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Yang Y, Hu Z, Ye Y, Wu H, Sun W, Wang N. Association of aggregate index of systemic inflammation with increased all-cause and cardiovascular mortality in female cancer patients. Front Oncol 2025; 15:1552341. [PMID: 40365348 PMCID: PMC12069043 DOI: 10.3389/fonc.2025.1552341] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/02/2025] [Accepted: 04/04/2025] [Indexed: 05/15/2025] Open
Abstract
Background Cancer is a leading cause of death, especially among women, with cancers like breast, ovarian, and cervical cancer presenting unique diagnostic and treatment challenges. Systemic inflammation plays a significant role in cancer progression, affecting both tumor development and therapeutic outcomes. Despite the established link between inflammation and cancer, comprehensive studies on the prognostic value of the Aggregate Index of Systemic Inflammation (AISI) in female cancer patients are lacking. This study explores the association between AISI and mortality outcomes, including all-cause and cardiovascular mortality, in female cancer patients. Methods This study analyzes data from the NHANES database and Dandong Central Hospital. Kaplan-Meier survival curves and multivariable Cox proportional hazards regression analyses were used to assess the relationship between AISI and all-cause and cardiovascular mortality. Restricted cubic spline plots and subgroup analyses were applied to explore potential interactions. Results Elevated AISI levels were strongly associated with increased all-cause and cardiovascular mortality. Patients in the highest AISI quartile demonstrated significantly higher mortality risks compared to those in the lowest quartile. ROC curve analysis indicated superior predictive performance of AISI over SII. Restricted cubic spline plots revealed a linear relationship, with mortality risk notably increasing when AISI levels were elevated. Conclusion AISI is a robust predictor of all-cause and cardiovascular mortality in female cancer patients. Its ease of measurement and strong prognostic value make it a valuable tool for risk assessment and management in this population.
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Affiliation(s)
- Ying Yang
- Dalian Medical University, Dalian, China
- The Dandong Central Hospital, Dandong, China
| | - Zelin Hu
- The Second Hospital of Dalian Medical University, Dalian, China
| | - Yuqin Ye
- Medical College of Wuhan University of Science and Technology, Wuhan, China
| | - Haoqi Wu
- The Second Hospital of Dalian Medical University, Dalian, China
| | - Wei Sun
- The Dandong Central Hospital, Dandong, China
| | - Ning Wang
- The Second Hospital of Dalian Medical University, Dalian, China
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2
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Bryzek D, Gasiorek A, Kowalczyk D, Santocki M, Ciaston I, Dobosz E, Kolaczkowska E, Kjøge K, Kantyka T, Lech M, Potempa B, Enghild JJ, Potempa J, Koziel J. Non-classical neutrophil extracellular traps induced by PAR2-signaling proteases. Cell Death Dis 2025; 16:109. [PMID: 39971938 PMCID: PMC11840154 DOI: 10.1038/s41419-025-07428-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/09/2024] [Revised: 01/21/2025] [Accepted: 02/04/2025] [Indexed: 02/21/2025]
Abstract
Neutrophil extracellular traps (NETs) are associated with diseases linked to aberrant coagulation. The blood clotting cascade involves a series of proteases, some of which induce NET formation via a yet unknown mechanism. We hypothesized that this formation involves signaling via a factor Xa (FXa) activation of the protease-activated receptor 2 (PAR2). Our findings revealed that NETs can be triggered in vitro by enzymatically active proteases and PAR2 agonists. Intravital microscopy of the liver vasculature revealed that both FXa infusion and activation of endogenous FX promoted NET formation, effects that were prevented by the FXa inhibitor, apixaban. Unlike classical NETs, these protease-induced NETs lacked bactericidal activity and their proteomic signature indicates their role in inflammatory disorders, including autoimmune diseases and carcinogenesis. Our findings suggest a novel mechanism of NET formation under aseptic conditions, potentially contributing to a self-amplifying clotting and NET formation cycle. This mechanism may underlie the pathogenesis of disseminated intravascular coagulation and other aseptic conditions.
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Affiliation(s)
- Danuta Bryzek
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
| | - Anna Gasiorek
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Dominik Kowalczyk
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Michal Santocki
- Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
| | - Izabela Ciaston
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Ewelina Dobosz
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
| | - Elzbieta Kolaczkowska
- Department of Experimental Hematology, Institute of Zoology and Biomedical Research, Jagiellonian University, Krakow, Poland
| | - Katarzyna Kjøge
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | | | - Maciej Lech
- LMU Hospital, Medizinische Klinik und Poliklinik IV, Ludwig-Maximilians University, Munich, Germany
| | - Barbara Potempa
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, USA
| | - Jan J Enghild
- Department of Molecular Biology and Genetics, Aarhus University, Aarhus, Denmark
| | - Jan Potempa
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland
- Department of Oral Immunology and Infectious Diseases, School of Dentistry, University of Louisville, Louisville, Kentucky, USA
| | - Joanna Koziel
- Microbiology Department, Faculty of Biochemistry Biophysics and Biotechnology, Jagiellonian University, Kraków, Poland.
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Benavent N, Cañete A, Argilés B, Juan-Ribelles A, Bonanad S, Oto J, Medina P. Delving into the clinical impact of NETs in pediatric cancer. Pediatr Res 2025; 97:898-907. [PMID: 39095576 DOI: 10.1038/s41390-024-03437-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2024] [Revised: 07/04/2024] [Accepted: 07/11/2024] [Indexed: 08/04/2024]
Abstract
Pediatric cancer, a complex and heterogeneous group of diseases, continues to challenge medical research and treatment strategies. Despite advances in precision medicine and immunotherapy, certain aggressive subtypes of pediatric cancer are resistant to conventional therapies, requiring further exploration of potential therapeutic targets. Neutrophil extracellular traps (NETs), net-like structures released by neutrophils, have emerged as a potential player in the pediatric cancer landscape. However, our understanding of their role in pediatric oncology remains limited. This systematic review examines the current state of the NETs literature in pediatric cancer, focusing on the most frequent subtypes. The review reveals the scarcity of research in this area, highlighting the need for further investigation. The few studies available suggest that NETs may influence infection risk, treatment resistance and prognosis in certain pediatric malignancies. Although the field is still in its infancy, it holds great promise for advancing our understanding of pediatric cancer biology and potential therapeutic pathways. IMPACT: This review identifies a significant gap in research on neutrophil extracellular traps (NETs) in pediatric cancer. It provides a summary of existing studies and their promising findings and potential, as well as a comprehensive overview of current research on NETs in certain tumor types. It also emphasizes the lack of specific studies in pediatric cancer. The review encourages the prioritization of NET research in pediatric oncology, with the aim of improving prognosis and developing new treatments through increased understanding and targeted studies.
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Affiliation(s)
- Nuria Benavent
- Clinical and Translational Research in Cancer, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain.
| | - Adela Cañete
- Clinical and Translational Research in Cancer, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
- Pediatric Oncology and hematology Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Bienvenida Argilés
- Pediatric Oncology and hematology Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Antonio Juan-Ribelles
- Clinical and Translational Research in Cancer, Health Research Institute Hospital La Fe (IIS La Fe), Valencia, Spain
- Pediatric Oncology and hematology Unit, La Fe University and Polytechnic Hospital, Valencia, Spain
| | - Santiago Bonanad
- Thrombosis and Haemostasis Unit, Hematology Service, La Fe University and Polytechnic Hospital, Valencia, Spain
- Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Valencia, Spain
| | - Julia Oto
- Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Valencia, Spain
| | - Pilar Medina
- Haemostasis, Thrombosis, Arteriosclerosis and Vascular Biology Research Group, Medical Research Institute Hospital La Fe, Valencia, Spain
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4
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Wan J, Zhao J, Fang X. Dynamics of the immune microenvironment and immune cell PANoptosis in colorectal cancer: recent advances and insights. Front Immunol 2024; 15:1502257. [PMID: 39676861 PMCID: PMC11638180 DOI: 10.3389/fimmu.2024.1502257] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Accepted: 11/13/2024] [Indexed: 12/17/2024] Open
Abstract
Colorectal cancer (CRC) is one of the most significant oncological threats to human health globally. Patients often exhibit a high propensity for tumor recurrence and metastasis post-surgery, resulting in suboptimal prognoses. One of the underlying reasons for the metastatic potential of CRC is the sustained abnormal state of the tumor immune microenvironment, particularly characterized by the atypical death of critical immune cells. In recent years, a novel concept of cell death known as PANoptosis has emerged. This form of cell death is regulated by the PANoptosome complex and encompasses key features of apoptosis, pyroptosis, and necroptosis, yet cannot be entirely substituted by any of these processes alone. Due to its widespread occurrence and complex mechanisms, PANoptosis has been increasingly reported in various malignancies, enhancing our understanding of its pathological mechanisms, particularly in the context of CRC. However, the characteristics of immune cell PANoptosis within the CRC immune microenvironment have not been thoroughly elucidated. In this review, we focus on the impact of CRC progression on various immune cell types and summarize the distinctive features of immune cell PANoptosis. Furthermore, we highlight the future research trends and challenges associated with the mechanisms of immune cell PANoptosis in CRC.
