traps (NETs) to kill pathogens. However, recent evidence indicates that neutrophil infiltration within the gut is associated with disrupted local immunological microenvironment and impaired epithelial barrier. Growing evidence implies that NETs are involved in the progression of many diseases, including cancer, diabetes, thrombosis, and autoimmune disease. Increased NET formation was found in acute or chronic conditions, including infection, sterile inflammation, cancer, and ischemia/reperfusion injury (IRI). Here, we present a comprehensive review of recent advances in the understanding of NETs, focusing on their effects in gut disease. We also discuss NETs as a potential therapeutic target in gut disease.

• Anti-NETs
• NETs
• Neutrophil extracellular traps
• PAD4
• Therapeutics

• Animals
• Arthritis, Rheumatoid/drug therapy
• Arthritis, Rheumatoid/pathology
• Autoimmune Diseases/drug therapy
• Autoimmune Diseases/pathology
• Extracellular Traps/drug effects
• Humans
• Lupus Erythematosus, Systemic/drug therapy
• Lupus Erythematosus, Systemic/pathology
• Neutrophils/drug effects
• Neutrophils/pathology
• Psoriasis/drug therapy
• Psoriasis/pathology

• T32 OD011147 NIH HHS
• NIH:T32 OD011147 UC Davis Comparative Medical Science Training Program
• USDA NIFA- grant #2016-11003 National Institute of Food and Agriculture
• UC Davis Comparative Medical Science Training Program

This review focuses on the pro-tumorigenic action of neutrophil extracellular traps (NETs). NETs were found in various samples of human and animal tumors. The role of the NETs in tumor development increasingly includes cancer immunoediting and interactions between immune system and cancer cells. NETs awake dormant cancer cells, play a key regulatory role in the tumor microenvironment, and exacerbate tumor aggressiveness by enhancing cancer migration and invasion capacity. Furthermore, NETs induce the epithelial to mesenchymal transition in tumor cells. NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation. Moreover, NETs can entrap circulating cancer cells and, in that way, facilitate metastasis. A better understanding of the crosstalk between cancer and NETs can help to devise novel approaches to the therapeutic interventions that block cancer evasion mechanisms and prevent metastatic spread.

The present review highlights the complex interactions between cancer and neutrophil extracellular traps (NETs). Neutrophils constitute the first line of defense against foreign invaders using major effector mechanisms: phagocytosis, degranulation, and NETs formation. NETs are composed from decondensed nuclear or mitochondrial DNA decorated with proteases and various inflammatory mediators. Although NETs play a crucial role in defense against systemic infections, they also participate in non-infectious conditions, such as inflammation, autoimmune disorders, and cancer. Cancer cells recruit neutrophils (tumor-associated neutrophils, TANs), releasing NETs to the tumor microenvironment. NETs were found in various samples of human and animal tumors, such as pancreatic, breast, liver, and gastric cancers and around metastatic tumors. The role of the NETs in tumor development increasingly includes cancer immunoediting and interactions between the immune system and cancer cells. According to the accumulated evidence, NETs awake dormant cancer cells, causing tumor relapse, as well as its unconstrained growth and spread. NETs play a key regulatory role in the tumor microenvironment, such as the development of distant metastases through the secretion of proteases, i.e., matrix metalloproteinases and proinflammatory cytokines. NETs, furthermore, directly exacerbate tumor aggressiveness by enhancing cancer migration and invasion capacity. The collected evidence also states that through the induction of the high-mobility group box 1, NETs induce the epithelial to mesenchymal transition in tumor cells and, thereby, potentiate their invasiveness. NET proteinases can also degrade the extracellular matrix, promoting cancer cell extravasation. Moreover, NETs can entrap circulating cancer cells and, in that way, facilitate metastasis. NETs directly trigger tumor cell proliferation through their proteases or activating signals. This review focused on the pro-tumorigenic action of NETs, in spite of its potential to also exhibit an antitumor effect. NET components, such as myeloperoxidase or histones, have been shown to directly kill cancer cells. A better understanding of the crosstalk between cancer and NETs can help to devise novel approaches to the therapeutic interventions that block cancer evasion mechanisms and prevent metastatic spread. This review sought to provide the most recent knowledge on the crosstalk between NETs and cancer, and bring more profound ideas for future scientists exploring this field.

