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Neutrophil Extracellular Traps (NETs) in Cancer Metastasis.

ABSTRACT: Metastasis is the leading cause of cancer related morbidity and mortality. The metastatic process involves several identifiable biological stages, including tumor cell dissemination, intravasation, and the extravasation of circulating cancer cells to facilitate colonization at a distant site. Immune cell infiltration and inflammation within the tumor microenvironment coincide with tumor progression and metastatic spread and are thought to be the key mediators of this complex process. Amongst many infiltrating cells, neutrophils have recently emerged as an important player in fueling tumor progression, both in animal models and cancer patients. The production of Neutrophil Extracellular Traps (NETs) is particularly important in the pathogenesis of the metastatic cascade. NETs are composed of web-like DNA structures with entangled proteins that are released in response to inflammatory cues in the environment. NETs play an important role in driving tumor progression both in experimental and clinical models. In this review, we aim to summarize the current advances in understanding the role of NETs in cancer, with a specific focus on their role in promoting premetastatic niche formation, interaction with circulating cancer cells, and in epithelial to mesenchymal transition during cancer metastasis. We will furthermore discuss the possible role and different treatment options for targeting NETs to prevent tumor progression.

SUBMITTER: Kaltenmeier C

PROVIDER: S-EPMC8657162 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy

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IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis.

Project description: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.

| S-EPMC7255375 | biostudies-literature

Pulmonary <i>Staphylococcus aureus</i> infection regulates breast cancer cell metastasis via neutrophil extracellular traps (NETs) formation.

Project description:The formation of neutrophil extracellular traps (NETs) was recently identified as one of the most important processes for the maintenance of host tissue homeostasis in bacterial infection. Meanwhile, pneumonia infection has a poor effect on cancer patients receiving immunotherapy. Whether pneumonia-mediated NETs increase lung metastasis remains unclear. In this study, we identified a critical role for multidrug-resistant Staphylococcus aureus infection-induced NETs in the regulation of cancer cell metastasis. Notably, S. aureus triggered autophagy-dependent NETs formation in vitro and in vivo and increased cancer cell metastasis. Targeting autophagy effectively regulated NETs formation, which contributed to the control of cancer metastasis in vivo. Moreover, the degradation of NETs by DNase I significantly suppresses metastasis in lung. Our work offers novel insight into the mechanisms of metastasis induced by bacterial pneumonia and provides a potential therapeutic strategy for pneumonia-related metastasis.

| S-EPMC8491238 | biostudies-literature

Neutrophil extracellular traps (NETs) exacerbate severity of infant sepsis.

Project description:BackgroundNeutrophil extracellular traps (NETs) are innate defense mechanisms that are also implicated in the pathogenesis of organ dysfunction. However, the role of NETs in pediatric sepsis is unknown.MethodsInfant (2 weeks old) and adult (6 weeks old) mice were submitted to sepsis by intraperitoneal (i.p.) injection of bacteria suspension or lipopolysaccharide (LPS). Neutrophil infiltration, bacteremia, organ injury, and concentrations of cytokine, NETs, and DNase in the plasma were measured. Production of reactive oxygen and nitrogen species and release of NETs by neutrophils were also evaluated. To investigate the functional role of NETs, mice undergoing sepsis were treated with antibiotic plus rhDNase and the survival, organ injury, and levels of inflammatory markers and NETs were determined. Blood samples from pediatric and adult sepsis patients were collected and the concentrations of NETs measured.ResultsInfant C57BL/6 mice subjected to sepsis or LPS-induced endotoxemia produced significantly higher levels of NETs than the adult mice. Moreover, compared to that of the adult mice, this outcome was accompanied by increased organ injury and production of inflammatory cytokines. The increased NETs were associated with elevated expression of Padi4 and histone H3 citrullination in the neutrophils. Furthermore, treatment of infant septic mice with rhDNase or a PAD-4 inhibitor markedly attenuated sepsis. Importantly, pediatric septic patients had high levels of NETs, and the severity of pediatric sepsis was positively correlated with the level of NETs.ConclusionThis study reveals a hitherto unrecognized mechanism of pediatric sepsis susceptibility and suggests that NETs represents a potential target to improve clinical outcomes of sepsis.

| S-EPMC6454713 | biostudies-literature

Cancer cells induce metastasis-supporting neutrophil extracellular DNA traps.

Project description:Neutrophils, the most abundant type of leukocytes in blood, can form neutrophil extracellular traps (NETs). These are pathogen-trapping structures generated by expulsion of the neutrophil's DNA with associated proteolytic enzymes. NETs produced by infection can promote cancer metastasis. We show that metastatic breast cancer cells can induce neutrophils to form metastasis-supporting NETs in the absence of infection. Using intravital imaging, we observed NET-like structures around metastatic 4T1 cancer cells that had reached the lungs of mice. We also found NETs in clinical samples of triple-negative human breast cancer. The formation of NETs stimulated the invasion and migration of breast cancer cells in vitro. Inhibiting NET formation or digesting NETs with deoxyribonuclease I (DNase I) blocked these processes. Treatment with NET-digesting, DNase I-coated nanoparticles markedly reduced lung metastases in mice. Our data suggest that induction of NETs by cancer cells is a previously unidentified metastasis-promoting tumor-host interaction and a potential therapeutic target.

| S-EPMC5550900 | biostudies-literature

Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis.