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Affiliation(s)
- Jinlong Wan
- Department of Gastroenterology, Gaozhou People’s Hospital, Maoming, China
| | - Jianzhong Zhao
- Department of Clinical Laboratory, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, China
| | - Xiaolu Fang
- Department of Clinical Laboratory, Xiangyang No.1 People’s Hospital, Hubei University of Medicine, Xiangyang, China
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5
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Qi C, Zhao Z, Chen L, Wang L, Zhou Y, Duan G. Exploring the role of neutrophil extracellular traps in neuroblastoma: identification of molecular subtypes and prognostic implications. Front Oncol 2024; 14:1361871. [PMID: 39575432 PMCID: PMC11578966 DOI: 10.3389/fonc.2024.1361871] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2023] [Accepted: 10/09/2024] [Indexed: 11/24/2024] Open
Abstract
Background Cancer cells induce neutrophil extracellular traps (NETs) to promote tumor progression and metastasis. However, only a few studies have focused on the role of NETs in Neuroblastoma (NB). Methods First, based on the expression of NET-related genes, consensus clustering analysis was conducted to cluster NB samples into different subtypes. Differential analysis was performed to identify DEGs between subtypes. Functional items and related pathways of DEGs were identified using enrichment analysis. Univariate Cox analysis and the LASSO algorithm were used to identify biomarkers for prognosis. Furthermore, independent prognostic analysis was performed. Immune infiltration analysis was performed to identify differential immune cells. Finally, the verification of prognostic model genes were taken by the immunohistochemical staining and quantitative real-time PCR. Results Consensus clustering analysis demonstrated that NB samples were clustered into two subtypes. There were 125 DEGs between the two subtypes of NB. Moreover, the enrichment analysis results showed that the DEGs were mainly associated with 'external side of plasma membrane,' 'immune receptor activity' 'regulation of leukocyte migration' GO items. There were also several GO items related to neutrophils, such as regulation of neutrophil migration and differentiation. KEGG pathways revealed that the DEGs were correlated with in immunity-related activities, including 'Complement and coagulation cascades,' 'Neutrophil extracellular trap formation, 'T cell receptor signaling pathway,' 'PD-L1 expression and PD-1 checkpoint pathway in cancer' and so on. A total of five biomarkers,[Selenoprotein P1 (SEPP1), Fibrinogen-like protein 2 (FGL2), NK cell lectin-like receptor K1 (KLRK1), ATP-binding cassette transporters 6(ABCA6) and Galectins(GAL)], were screened, and a risk model based on the biomarkers was created. Furthermore, a nomogram for forecasting the survival rates of patients with NB was established based on the risk score, age at diagnosis, and MYCN status. Eight differential immune cells (CD8 + T cells, resting mast cells, etc.) were acquired between the two risk subgroups. The expression levels of five prognostic model genes at the protein and mRNA were verified and all results were consistent with the results of our bioinformatics analysis. Conclusion We initially found that five NET-related genes were significantly differentially expressed in NETs-associated molecular isoforms and two Netrg molecular isoforms were found to be associated with poorer prognosis. This stratification might provide insight into the prediction of prognosis and ideal immunotherapy strategies for patients with NB. However, we also noted that the formation of NETs is a complex biological process involving the regulation of multiple cytokines and cellular interactions. Therefore, the exact roles of these genes and their specific mechanisms in the formation of NETs and the development of NB still need to be further investigated.
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Affiliation(s)
- Can Qi
- Study Office of Pediatric and Thoracic Surgery, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Pediatric Surgery, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Ziwei Zhao
- Department of Pediatric Surgery, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Lin Chen
- Department of Pediatric Surgery, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Le Wang
- Department of Pediatric Surgery, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Yun Zhou
- Department of Pediatric Surgery, Children's Hospital of Hebei Province, Shijiazhuang, China
| | - Guochen Duan
- Study Office of Pediatric and Thoracic Surgery, Hebei Medical University, Shijiazhuang, Hebei, China
- Department of Pediatric Surgery, Children's Hospital of Hebei Province, Shijiazhuang, China
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6
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Chen D, Liang H, Huang L, Zhou H, Wang Z. Liraglutide enhances the effect of checkpoint blockade in lung and liver cancers through the inhibition of neutrophil extracellular traps. FEBS Open Bio 2024; 14:1365-1377. [PMID: 36271684 PMCID: PMC11301266 DOI: 10.1002/2211-5463.13499] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2022] [Revised: 09/20/2022] [Accepted: 10/20/2022] [Indexed: 11/09/2022] Open
Abstract
Glucagon-like peptide-1 (GLP-1) regulates glycemic excursions by augmenting insulin production and inhibiting glucagon secretion. Liraglutide, a long-acting GLP-1 analog, can improve glycemic control for treating type 2 diabetes and prevent neutrophil extravasation in inflammation. Here, we explored the role of liraglutide in the development and therapy of murine lung and liver cancers. In this study, liraglutide substantially decreased circulating neutrophil extracellular trap (NET) markers myeloperoxidase, elastase, and dsDNA in Lewis lung cancer (LLC) and Hepa1-6 tumor-bearing mice. Furthermore, liraglutide downregulated NETs and reactive oxygen species (ROS) of neutrophils in the tumor microenvironment. Functionally, in vitro experiments showed that liraglutide reduced NET formation by inhibiting ROS. In addition, we showed that liraglutide enhanced the anti-tumoral efficiency of programmed cell death-1 (PD-1) inhibition in LLC and Hepa1-6 tumor-bearing C57BL/6 mice. However, the removal of NETs significantly weakened the antitumor efficiency of liraglutide. We further demonstrated that the long-term antitumor CD8+ T cell responses induced by the combination therapy rejected rechallenges by respective tumor cell lines. Taken together, our findings suggest that liraglutide may promote the anti-tumoral efficiency of PD-1 inhibition by reducing NETs in lung and liver cancers.
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Affiliation(s)
- Duo Chen
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
| | - Hongxin Liang
- Department of Thoracic Surgery, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Luyu Huang
- Department of Surgery, Competence Center of Thoracic SurgeryCharité Universitätsmedizin BerlinGermany
| | - Haiyu Zhou
- Department of Thoracic Surgery, Guangdong Provincial People's HospitalGuangdong Academy of Medical SciencesGuangzhouChina
| | - Zheng Wang
- Department of Respiratory and Critical Care Medicine, Beijing Institute of Respiratory Medicine, Beijing Chao‐Yang HospitalCapital Medical UniversityBeijingChina
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7
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Zhai R, Gong Z, Wang M, Ni Z, Zhang J, Wang M, Zhang Y, Zeng F, Gu Z, Chen X, Wang X, Zhou P, Liu L, Zhu W. Neutrophil extracellular traps promote invasion and metastasis via NLRP3-mediated oral squamous cell carcinoma pyroptosis inhibition. Cell Death Discov 2024; 10:214. [PMID: 38697992 PMCID: PMC11066066 DOI: 10.1038/s41420-024-01982-9] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2024] [Revised: 04/16/2024] [Accepted: 04/19/2024] [Indexed: 05/05/2024] Open
Abstract
Neutrophil extracellular traps (NETs) are reticular structures composed of neutrophil elastase (NE), cathepsin G (CG) and DNA-histone enzyme complexes. Accumulating evidence has revealed that NETs play important roles in tumor progression, metastasis, and thrombosis. However, our understanding of its clinical value and mechanism of action in oral squamous cell carcinoma (OSCC) is limited and has not yet been systematically described. Here, we aimed to investigate the clinical significance of NETs in OSCC and the mechanisms by which they affect its invasive and metastatic capacity. Our results demonstrated that high enrichment of NETs is associated with poor prognosis in OSCC, and mechanistic studies have shown that NE in NETs promotes invasion and metastasis via NLRP3-mediated inhibition of pyroptosis in OSCC. These findings may provide a new therapeutic approach for OSCC.
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Affiliation(s)
- Rundong Zhai
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Zizhen Gong
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Mengqi Wang
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Zihui Ni
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Jiayi Zhang
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Mengyao Wang
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Yu Zhang
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Fanrui Zeng
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Ziyue Gu
- Department of Oral and Maxillofacial-Head Neck Oncology, Shanghai Ninth People's Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, 200011, China
- College of Stomatology, Shanghai Jiao Tong University, National Center for Stomatology, National Clinical Research Center for Oral Diseases, Shanghai Key Laboratory of Stomatology, Shanghai, 200011, China
| | - Xingyu Chen
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Xiudi Wang
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Pengcheng Zhou
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China
| | - Laikui Liu
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China.
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China.
| | - Weiwen Zhu
- State Key Laboratory Cultivation Base of Research, Prevention and Treatment for Oral Diseases, Nanjing Medical University, Jiangsu, China.