• cancer
• evasion
• metastasis
• neutrophil extracellular traps

• brain metastases
• gliobastoma
• nanocarrier
• neutrophil extracellular traps
• neutrophils

• Brain Neoplasms/immunology
• Brain Neoplasms/pathology
• Glioma/immunology
• Glioma/pathology
• Humans
• Neutrophils/immunology
• Tumor Microenvironment/immunology

• cancer
• immunity
• inflammation
• neutrophil
• neutrophil extracellular trap

• cervical cancer
• neutrophil extracellular traps (NETs)
• polymorphonuclear neutrophils (PMNs)
• prognosis
• recurrence-free survival (RFS)

Neutrophil extracellular trap (NET) formation is a newly discovered, reactive oxygen species-dependent regulated process, whereby neutrophils degranulate and extrude genetic material, after engulfing various infectious or neoplastic antigens, culminating in a measurable serologic footprint. Recent research has highlighted the involvement of NETs in cancer and cancer-related pathologies. We review the role of NET formation in cancer biology, prognosis and potential therapeutic modulators.

Elevated NET levels are associated with cancer metastasis and may be modified by some anaesthetic-analgesic techniques during tumour resection surgery. It promotes tumour cell migration, angiogenesis and hypercoagulability. Although there are potential anti-NET formation therapeutics available, their role has not been formally assessed in cancer patients.

Limited available evidence suggests an association between elevated NET expression and cancer metastasis, but its validity as a prognostic indicator for cancer-related outcomes is inconclusive. Further observational and interventional studies are warranted to comprehend the potential prognostic and therapeutic role of NETs in cancer.

The online version contains supplementary material available at 10.1007/s11912-021-01103-0.

• Cancer
• Metastases
• NETosis
• NETs
• Neutrophil extracellular trapping
• Neutrophils
• Thrombosis
• White blood cells

• Analgesia
• Biomarkers, Tumor/immunology
• Biomarkers, Tumor/metabolism
• Extracellular Traps/drug effects
• Extracellular Traps/immunology
• Extracellular Traps/metabolism
• Humans
• Neoplasm Metastasis
• Neoplasms/immunology
• Neoplasms/pathology
• Neoplasms/therapy
• Neovascularization, Pathologic
• Neutrophils/drug effects
• Neutrophils/immunology
• Neutrophils/metabolism
• Neutrophils/pathology
• Perioperative Care
• Thrombosis/immunology
• Thrombosis/pathology
• Thrombosis/therapy

Neutrophils form sticky web-like structures known as neutrophil extracellular traps (NETs) as part of innate immune response. NETs are decondensed extracellular chromatin filaments comprising nuclear and cytoplasmic proteins. NETs have been implicated in many gastrointestinal diseases including colorectal cancer (CRC). However, the regulatory mechanisms of NET formation and potential pharmacological inhibitors in the context of CRC have not been thoroughly discussed. In this review, we intend to highlight roles of NETs in CRC progression and metastasis as well as the potential of targeting NETs during colon cancer therapy.

• colorectal cancer
• extracellular DNA
• metastasis
• neutrophil
• therapeutics

• Animals
• Colorectal Neoplasms/immunology
• Colorectal Neoplasms/pathology
• Disease Progression
• Extracellular Traps/immunology
• Extracellular Traps/physiology
• Humans
• Neoplasm Metastasis/immunology
• Neutrophils/immunology
• Neutrophils/pathology

• NETosis
• cancer
• neutrophils
• tumor microenvironment

Tumor-associated neutrophils constitute an important portion of the infiltrating immune cells in the tumor microenvironment. One of the abilities of neutrophils is forming neutrophil extracellular traps. Recent studies on tumor-associated neutrophils have drawn increasing attention to the role of neutrophil extracellular traps in the tumor microenvironment. There were also some reviews summarize the pro-tumorigenic activity of NETs in tumors. The specific novelty of this article is the specific summarization on the pivotal roles of NETs in tumor invasion-metastasis cascade and the recapitulation on the potential of NETs in clinical applications.