Project description: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.

| S-EPMC8307027 | biostudies-literature

DDR1-induced neutrophil extracellular traps drive pancreatic cancer metastasis.

Project description:Pancreatic ductal adenocarcinoma (PDAC) tumors are characterized by a desmoplastic reaction resulting in dense deposition of collagen that is known to promote cancer progression. A central mediator of protumorigenic collagen signaling is the receptor tyrosine kinase discoid domain receptor 1 (DDR1). DDR1 is a critical driver of a mesenchymal and invasive cancer cell PDAC phenotype. Previous studies have demonstrated that genetic or pharmacologic inhibition of DDR1 reduces PDAC tumorigenesis and metastasis. Here, we investigated whether DDR1 signaling has cancer cell nonautonomous effects that promote PDAC progression and metastasis. We demonstrate that collagen-induced DDR1 activation in cancer cells is a major stimulus for CXCL5 production, resulting in the recruitment of tumor-associated neutrophils (TANs), the formation of neutrophil extracellular traps (NETs), and subsequent cancer cell invasion and metastasis. Moreover, we have identified that collagen-induced CXCL5 production was mediated by a DDR1/PKCθ/SYK/NF-κB signaling cascade. Together, these results highlight the critical contribution of the collagen I-DDR1 interaction in the formation of an immune microenvironment that promotes PDAC metastasis.

| S-EPMC8492346 | biostudies-literature

Cell Cycle Proteins Control Production of Neutrophil Extracellular Traps (NETs)

Project description:Microarray expression profiling of unstimulated human neutrophils from 8 healthy donors

2017-09-13 | GSE103755 | GEO

Adenosine from a biologic source regulates neutrophil extracellular traps (NETs).

Project description:Neutrophil extracellular traps (NETs) are implicated in autoimmune, thrombotic, malignant, and inflammatory diseases; however, little is known of their endogenous regulation under basal conditions. Inflammatory effects of neutrophils are modulated by extracellular purines such as adenosine (ADO) that is inhibitory or ATP that generally up-regulates effector functions. In order to evaluate the effects of ADO on NETs, human neutrophils were isolated from peripheral venous blood from healthy donors and stimulated to make NETs. Treatment with ADO inhibited NET production as quantified by 2 methods: SYTOX green fluorescence and human neutrophil elastase (HNE)-DNA ELISA assay. Specific ADO receptor agonist and antagonist were tested for their effects on NET production. The ADO 2A receptor (A2A R) agonist CSG21680 inhibited NETs to a similar degree as ADO, whereas the A2A R antagonist ZM241385 prevented ADO's NET-inhibitory effects. Additionally, CD73 is a membrane bound ectonucleotidase expressed on mesenchymal stromal cells (MSCs) that allows manipulation of extracellular purines in tissues such as bone marrow. The effects of MSCs on NET formation were evaluated in coculture. MSCs reduced NET formation in a CD73-dependent manner. These results imply that extracellular purine balance may locally regulate NETosis and may be actively modulated by stromal cells to maintain tissue homeostasis.

| S-EPMC6536338 | biostudies-literature

Neutrophil extracellular traps facilitate cancer metastasis: cellular mechanisms and therapeutic strategies.

Project description:BackgroundThe formation of neutrophil extracellular traps (NETs) was initially discovered as a novel immune response against pathogens. Recent studies have also suggested that NETs play an important role in tumor progression. This review summarizes the cellular mechanisms by which NETs promote distant metastasis and discusses the possible clinical applications targeting NETs.MethodThe relevant literature from PubMed and Google Scholar (2001-2021) have been reviewed for this article.ResultsThe presence of NETs has been detected in various primary tumors and metastatic sites. NET-associated interactions have been observed throughout the different stages of metastasis, including initial tumor cell detachment, intravasation and extravasation, the survival of circulating tumor cells, the settlement and the growth of metastatic tumor cells. Several in vitro and in vivo studies proved that inhibiting NET formation resulted in anti-cancer effects. The biosafety and efficacy of some NET inhibitors have also been demonstrated in early phase clinical trials.ConclusionsConsidering the role of NETs in tumor progression, NETs could be a promising diagnostic and therapeutic target for cancer management. However, current evidence is mostly derived from experimental models and as such more clinical studies are still needed to verify the clinical significance of NETs in oncological settings.

| S-EPMC9436160 | biostudies-literature

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