- Department of Basic Science of Stomatology, The Affiliated Stomatological Hospital of Nanjing Medical University, Jiangsu, China.
- Jiangsu Province Engineering Research Center of Stomatological Translational Medicine, Jiangsu, China.
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Chen J, Xu Y, Yu F, Ma Z, Yu J, Zhang X. NETs: an extracellular DNA network structure with implication for cardiovascular disease and cancer. Hypertens Res 2024; 47:1260-1272. [PMID: 38443616 DOI: 10.1038/s41440-023-01574-7] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/24/2023] [Revised: 12/19/2023] [Accepted: 12/20/2023] [Indexed: 03/07/2024]
Abstract
Cardiovascular (CV) diseases and tumors are best known for its high morbidity and mortality worldwide. There is a growing recognition of the association between CV diseases and tumorigenesis. In addition to CV damage caused by anti-tumor drugs and tumor-induced organ dysfunction, CV events themselves and their treatment may also have a role in promoting tumorigenesis. Therefore, Therefore, the diagnosis and treatment of the two kinds of diseases have entered the era of clinical convergence. Emerging evidence indicates significant biologic overlap between cancer and CV diseases, with the recognition of shared biologic mechanisms. Neutrophil extracellular traps (NETs) represent an immune mechanism of neutrophils promoting the development of tumors and their metastasis. It has been recently demonstrated that NETs exist in various stages of hypertension and heart failure, exacerbating disease progression. At present, most studies focus on the biological role of NETs in CV diseases and tumor respectively, and there are relatively few studies on the specific regulatory mechanisms and effects of NETs in cardiovascular diseases associated with tumors. In this narrative review, we summarize some recent basic and clinical findings on how NETs are involved in the pathogenesis of cardiovascular diseases associated with tumors. We also highlight that the development of treatments targeting NETs may be one of the effective ways to prevent and treat cardiovascular diseases associated with tumors.
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Affiliation(s)
- Jianshu Chen
- Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Yuansheng Xu
- Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Fei Yu
- Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Zhengke Ma
- Lanzhou University Second Hospital, Lanzhou, 730030, China
| | - Jing Yu
- Lanzhou University Second Hospital, Lanzhou, 730030, China
- Lanzhou University Second College of Clinical Medicine, Lanzhou, 730030, China
| | - Xiaowei Zhang
- Lanzhou University Second Hospital, Lanzhou, 730030, China.
- Lanzhou University Second College of Clinical Medicine, Lanzhou, 730030, China.
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Wu H, Wang S, Lv H, Lou F, Yin H, Gu Y, Zhang J, Xu Y. Effect of Thoracic Epidural Anesthesia on Perioperative Neutrophil Extracellular Trapping Markers in Patients Undergoing Anesthesia and Surgery for Colorectal Cancer: A Randomized, Controlled Trial. Ann Surg Oncol 2023; 30:7561-7568. [PMID: 37606842 DOI: 10.1245/s10434-023-14077-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/14/2023] [Accepted: 07/17/2023] [Indexed: 08/23/2023]
Abstract
BACKGROUND Neutrophil extracellular trapping (NETosis) is an immunologic mechanism strongly linked with increased metastatic risk in colorectal cancer. The authors hypothesized that patients who received propofol-epidural anesthesia (PEA) would exhibit decreases in the expression of serum neutrophil myeloperoxidase (MPO) and citrullinated histone H3 (H3Cit) levels compared with patients who received general anesthesia (GA). METHODS Colorectal cancer surgery patients were randomly assigned to the PEA (n = 30) or GA (n = 30) group. Serum MPO, H3Cit, and metalloproteinase-9 (MMP-9) levels before surgery and 24 h after surgery were measured, and visual analogue scale (VAS) scores were recorded. RESULTS The patients who received PEA showed decreases in MPO (28.06 ± 11.23 vs 20.54 ± 7.29 ng/ ml; P = 0.004) and H3Cit [3.22 ± 0.86 vs 2.73 ± 0.94 ng/ ml; P = 0.042) 24 h after surgery compared with the patients subjected to GA. In addition, there was no difference in MMP-9 levels (75.98 ± 26.9 vs 73.45 ± 28.4 ng/ ml; P = 0.726). The visual analogue scale scores 2 h and 24 h after operation were significantly lower in PEA group (P < 0.05). The number of postoperative analgesia pump pressings and sufentanil consumptions within 48 h after surgery were significantly lower in the PEA group (P < 0.001). CONCLUSIONS Propofol-epidural anesthesia reduces the expression of NETosis (MPO and H3Cit) in serum during colorectal cancer surgery. CLINICAL TRIAL REGISTRATION ChiCTR2200066708 ( www.chictr.org.cn ).
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Affiliation(s)
- Han Wu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shilai Wang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hu Lv
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Feifei Lou
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Hua Yin
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Yuechao Gu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jun Zhang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
| | - Yajun Xu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China.
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10
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Ren SN, Zhang ZY, Guo RJ, Wang DR, Chen FF, Chen XB, Fang XD. Application of nanotechnology in reversing therapeutic resistance and controlling metastasis of colorectal cancer. World J Gastroenterol 2023; 29:1911-1941. [PMID: 37155531 PMCID: PMC10122790 DOI: 10.3748/wjg.v29.i13.1911] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/25/2022] [Revised: 02/02/2023] [Accepted: 03/21/2023] [Indexed: 04/06/2023] Open
Abstract
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.
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Affiliation(s)
- Sheng-Nan Ren
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Zhan-Yi Zhang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Rui-Jie Guo
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Da-Ren Wang
- Bethune Third Clinical Medical College, Jilin University, Changchun 130021, Jilin Province, China
| | - Fang-Fang Chen
- Nanomedicine and Translational Research Center, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Bo Chen
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
| | - Xue-Dong Fang
- Department of Gastrointestinal, Colorectal and Anal Surgery, China-Japan Union Hospital of Jilin University, Changchun 130033, Jilin Province, China
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11
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Zhang A, Zou X, Yang S, Yang H, Ma Z, Li J. Effect of NETs/COX-2 pathway on immune microenvironment and metastasis in gastric cancer. Front Immunol 2023; 14:1177604. [PMID: 37153547 PMCID: PMC10156975 DOI: 10.3389/fimmu.2023.1177604] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2023] [Accepted: 04/10/2023] [Indexed: 05/09/2023] Open
Abstract
Background Neutrophil extracellular traps (NETs) are crucial in the progression of several cancers. The formation of NETs is closely related to reactive oxygen species (ROS), and the granule proteins involved in nucleosome depolymerization under the action of ROS together with the loosened DNA compose the basic structure of NETs. This study aims to investigate the specific mechanisms of NETs promoting gastric cancer metastasis in order to perfect the existing immunotherapy strategies. Methods In this study, the cells and tumor tissues of gastric cancer were detected by immunological experiments, real-time polymerase chain reaction and cytology experiments. Besides, bioinformatics analysis was used to analyze the correlation between cyclooxygenase-2 (COX-2) and the immune microenvironment of gastric cancer, as well as its effect on immunotherapy. Results Examination of clinical specimens showed that NETs were deposited in tumor tissues of patients with gastric cancer and their expression was significantly correlated with tumor staging. Bioinformatics analysis showed that COX-2 was involved in gastric cancer progression and was associated with immune cell infiltration as well as immunotherapy. In vitro experiments, we demonstrated that NETs could activate COX-2 through Toll-like receptor 2 (TLR2) and thus enhance the metastatic ability of gastric cancer cells. In addition, in a liver metastasis model of nude mice we also demonstrated the critical role of NETs and COX-2 in the distant metastasis of gastric cancer. Conclusion NETs can promote gastric cancer metastasis by initiating COX-2 through TLR2, and COX-2 may become a target for gastric cancer immunotherapy.
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Affiliation(s)
- Ange Zhang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Xiaoming Zou
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- *Correspondence: Xiaoming Zou,
| | - Shifeng Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Hao Yang
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Zhen Ma
- Department of Gastrointestinal Surgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
- The Key Laboratory of Myocardial Ischemia, Ministry of Education, Harbin, China
| | - Jiacheng Li
- Department of General Surgery, The First Affiliated Hospital of Jiamusi University, Jiamusi, Heilongjiang, China
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12
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Song YH, Wang ZJ, Kang L, He ZX, Zhao SB, Fang X, Li ZS, Wang SL, Bai Y. PADs and NETs in digestive system: From physiology to pathology. Front Immunol 2023; 14:1077041. [PMID: 36761761 PMCID: PMC9902375 DOI: 10.3389/fimmu.2023.1077041] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/22/2022] [Accepted: 01/09/2023] [Indexed: 01/26/2023] Open
Abstract
Peptidylarginine deiminases (PADs) are the only enzyme class known to deiminate arginine residues into citrulline in proteins, a process known as citrullination. This is an important post-translational modification that functions in several physiological and pathological processes. Neutrophil extracellular traps (NETs) are generated by NETosis, a novel cell death in neutrophils and a double-edged sword in inflammation. Excessive activation of PADs and NETs is critically implicated in their transformation from a physiological to a pathological state. Herein, we review the physiological and pathological functions of PADs and NETs, in particular, the involvement of PAD2 and PAD4 in the digestive system, from inflammatory to oncological diseases, along with related therapeutic prospects.