Neutrophil extracellular trap (NET) formation is an ability of neutrophils to capture and kill pathogens by releasing chromatin scaffolds, along with associated cytotoxic enzymes and proteases, into the extracellular space. NETs are usually stimulated by pathogenic microorganisms and their products, surgical pressure or hypoxia. Interestingly, a number of recent studies suggest that tumor cells can induce NET formation, which in turn confers tumor cell malignancy. Notably, emerging studies indicate that NETs are involved in enhancing local invasion, increasing vascular permeability and facilitating immune escape and colonization, thus promoting tumor metastasis. In this article, we review the pivotal roles of NETs in the tumor metastasis cascade. We also recapitulate the potential of NETs as a cancer prognostic biomarker and therapeutic target.

• neutrophil
• neutrophil extracellular trap
• tumor metastasis

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.

• epithelial‑mesenchymal transition
• gastric cancer
• metastasis
• neutrophil extracellular traps

• cancer microenvironment
• tumour immunology
• inflammation
• neutrophils

• Amyloid Precursor Protein Secretases/antagonists & inhibitors
• Amyloid Precursor Protein Secretases/metabolism
• Amyloid beta-Peptides/metabolism
• Animals
• Bone Marrow/pathology
• CD11b Antigen/metabolism
• Cancer-Associated Fibroblasts/drug effects
• Cancer-Associated Fibroblasts/metabolism
• Carcinogenesis/pathology
• Cell Communication/drug effects
• Disease Models, Animal
• Extracellular Traps/drug effects
• Extracellular Traps/metabolism
• Female
• Healthy Volunteers
• Humans
• Male
• Mice
• Mice, Transgenic
• Neoplasms/blood
• Neoplasms/genetics
• Neoplasms/mortality
• Neoplasms/pathology
• Neutrophils/drug effects
• Neutrophils/metabolism
• Observational Studies as Topic
• Primary Cell Culture
• Prognosis
• Protein-Arginine Deiminase Type 4/antagonists & inhibitors
• Protein-Arginine Deiminase Type 4/metabolism
• Reactive Oxygen Species/metabolism
• Tumor Cells, Cultured
• Tumor Microenvironment/drug effects

• MC_UP_1101/2 Medical Research Council
• MC_UU_12022/5 Medical Research Council
• 24868 Cancer Research UK
• C42738/A24868 Cancer Research UK
• G101982 Medical Research Council
• P30 CA045508 NCI NIH HHS

• Cancer therapeutics
• Effector functions
• Neutrophil-derived granule cargoes
• Tumor-associated neutrophils

Neutrophil Extracellular Traps (NETs) are net-like structures composed of DNA-histone complexes and proteins released by activated neutrophils. In addition to their key role in the neutrophil innate immune response, NETs are also involved in autoimmune diseases, like systemic lupus erythematosus, rheumatoid arthritis, psoriasis, and in other non-infectious pathological processes, as coagulation disorders, thrombosis, diabetes, atherosclerosis, vasculitis, and cancer. Recently, a large body of evidence indicates that NETs are involved in cancer progression and metastatic dissemination, both in animal models and cancer patients. Interestingly, a close correlation between cancer cell recruitment of neutrophils in the tumor microenvironment (Tumor Associated Neutrophils. TANs) and NET formation has been also observed either in primary tumors and metastatic sites. Moreover, NETs can also catch circulating cancer cells and promote metastasis. Furthermore, it has been reported that wake dormant cancer cells, causing tumor relapse and metastasis. This review will primarily focus on the pro-tumorigenic activity of NETs in tumors highlighting their ability to serve as a potential target for cancer therapy.