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Affiliation(s)
- Yi-Hang Song
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhi-Jie Wang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Le Kang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zi-Xuan He
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Sheng-Bing Zhao
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Xue Fang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Zhao-Shen Li
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Shu-Ling Wang
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
| | - Yu Bai
- Department of Gastroenterology, Changhai Hospital, Naval Medical University, Shanghai, China
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13
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Wan Y, Shen J, Ouyang J, Dong P, Hong Y, Liang L, Liu J. Bibliometric and visual analysis of neutrophil extracellular traps from 2004 to 2022. Front Immunol 2022; 13:1025861. [PMID: 36341351 PMCID: PMC9634160 DOI: 10.3389/fimmu.2022.1025861] [Citation(s) in RCA: 40] [Impact Index Per Article: 13.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/23/2022] [Accepted: 10/10/2022] [Indexed: 12/27/2022] Open
Abstract
Background Neutrophil extracellular traps (NETs) are specialized structures formed by neutrophils that were initially found to be important in killing pathogenic bacteria during infection. With the development of related research, the relationship between NETs and diseases such as sepsis, cancer, and systemic lupus erythematosus has received close attention. However, there is a lack of reports that comprehensively and objectively present the current status of NETs-related studies. Therefore, this study aims to visually analyze the current status and trends of NETs-related research by means of bibliometrics and knowledge mapping. Methods NETs-related articles and reviews were retrieved using the Web of Science core collection subject search, and bibliometric analysis was performed in Excel 365, CiteSpace, VOSviewer, and Bibliometrix (R-Tool of R-Studio). Results A total of 4866 publications from 2004 to 2022 were included in the bibliometric analysis. The number of publications shows an increasing trend from year to year. Collaborative network analysis shows that the United States and Germany are the most influential countries in this field, with the highest number of publications and citations. The journal with the most publications is Frontiers in Immunology. Brinkmann Volker is an authoritative author in this field, and his publication "Neutrophil extracellular traps kill bacteria" is the most frequently cited. The literature and keyword analysis shows that the relationship between NETs and diseases (hematological diseases, sepsis, cancer, etc.) and cell death (apoptosis, necroptosis, pyroptosis, etc.) is a popular research topic. Currently, NETs and SARS-CoV-2-related studies are at the forefront of the field. Conclusion This study is the first to visualize the research in NETs-related fields using bibliometric methods, revealing the trends and frontiers of NETs research. This study will provide valuable references for scholars to find research focus questions and partners.
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Affiliation(s)
- Yantong Wan
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Junyi Shen
- The Second Clinical Medical College, Southern Medical University, Guangzhou, China
| | - Jiafu Ouyang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Peng Dong
- College of Anesthesiology, Southern Medical University, Guangzhou, China
| | - Yinghao Hong
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Lixin Liang
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China
| | - Jinghua Liu
- Guangdong Provincial Key Laboratory of Proteomics, Department of Pathophysiology, School of Basic Medical Sciences, Southern Medical University, Guangzhou, China,*Correspondence: Jinghua Liu,
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14
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Chen X, Ma H, Mo S, Yu S, Lu Z, Chen J. Intratumoral neutrophil extracellular traps are associated with unfavorable clinical outcomes and immunogenic context in pancreatic ductal adenocarcinoma. Front Immunol 2022; 13:1027459. [PMID: 36325339 PMCID: PMC9618733 DOI: 10.3389/fimmu.2022.1027459] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2022] [Accepted: 10/05/2022] [Indexed: 11/15/2022] Open
Abstract
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.
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15
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Zhao J, Jin J. Neutrophil extracellular traps: New players in cancer research. Front Immunol 2022; 13:937565. [PMID: 36059520 PMCID: PMC9437524 DOI: 10.3389/fimmu.2022.937565] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/06/2022] [Accepted: 08/02/2022] [Indexed: 11/13/2022] Open
Abstract
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.
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Affiliation(s)
- Junjie Zhao
- Department of General Surgery, Changsha Hospital Affiliated to Hunan Normal University/The Fourth Hospital of Changsha, Changsha, China
- *Correspondence: Junjie Zhao, ; Jiaqi Jin,
| | - Jiaqi Jin
- Department of Neurosurgery, The Second Affiliated Hospital of Harbin Medical University, Harbin, China
- *Correspondence: Junjie Zhao, ; Jiaqi Jin,
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16
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Qi L, Wang L, Song F, Ding Z, Zhang Y. The role of miR-4469 as a tumor suppressor regulating inflammatory cell infiltration in colorectal cancer. Comput Struct Biotechnol J 2022; 20:3755-3763. [PMID: 35891783 PMCID: PMC9304430 DOI: 10.1016/j.csbj.2022.07.021] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 07/11/2022] [Accepted: 07/11/2022] [Indexed: 12/30/2022] Open
Abstract
Background 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. Methods 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. Results 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. Conclusion miR-4469 is a tumor suppressor in CRC, and its regulatory mechanism mainly affects the infiltration of inflammatory cells in the cancer tissue.
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Affiliation(s)
- Lu Qi
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou 510515, China
| | - Lu Wang
- Department of Radiation Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, China.,Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou 510515, China
| | - Fuyao Song
- Department of Pathology, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China.,Department of Pathology, School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China.,Guangdong Provincial Key Laboratory of Molecular Oncologic Pathology, Guangzhou 510515, China
| | - Zhenhua Ding
- Department of Radiation Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, China.,Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou 510515, China
| | - Ying Zhang
- Department of Radiation Medicine, School of Public Health, Southern Medical University, Guangzhou 510515, China.,Guangdong Provincial Key Laboratory of Tropical Disease Research, Guangzhou 510515, China
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17
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Chen F, Liu Y, Shi Y, Zhang J, Liu X, Liu Z, Lv J, Leng Y. The emerging role of neutrophilic extracellular traps in intestinal disease. Gut Pathog 2022; 14:27. [PMID: 35733158 PMCID: PMC9214684 DOI: 10.1186/s13099-022-00497-x] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2021] [Accepted: 05/19/2022] [Indexed: 11/10/2022] Open
Abstract
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.
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Affiliation(s)
- Feng Chen
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Yongqiang Liu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.,Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Yajing Shi
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Jianmin Zhang
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Xin Liu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.,Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Zhenzhen Liu
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Jipeng Lv
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China
| | - Yufang Leng
- The First Clinical Medical College of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China. .,Department of Anesthesiology, First Hospital of Lanzhou University, Lanzhou, 730000, Gansu, People's Republic of China.
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18
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Li D, Shao J, Cao B, Zhao R, Li H, Gao W, Chen P, Jin L, Cao L, Ji S, Dong G. The Significance of Neutrophil Extracellular Traps in Colorectal Cancer and Beyond: From Bench to Bedside. Front Oncol 2022; 12:848594. [PMID: 35747797 PMCID: PMC9209713 DOI: 10.3389/fonc.2022.848594] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2022] [Accepted: 05/09/2022] [Indexed: 12/30/2022] Open
Abstract
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.
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Affiliation(s)
- Dingchang Li
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | | | - Bo Cao
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Ruiyang Zhao
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Hanghang Li
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Wenxing Gao
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Peng Chen
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Lujia Jin
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- Medical School of Chinese PLA, Beijing, China
| | - Li Cao
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
| | - Shuaifei Ji
- Medical School of Chinese PLA, Beijing, China
- *Correspondence: Shuaifei Ji, ; Guanglong Dong,
| | - Guanglong Dong
- Department of General Surgery, the First Medical Centre, Chinese PLA General Hospital, Beijing, China
- *Correspondence: Shuaifei Ji, ; Guanglong Dong,
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19
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Kwak SB, Kim SJ, Kim J, Kang YL, Ko CW, Kim I, Park JW. Tumor regionalization after surgery: Roles of the tumor microenvironment and neutrophil extracellular traps. EXPERIMENTAL & MOLECULAR MEDICINE 2022; 54:720-729. [PMID: 35764882 PMCID: PMC9256747 DOI: 10.1038/s12276-022-00784-2] [Citation(s) in RCA: 39] [Impact Index Per Article: 13.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/16/2022] [Revised: 03/20/2022] [Accepted: 03/30/2022] [Indexed: 11/09/2022]
Abstract
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.
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Affiliation(s)
- Su-Bin Kwak
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Sang Jin Kim
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Jiyoung Kim
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Ye-Lim Kang
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Chang Woo Ko
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea
| | - Iljin Kim
- Department of Pharmacology, Inha University College of Medicine, Inha-ro, Michuhol-gu, Incheon, 22212, Korea
| | - Jong-Wan Park
- Department of Pharmacology, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Department of Biomedical Science, BK21-plus Education Program, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea. .,Cancer Research Institute and Ischemic/Hypoxic Disease Institute, Seoul National University College of Medicine, Daehak-ro, Jongno-gu, Seoul, 03080, Korea.
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Chen N, He D, Cui J. A Neutrophil Extracellular Traps Signature Predicts the Clinical Outcomes and Immunotherapy Response in Head and Neck Squamous Cell Carcinoma. Front Mol Biosci 2022; 9:833771. [PMID: 35252353 PMCID: PMC8894649 DOI: 10.3389/fmolb.2022.833771] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 02/04/2022] [Indexed: 12/13/2022] Open
Abstract
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.
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Affiliation(s)
- Naifei Chen
- Cancer Center, The First Hospital of Jilin University, Changchun, China
| | - Dongsheng He
- Department of Medical Oncology, The First Hospital of Putian, Teaching Hospital, Fujian Medical University, Putian, China
| | - Jiuwei Cui
- Cancer Center, The First Hospital of Jilin University, Changchun, China
- *Correspondence: Jiuwei Cui,
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21
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Jalodia R, Kolli U, Braniff RG, Tao J, Abu YF, Chupikova I, Moidunny S, Ramakrishnan S, Roy S. Morphine mediated neutrophil infiltration in intestinal tissue play essential role in histological damage and microbial dysbiosis. Gut Microbes 2022; 14:2143225. [PMID: 36409161 PMCID: PMC9683065 DOI: 10.1080/19490976.2022.2143225] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/27/2022] [Revised: 09/01/2022] [Accepted: 10/17/2022] [Indexed: 11/23/2022] Open
Abstract
The gut microbial ecosystem exhibits a complex bidirectional communication with the host and is one of the key contributing factors in determining mucosal immune homeostasis or an inflammatory state. Opioid use has been established to induce gut microbial dysbiosis consistent with increased intestinal tissue inflammation. In this study, we investigated the role of infiltrated immune cells in morphine-induced intestinal tissue damage and gut microbial dysbiosis in mice. Results reveal a significant increase in chemokine expression in intestinal tissues followed by increased neutrophil infiltration post morphine treatment which is direct consequence of a dysbiotic microbiome since the effect is attenuated in antibiotics treated animals and in germ-free mice. Neutrophil neutralization using anti-Ly6G monoclonal antibody showed a significant decrease in tissue damage and an increase in tight junction protein organization. 16S rRNA sequencing on intestinal samples highlighted the role of infiltrated neutrophils in modulating microbial community structure by providing a growth benefit for pathogenic bacteria, such as Enterococcus, and simultaneously causing a significant depletion of commensal bacteria, such as Lactobacillus. Taken together, we provide the first direct evidence that neutrophil infiltration contributes to morphine-induced intestinal tissue damage and gut microbial dysbiosis. Our findings implicate that inhibition of neutrophil infiltration may provide therapeutic benefits against gastrointestinal dysfunctions associated with opioid use.
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Affiliation(s)
- Richa Jalodia
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Udhghatri Kolli
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | | | - Junyi Tao
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Yaa Fosuah Abu
- Department of Microbiology and Immunology, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Irina Chupikova
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Shamsudheen Moidunny
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sundaram Ramakrishnan
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
| | - Sabita Roy
- Department of Surgery, University of Miami Miller School of Medicine, Miami, FL, USA
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22
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Chen Y, Han L, Qiu X, Wang G, Zheng J. Neutrophil Extracellular Traps in Digestive Cancers: Warrior or Accomplice. Front Oncol 2021; 11:766636. [PMID: 34868992 PMCID: PMC8639597 DOI: 10.3389/fonc.2021.766636] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/29/2021] [Accepted: 11/03/2021] [Indexed: 12/24/2022] Open
Abstract
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.
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Affiliation(s)
- Yuxin Chen
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Lulu Han
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Xiaoyan Qiu
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China
| | - Gang Wang
- Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
| | - Junnian Zheng
- Jiangsu Center for the Collaboration and Innovation of Cancer Biotherapy, Cancer Institute, Xuzhou Medical University, Xuzhou, China.,Center of Clinical Oncology, The Affiliated Hospital of Xuzhou Medical University, Xuzhou, China
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23
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Subhan MA, Torchilin VP. Neutrophils as an emerging therapeutic target and tool for cancer therapy. Life Sci 2021; 285:119952. [PMID: 34520766 DOI: 10.1016/j.lfs.2021.119952] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2021] [Revised: 09/02/2021] [Accepted: 09/08/2021] [Indexed: 02/09/2023]
Abstract
Activation of neutrophils is necessary for the protection of the host against microbial infection. This property can be used as mode of therapy for cancer treatment. Neutrophils have conflicting dual functions in cancer as either a tumor promoter or inhibitor. Neutrophil-based drug delivery has achieved increased attention in pre-clinical models. This review addresses in detail the different neutrophil constituents, the conflicting function of neutrophils and activation of the neutrophil as an important target of therapy for cancer treatment, and use of neutrophils or neutrophil membrane-derived vesicles as vehicles for drug delivery and targeting.
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Affiliation(s)
- Md Abdus Subhan
- Department of Chemistry, ShahJalal University of Science and Technology, Sylhet 3114, Bangladesh..
| | - Vladimir P Torchilin
- CPBN, Department of Pharmaceutical Sciences, Northeastern University, Boston, MA, USA; Department of Oncology, Radiotherapy and Plastic Surgery, I.M. Sechenov First Moscow State Medical University (Sechenov University), Moscow, Russia.
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24
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Wang H, Zhang Y, Wang Q, Wei X, Wang H, Gu K. The regulatory mechanism of neutrophil extracellular traps in cancer biological behavior. Cell Biosci 2021; 11:193. [PMID: 34758877 PMCID: PMC8579641 DOI: 10.1186/s13578-021-00708-z] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/28/2021] [Accepted: 10/31/2021] [Indexed: 11/10/2022] Open
Abstract
As the predominant host defense against pathogens, neutrophil extracellular traps (NETs) have attracted increasing attention due to their vital roles in infectious inflammation in the past few years. Interestingly, NETs also play important roles in noninfectious conditions, such as rheumatism and cancer. The process of NETs formation can be regulated and the form of cell death accompanied by the formation of NETs is regarded as "NETosis". A large amount of evidence has confirmed that many stimuli can facilitate the release of NETs from neutrophils. Furthermore, it has been illustrated that NETs promote tumor growth and progression via many molecular pathways. Meanwhile, NETs also can promote metastasis in many kinds of cancers based on multiple studies. In addition, some researchs have found that NETs can promote coagulation and cancer-associated thrombosis. In the present review, it will highlight how NETosis, which is stimulated by various stimuli and signaling pathways, affects cancer biological behaviors via NETs. Given their crucial roles in cancer, NETs will become possible therapeutic targets for inhibiting proliferation, metastasis and thrombosis in cancer patients.
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Affiliation(s)
- Hui Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China
| | - Yiyin Zhang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China
| | - Qianling Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China
| | - Xiaoli Wei
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China
| | - Hua Wang
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China.
| | - Kangsheng Gu
- Department of Oncology, The First Affiliated Hospital of Anhui Medical University, No. 218 Jixi Road, Hefei, 230022, Anhui, People's Republic of China.
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25
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Netting Gut Disease: Neutrophil Extracellular Trap in Intestinal Pathology. OXIDATIVE MEDICINE AND CELLULAR LONGEVITY 2021; 2021:5541222. [PMID: 34712384 PMCID: PMC8548149 DOI: 10.1155/2021/5541222] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/11/2021] [Revised: 07/04/2021] [Accepted: 09/29/2021] [Indexed: 12/26/2022]
Abstract
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.
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26
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Abstract
The mutational landscape of colorectal cancer (CRC) does not enable predictions to be made about the survival of patients or their response to therapy. Instead, studying the polarization and activation profiles of immune cells and stromal cells in the tumour microenvironment has been shown to be more informative, thus making CRC a prototypical example of the importance of an inflammatory microenvironment for tumorigenesis. Here, we review our current understanding of how colon cancer cells interact with their microenvironment, comprised of immune cells, stromal cells and the intestinal microbiome, to suppress or escape immune responses and how inflammatory processes shape the immune pathogenesis of CRC.
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27
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Mutua V, Gershwin LJ. A Review of Neutrophil Extracellular Traps (NETs) in Disease: Potential Anti-NETs Therapeutics. Clin Rev Allergy Immunol 2021; 61:194-211. [PMID: 32740860 PMCID: PMC7395212 DOI: 10.1007/s12016-020-08804-7] [Citation(s) in RCA: 358] [Impact Index Per Article: 89.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Activated neutrophils release neutrophil extracellular traps (NETs) in response to a variety of stimuli. NETosis is driven by protein-arginine deiminase type 4, with the release of intracellular granule components that function by capturing and destroying microbes, including viral, fungal, bacterial, and protozoal pathogens. The positive effects of pathogen control are countered by pro-inflammatory effects as demonstrated in a variety of diseases. Components of NETS are non-specific, and other than controlling microbes, they cause injury to surrounding tissue by themselves or by increasing the pro-inflammatory response. NETs can play a role in enhancement of the inflammation seen in autoimmune diseases including psoriasis, rheumatoid arthritis, and systemic lupus erythematosis. In addition, autoinflammatory diseases such as gout have been associated with NETosis. Inhibition of NETs may decrease the severity of many diseases improving survival. Herein, we describe NETosis in different diseases focusing on the detrimental effect of NETs and outline possible therapeutics that can be used to mitigate netosis. There is a need for more studies and clinical trials on these and other compounds that could prevent or destroy NETs, thereby decreasing damage to patients.