• NETosis
• neutrophil extracellular trap (NET)
• tumor associated neutrophils (TANs)
• tumor microenvironment (TEM)
• tumors

Over the last decades, cancer immunotherapies such as checkpoint blockade and adoptive T cell transfer have been a game changer in many aspects and have improved the treatment for various malignancies considerably. Despite the clinical success of harnessing the adaptive immunity to combat the tumor, the benefits of immunotherapy are still limited to a subset of patients and cancer types. In recent years, neutrophils, the most abundant circulating leukocytes, have emerged as promising targets for anti-cancer therapies. Traditionally regarded as the first line of defense against infections, neutrophils are increasingly recognized as critical players during cancer progression. Evidence shows the functional plasticity of neutrophils in the tumor microenvironment, allowing neutrophils to exert either pro-tumor or anti-tumor effects. This review describes the tumor-promoting roles of neutrophils, focusing on their myeloid-derived suppressor cell activity, as well as their role in tumor elimination, exerted mainly via antibody-dependent cellular cytotoxicity. We will discuss potential approaches to therapeutically target neutrophils in cancer. These include strategies in humans to either silence the pro-tumor activity of neutrophils, or to activate or enhance their anti-tumor functions. Redirecting neutrophils seems a promising approach to harness innate immunity to improve treatment for cancer patients.

• antibody therapy
• antibody-dependent cellular cytotoxicity
• cancer
• myeloid-derived suppressor cells
• neutrophils
• tumor microenvironment

• CAR-T-cell therapy
• Toll-like receptor agonists
• bi-specific T-cell engagers
• colorectal cancer
• dendritic cell vaccine
• immune checkpoint inhibitors
• immune microenvironment
• liver metastases
• metastasis
• microsatellite instability

• platelet adhesion
• innate immune surveillance
• CD44 isoform
• infectious complication
• hematogenous distant metastasis

Host and tumorous inflammation actively affect liver metastasis of colorectal cancer (CRC). Neutrophils have been recognized as one active participant in metastasis procedure, with controversial roles however. Activated neutrophils release extracellular traps (NETs) which are involved in infection and multiple pathological conditions. NETs on cancer metastasis is getting recognized but less elucidated in mechanism. How NETs interact with cancer cells is still largely unknown. In this study, we found that neutrophils from CRC patients, especially those with liver metastatic, underwent remarkably enhanced NETs. Clinically, sera and pathological NETs marker closely correlated with onset of liver metastasis. Through in vivo and in vitro studies, we proved that increased NETs positively contribute to onset of CRC liver metastasis. Digesting NETs with DNase 1 diminished the increased liver metastasis associated with NETs. In detail, NETs trapped CRC cells in liver and exerted no cytotoxicity on tumor cells, but boosted tumorous proliferation and invasion capacity. We further found this enhanced malignancy of trapped CRC cells was due to the elevated tumorous interleukin (IL)-8 expression triggered by NETs. Blocking IL-8 activity effectively abrogated the enhanced proliferation and invasion triggered by NETs. Moreover, overproduced IL-8 in turn activate neutrophils towards NETs formation, thus forming a positive loop optimizing CRC liver metastasis. Collectively, our study propose a novel positive feedback between elevated tumorous IL-8 and NETs to promote CRC liver metastasis, and identify potential strategy against liver metastasis.

• IL-8
• Neutrophil extracellular traps (NETs)
• colorectal cancer (CRC)
• liver metastasis

肺癌为全球性高发病率、高死亡率疾病，严重影响人类健康。其中肺部慢性炎症的长期存在与肺癌的发生发展关系密切，中性粒细胞不但参与急、慢性炎症反应，而且参与肿瘤微环境（tumor-microenvironment, TME）中的组成，与肿瘤的发生、发展密切相关。近年来研究发现，肿瘤相关中性粒细胞（tumor-associated neutrophils, TANs）在肺癌的发生和发展中发挥着重要的作用。本文就肿瘤相关中性粒细胞在肺癌中的作用、机制以及临床意义进行综述。

• Lung neoplasms
• Prognosis
• Tumor microenvironment
• Tumor-associated neutrophils