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Affiliation(s)
- Victoria Mutua
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, CA, USA.
| | - Laurel J Gershwin
- Department of Pathology, Microbiology, and Immunology, School of Veterinary Medicine, University of California Davis, 1 Shields Ave, Davis, CA, USA
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28
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Neutrophil Extracellular Traps (NETs) in Cancer Invasion, Evasion and Metastasis. Cancers (Basel) 2021; 13:cancers13174495. [PMID: 34503307 PMCID: PMC8431228 DOI: 10.3390/cancers13174495] [Citation(s) in RCA: 127] [Impact Index Per Article: 31.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2021] [Revised: 08/31/2021] [Accepted: 09/02/2021] [Indexed: 12/14/2022] Open
Abstract
Simple Summary 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. Abstract 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.
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29
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Lin YJ, Wei KC, Chen PY, Lim M, Hwang TL. Roles of Neutrophils in Glioma and Brain Metastases. Front Immunol 2021; 12:701383. [PMID: 34484197 PMCID: PMC8411705 DOI: 10.3389/fimmu.2021.701383] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Accepted: 07/19/2021] [Indexed: 12/16/2022] Open
Abstract
Neutrophils, which are the most abundant circulating leukocytes in humans, are the first line of defense against bacterial and fungal infections. Recent studies have reported the role and importance of neutrophils in cancers. Glioma and brain metastases are the most common malignant tumors of the brain. The tumor microenvironment (TME) in the brain is complex and unique owing to the brain-blood barrier or brain-tumor barrier, which may prevent drug penetration and decrease the efficacy of immunotherapy. However, there are limited studies on the correlation between brain cancer and neutrophils. This review discusses the origin and functions of neutrophils. Additionally, the current knowledge on the correlation between neutrophil-to-lymphocyte ratio and prognosis of glioma and brain metastases has been summarized. Furthermore, the implications of tumor-associated neutrophil (TAN) phenotypes and the functions of TANs have been discussed. Finally, the potential effects of various treatments on TANs and the ability of neutrophils to function as a nanocarrier of drugs to the brain TME have been summarized. However, further studies are needed to elucidate the complex interactions between neutrophils, other immune cells, and brain tumor cells.
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Affiliation(s)
- Ya-Jui Lin
- Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan
- Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
| | - Kuo-Chen Wei
- Department of Neurosurgery, Chang Gung Memorial Hospital, Linkou, Taiwan
- Department of Neurosurgery, New Taipei Municipal TuCheng Hospital, Chang Gung Medical Foundation, New Taipei, Taiwan
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
| | - Pin-Yuan Chen
- School of Medicine, Chang Gung University, Taoyuan, Taiwan
- Department of Neurosurgery, Chang Gung Memorial Hospital, Keelung, Taiwan
| | - Michael Lim
- Department of Neurosurgery, Stanford University School of Medicine, Stanford, CA, United States
| | - Tsong-Long Hwang
- Graduate Institute of Natural Products, College of Medicine, Chang Gung University, Taoyuan, Taiwan
- Research Center for Chinese Herbal Medicine, Research Center for Food and Cosmetic Safety, and Graduate Institute of Health Industry Technology, Chang Gung University of Science and Technology, Taoyuan, Taiwan
- Department of Anesthesiology, Chang Gung Memorial Hospital, Taoyuan, Taiwan
- Department of Chemical Engineering, Ming Chi University of Technology, New Taipei City, Taiwan
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30
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Shao BZ, Yao Y, Li JP, Chai NL, Linghu EQ. The Role of Neutrophil Extracellular Traps in Cancer. Front Oncol 2021; 11:714357. [PMID: 34476216 PMCID: PMC8406742 DOI: 10.3389/fonc.2021.714357] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/30/2021] [Accepted: 07/22/2021] [Indexed: 12/14/2022] Open
Abstract
Neutrophils are vital components of innate and adaptive immunity. It is widely acknowledged that in various pathological conditions, neutrophils are activated and release condensed DNA strands, triggering the formation of neutrophil extracellular traps (NETs). NETs have been shown to be effective in fighting against microbial infections and modulating the pathogenesis and progression of diseases, including malignant tumors. This review describes the current knowledge on the biological characteristics of NETs. Additionally, the mechanisms of NETs in cancer are discussed, including the involvement of signaling pathways and the crosstalk between other cancer-related mechanisms, including inflammasomes and autophagy. Finally, based on previous and current studies, the roles of NET formation and the potential therapeutic targets and strategies related to NETs in several well-studied types of cancers, including breast, lung, colorectal, pancreatic, blood, neurological, and cutaneous cancers, are separately reviewed and discussed.
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Affiliation(s)
| | | | | | - Ning-Li Chai
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
| | - En-Qiang Linghu
- Department of Gastroenterology, General Hospital of the Chinese People’s Liberation Army, Beijing, China
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31
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Yan B, Dai X, Ma Q, Wu X. Stromal Neutrophil Extracellular Trap Density Is an Independent Prognostic Factor for Cervical Cancer Recurrence. Front Oncol 2021; 11:659445. [PMID: 34458135 PMCID: PMC8386589 DOI: 10.3389/fonc.2021.659445] [Citation(s) in RCA: 17] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2021] [Accepted: 07/21/2021] [Indexed: 12/24/2022] Open
Abstract
BACKGROUND Emerging evidence indicates that the tumor microenvironment influences tumor progression and patient prognosis through various inflammatory cells. Polymorphonuclear neutrophils (PMNs) and their functional structures termed neutrophil extracellular traps (NETs) are prominent constituents of several malignant tumors and affect the tumor microenvironment and cancer evolution. Here, we investigate the prognostic value of PMNs and NETs for recurrence in patients with cervical cancer. METHODS The study comprised 126 cervical cancer patients who were retrospectively enrolled. CD66b+ neutrophils and myeloperoxidase/citrullinated histone H3 (MPO/H3Cit)-labeled NETs were assessed by immunofluorescence, and the relationships with clinical and histopathologic features and patient outcome were evaluated. RESULTS The highest density of CD66b+ neutrophils were observed in the stromal compartment (median 55 cells/mm2). Above median densities of stromal CD66b+ neutrophils and NETs were significantly associated with short recurrence-free survival (RFS) (P = 0.041 and P = 0.006, respectively). Multivariate analysis identified high clinical stage (hazard ratio [HR] 6.40; 95% confidence interval [CI] 3.51-11.64; P < 0.001), lymph node metastases (HR 4.69; 95% CI 3.09-9.66; P = 0.006) and high density of NETs (HR 2.66; 95% CI 1.21-5.82; P = 0.015) as independent prognostic factors for short RFS, whereas a high density of CD66b+ neutrophils was not significant. Patients with a high NET density showed worse recurrence status in every stage, but the difference was only significant for stage I (P = 0.042), not stages II, III, or IV (all P > 0.05). Combining stromal NET density and the tumor, nodes, metastasis (TNM) staging system had better prognostic accuracy for cervical cancer than the TNM staging system alone at five and six years respectively (P = 0.010 and P = 0.023). CONCLUSION Stromal NET density is an independent prognostic factor for RFS in cervical cancer. Combining NETs with the TNM staging system may further improve prognostic stratification.
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Affiliation(s)
| | | | - Quanfu Ma
- Department of Gynecologic Oncology, Maternal and Child Health Hospital of Hubei Province, Huazhong University of Science and Technology, Wuhan, China
| | - Xufeng Wu
- Department of Gynecologic Oncology, Maternal and Child Health Hospital of Hubei Province, Huazhong University of Science and Technology, Wuhan, China
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32
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Efrimescu CI, Buggy PM, Buggy DJ. Neutrophil Extracellular Trapping Role in Cancer, Metastases, and Cancer-Related Thrombosis: a Narrative Review of the Current Evidence Base. Curr Oncol Rep 2021; 23:118. [PMID: 34342735 PMCID: PMC8330188 DOI: 10.1007/s11912-021-01103-0] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 03/19/2021] [Indexed: 12/31/2022]
Abstract
Purpose of Review 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. Recent Findings 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. Summary 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. Supplementary Information The online version contains supplementary material available at 10.1007/s11912-021-01103-0.
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Affiliation(s)
- Catalin I Efrimescu
- Department of Anaesthesiology & Perioperative Medicine, Mater Misericordiae University Hospital Eccles St, Dublin, 7 D07 R2WY, Ireland.
| | | | - Donal J Buggy
- Department of Anaesthesiology & Perioperative Medicine, Mater Misericordiae University Hospital Eccles St, Dublin, 7 D07 R2WY, Ireland
- UCD School of Medicine, University College Dublin, Dublin, Ireland
- Department of Outcomes Research, Cleveland Clinic, Cleveland, OH, USA
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33
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Khan U, Chowdhury S, Billah MM, Islam KMD, Thorlacius H, Rahman M. Neutrophil Extracellular Traps in Colorectal Cancer Progression and Metastasis. Int J Mol Sci 2021; 22:ijms22147260. [PMID: 34298878 PMCID: PMC8307027 DOI: 10.3390/ijms22147260] [Citation(s) in RCA: 59] [Impact Index Per Article: 14.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2021] [Revised: 06/30/2021] [Accepted: 07/02/2021] [Indexed: 12/24/2022] Open
Abstract
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.
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Affiliation(s)
- Umama Khan
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; (U.K.); (M.M.B.); (K.M.D.I.)
| | - Sabrina Chowdhury
- Biochemistry and Biotechnology, North South University, Dhaka 1229, Bangladesh;
| | - Md Morsaline Billah
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; (U.K.); (M.M.B.); (K.M.D.I.)
| | - Kazi Mohammed Didarul Islam
- Biotechnology and Genetic Engineering Discipline, Khulna University, Khulna 9208, Bangladesh; (U.K.); (M.M.B.); (K.M.D.I.)
| | - Henrik Thorlacius
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 214 28 Malmö, Sweden;
| | - Milladur Rahman
- Department of Clinical Sciences, Malmö, Section for Surgery, Lund University, 214 28 Malmö, Sweden;
- Correspondence:
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34
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Volkov DV, Tetz GV, Rubtsov YP, Stepanov AV, Gabibov AG. Neutrophil Extracellular Traps (NETs): Opportunities for Targeted Therapy. Acta Naturae 2021; 13:15-23. [PMID: 34707894 PMCID: PMC8526190 DOI: 10.32607/actanaturae.11503] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2021] [Accepted: 09/06/2021] [Indexed: 12/21/2022] Open
Abstract
Antitumor therapy, including adoptive immunotherapy, inevitably faces powerful counteraction from advanced cancer. If hematological malignancies are currently amenable to therapy with CAR-T lymphocytes (T-cells modified by the chimeric antigen receptor), solid tumors, unfortunately, show a significantly higher degree of resistance to this type of therapy. As recent studies show, the leading role in the escape of solid tumors from the cytotoxic activity of immune cells belongs to the tumor microenvironment (TME). TME consists of several types of cells, including neutrophils, the most numerous cells of the immune system. Recent studies show that the development of the tumor and its ability to metastasize directly affect the extracellular traps of neutrophils (neutrophil extracellular traps, NETs) formed as a result of the response to tumor stimuli. In addition, the nuclear DNA of neutrophils - the main component of NETs - erects a spatial barrier to the interaction of CAR-T with tumor cells. Previous studies have demonstrated the promising potential of deoxyribonuclease I (DNase I) in the destruction of NETs. In this regard, the use of eukaryotic deoxyribonuclease I (DNase I) is promising in the effort to increase the efficiency of CAR-T by reducing the NETs influence in TME. We will examine the role of NETs in TME and the various approaches in the effort to reduce the effect of NETs on a tumor.
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Affiliation(s)
- D. V. Volkov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997 Russia
| | - G. V. Tetz
- Pavlov First State Medical University of St. Petersburg, St Petersburg, 197022 Russia
| | - Y. P. Rubtsov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997 Russia
| | - A. V. Stepanov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997 Russia
| | - A. G. Gabibov
- Shemyakin-Ovchinnikov Institute of Bioorganic Chemistry RAS, Moscow, 117997 Russia
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35
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Neutrophil Extracellular Traps in Tumor Metastasis: Pathological Functions and Clinical Applications. Cancers (Basel) 2021; 13:cancers13112832. [PMID: 34204148 PMCID: PMC8200981 DOI: 10.3390/cancers13112832] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2021] [Revised: 05/28/2021] [Accepted: 06/02/2021] [Indexed: 01/04/2023] Open
Abstract
Simple Summary 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. Abstract 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.
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36
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Zhu T, Zou X, Yang C, Li L, Wang B, Li R, Li H, Xu Z, Huang D, Wu Q. Neutrophil extracellular traps promote gastric cancer metastasis by inducing epithelial‑mesenchymal transition. Int J Mol Med 2021; 48:127. [PMID: 34013374 PMCID: PMC8128417 DOI: 10.3892/ijmm.2021.4960] [Citation(s) in RCA: 89] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/20/2020] [Accepted: 06/19/2020] [Indexed: 12/13/2022] Open
Abstract
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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Affiliation(s)
- Tong Zhu
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Xiaoming Zou
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Chunfa Yang
- Shuangyashan Shuangkuang Hospital, Shuangyashan, Heilongjiang 155100, P.R. China
| | - Liangliang Li
- Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Bing Wang
- Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Rong Li
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Hongxuan Li
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Zhangxuan Xu
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Di Huang
- Department of Pharmacology, Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
| | - Qingyun Wu
- The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang 150086, P.R. China
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Munir H, Jones JO, Janowitz T, Hoffmann M, Euler M, Martins CP, Welsh SJ, Shields JD. Stromal-driven and Amyloid β-dependent induction of neutrophil extracellular traps modulates tumor growth. Nat Commun 2021; 12:683. [PMID: 33514748 PMCID: PMC7846803 DOI: 10.1038/s41467-021-20982-2] [Citation(s) in RCA: 97] [Impact Index Per Article: 24.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2020] [Accepted: 12/17/2020] [Indexed: 02/07/2023] Open
Abstract
Tumors consist of cancer cells and a network of non-cancerous stroma. Cancer-associated fibroblasts (CAF) are known to support tumorigenesis, and are emerging as immune modulators. Neutrophils release histone-bound nuclear DNA and cytotoxic granules as extracellular traps (NET). Here we show that CAFs induce NET formation within the tumor and systemically in the blood and bone marrow. These tumor-induced NETs (t-NETs) are driven by a ROS-mediated pathway dependent on CAF-derived Amyloid β, a peptide implicated in both neurodegenerative and inflammatory disorders. Inhibition of NETosis in murine tumors skews neutrophils to an anti-tumor phenotype, preventing tumor growth; reciprocally, t-NETs enhance CAF activation. Mirroring observations in mice, CAFs are detected juxtaposed to NETs in human melanoma and pancreatic adenocarcinoma, and show elevated amyloid and β-Secretase expression which correlates with poor prognosis. In summary, we report that CAFs drive NETosis to support cancer progression, identifying Amyloid β as the protagonist and potential therapeutic target.
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Affiliation(s)
- Hafsa Munir
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, England
| | - James O Jones
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, England
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, England
| | - Tobias Janowitz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, New York, NY, 11724, USA
- Northwell Health Cancer Institute, New York, NY, 11021, USA
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK
| | - Markus Hoffmann
- Friedrich Alexander University Erlangen-Nuremberg, Universitätsklinikum Erlangen, Department of Medicine 3, Universitätsstrasse 25a, 91054, Erlangen, Germany
| | - Maximilien Euler
- Friedrich Alexander University Erlangen-Nuremberg, Universitätsklinikum Erlangen, Department of Medicine 3, Universitätsstrasse 25a, 91054, Erlangen, Germany
| | - Carla P Martins
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, England
- Early Oncology TDE, Oncology R&D, AstraZeneca, Cambridge, CB2 0RE, England
| | - Sarah J Welsh
- Department of Oncology, Cambridge University Hospitals NHS Foundation Trust, Cambridge Biomedical Campus, Hills Road, Cambridge, CB2 0QQ, England
- Cancer Research UK Cambridge Institute, University of Cambridge, Li Ka Shing Centre, Cambridge, CB2 0RE, UK
| | - Jacqueline D Shields
- MRC Cancer Unit, Hutchison/MRC Research Centre, University of Cambridge, Box 197 Cambridge Biomedical Campus, Cambridge, CB2 0XZ, England.
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38
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Rawat K, Syeda S, Shrivastava A. Neutrophil-derived granule cargoes: paving the way for tumor growth and progression. Cancer Metastasis Rev 2021; 40:221-244. [PMID: 33438104 PMCID: PMC7802614 DOI: 10.1007/s10555-020-09951-1] [Citation(s) in RCA: 40] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/16/2020] [Accepted: 12/22/2020] [Indexed: 01/31/2023]
Abstract
Neutrophils are the key cells of our innate immune system mediating host defense via a range of effector functions including phagocytosis, degranulation, and NETosis. For this, they employ an arsenal of anti-microbial cargoes packed in their readily mobilizable granule subsets. Notably, the release of granule content is tightly regulated; however, under certain circumstances, their unregulated release can aggravate tissue damage and could be detrimental to the host. Several constituents of neutrophil granules have also been associated with various inflammatory diseases including cancer. In cancer setting, their excessive release may modulate tissue microenvironment which ultimately leads the way for tumor initiation, growth and metastasis. Neutrophils actively infiltrate within tumor tissues, wherein they show diverse phenotypic and functional heterogeneity. While most studies are focused at understanding the phenotypic heterogeneity of neutrophils, their functional heterogeneity, much of which is likely orchestrated by their granule cargoes, is beginning to emerge. Therefore, a better understanding of neutrophil granules and their cargoes will not only shed light on their diverse role in cancer but will also reveal them as novel therapeutic targets. This review provides an overview on existing knowledge of neutrophil granules and detailed insight into the pathological relevance of their cargoes in cancer. In addition, we also discuss the therapeutic approach for targeting neutrophils or their microenvironment in disease setting that will pave the way forward for future research.
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Affiliation(s)
- Kavita Rawat
- grid.8195.50000 0001 2109 4999Department of Zoology, University of Delhi, Delhi, 110007 India
| | - Saima Syeda
- grid.8195.50000 0001 2109 4999Department of Zoology, University of Delhi, Delhi, 110007 India
| | - Anju Shrivastava
- grid.8195.50000 0001 2109 4999Department of Zoology, University of Delhi, Delhi, 110007 India
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39
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Masucci MT, Minopoli M, Del Vecchio S, Carriero MV. The Emerging Role of Neutrophil Extracellular Traps (NETs) in Tumor Progression and Metastasis. Front Immunol 2020; 11:1749. [PMID: 33042107 PMCID: PMC7524869 DOI: 10.3389/fimmu.2020.01749] [Citation(s) in RCA: 324] [Impact Index Per Article: 64.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2020] [Accepted: 06/30/2020] [Indexed: 12/12/2022] Open
Abstract
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.
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Affiliation(s)
- Maria Teresa Masucci
- Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Michele Minopoli
- Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
| | - Silvana Del Vecchio
- Department of Advanced Biomedical Sciences, University of Naples "Federico II", Naples, Italy
| | - Maria Vincenza Carriero
- Neoplastic Progression Unit, Istituto Nazionale Tumori IRCCS "Fondazione G. Pascale", Naples, Italy
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40
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Furumaya C, Martinez-Sanz P, Bouti P, Kuijpers TW, Matlung HL. Plasticity in Pro- and Anti-tumor Activity of Neutrophils: Shifting the Balance. Front Immunol 2020; 11:2100. [PMID: 32983165 PMCID: PMC7492657 DOI: 10.3389/fimmu.2020.02100] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2020] [Accepted: 08/03/2020] [Indexed: 12/11/2022] Open
Abstract
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.
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Affiliation(s)
- Charita Furumaya
- Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Paula Martinez-Sanz
- Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Panagiota Bouti
- Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Taco W Kuijpers
- Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands.,Department of Pediatric Immunology, Rheumatology and Infectious Diseases, Emma Children's Hospital, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
| | - Hanke L Matlung
- Department of Blood Cell Research, Sanquin Research, Amsterdam University Medical Center, University of Amsterdam, Amsterdam, Netherlands
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41
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Kamal Y, Schmit SL, Frost HR, Amos CI. The tumor microenvironment of colorectal cancer metastases: opportunities in cancer immunotherapy. Immunotherapy 2020; 12:1083-1100. [PMID: 32787587 DOI: 10.2217/imt-2020-0026] [Citation(s) in RCA: 31] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/08/2023] Open
Abstract
About a fifth of individuals with colorectal cancer (CRC) present with disease metastasis at the time of diagnosis. While the role of the tumor microenvironment (TME) in governing CRC progression is undeniable, the role of the TME in either establishing or suppressing the formation of distant metastases of CRC is less well established. Despite advances in immunotherapy, many individuals with metastatic CRC do not respond to standard-of-care therapy. Therefore, understanding the role of the TME in establishing distant metastases is essential for developing new immunological agents. Here, we summarize our current understanding of the TME of CRC metastases, describe differences between the TME of primary tumors and their distant metastases, and discuss advances in the design and combinations of immunotherapeutic agents.
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Affiliation(s)
- Yasmin Kamal
- Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Stephanie L Schmit
- Department of Cancer Epidemiology, H Lee Moffitt Cancer Center & Research Institute, Tampa, FL 33612, USA
| | - Hildreth Robert Frost
- Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA
| | - Christopher I Amos
- Department of Biomedical Data Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Quantitative Biomedical Sciences, Geisel School of Medicine at Dartmouth, Hanover, NH 03755, USA.,Dan L Duncan Comprehensive Cancer Center at Baylor College of Medicine, Houston, TX 77030, USA
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42
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Okazaki M, Yamaguchi T, Tajima H, Fushida S, Ohta T. Platelet adherence to cancer cells promotes escape from innate immune surveillance in cancer metastasis. Int J Oncol 2020; 57:980-988. [PMID: 32945350 DOI: 10.3892/ijo.2020.5102] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Accepted: 07/07/2020] [Indexed: 11/05/2022] Open
Abstract
The impacts of post‑operative abdominal infectious complications increase hematogenous distant metastasis and result in poor long‑term survival after curative resection. Even if curative resection can be performed, the presence of circulating tumor cells is affected. The liver, the most common site of metastases, is an important organ in innate immune surveillance. However, the molecular mechanisms of distant hematogenous metastasis are not yet fully known. Platelets are crucial components in the tumor microenvironment that function to promote tumor progression and metastasis. The purpose of this study was to identify the effect of platelets on escape from innate immune surveillance in post‑operative abdominal infectious complications. Platelet adherence was assessed by co‑culturing human pancreatic cancer cells including transforming growth factor (TGF‑β)‑treated BxPC‑3. CD44 isoform, transcription factors and epithelial‑mesenchymal transition markers were examined using western blotting. We also assessed whether cancer cells surrounded by activated platelets could escape from innate immune surveillance, using infectious and non‑infectious mouse models injected intraperitoneally with LPS. Platelets were found to preferentially adhere to mesenchymal cells rather than epithelial cells. BxPC‑3 epithelial cells showed upregulation of CD44‑variant and epithelial splicing regulatory protein 1 (ESRP‑1) expression. However, Panc‑1 mesenchymal cells and TGF‑β‑treated BxPC‑3 cells showed upregulation of CD44‑standard and zinc finger E‑box‑binding homeobox 1 (ZEB‑1) expression and a reduction in ESRP‑1. In the non‑infectious model, cancer cells were not found in the liver. In the infectious model, although epithelial cells without platelet adhesion were in an apoptotic state, mesenchymal cells showed many viable cancer cells surrounded by activated platelets. Cancer cells were suggested to have phenotypic plasticity through the switching of CD44 isoforms. Mesenchymal cells, which express CD44‑standard, could escape from immune surveillance by becoming surrounded by adhered activated platelets. Therefore, it may be necessary to administer antiplatelet agents to prevent distant hematogenous metastasis when post‑operative abdominal infectious complications occur.
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Affiliation(s)
- Mitsuyoshi Okazaki
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Takahisa Yamaguchi
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Hidehiro Tajima
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Sachio Fushida
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
| | - Tetsuo Ohta
- Department of Gastroenterological Surgery, Division of Cancer Medicine, Graduate School of Medical Science, Kanazawa University, Kanazawa, Ishikawa 920‑8641, Japan
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43
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Yang L, Liu L, Zhang R, Hong J, Wang Y, Wang J, Zuo J, Zhang J, Chen J, Hao H. IL-8 mediates a positive loop connecting increased neutrophil extracellular traps (NETs) and colorectal cancer liver metastasis. J Cancer 2020; 11:4384-4396. [PMID: 32489457 PMCID: PMC7255375 DOI: 10.7150/jca.44215] [Citation(s) in RCA: 95] [Impact Index Per Article: 19.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2020] [Accepted: 05/04/2020] [Indexed: 12/21/2022] Open
Abstract
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.
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Affiliation(s)
- Luyu Yang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China.,Caner Metastasis Institute, Fudan University, Shanghai, China
| | - Lu Liu
- Department of Infection Disease, Huashan Hospital, Fudan University, Shanghai, China
| | - Rui Zhang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jun Hong
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yaping Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jian Wang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jieliang Zuo
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jubo Zhang
- Department of Infection Disease, Huashan Hospital, Fudan University, Shanghai, China
| | - Jinhong Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Hankun Hao
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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Li M, Lin C, Deng H, Strnad J, Bernabei L, Vogl DT, Burke JJ, Nefedova Y. A Novel Peptidylarginine Deiminase 4 (PAD4) Inhibitor BMS-P5 Blocks Formation of Neutrophil Extracellular Traps and Delays Progression of Multiple Myeloma. Mol Cancer Ther 2020; 19:1530-1538. [PMID: 32371579 DOI: 10.1158/1535-7163.mct-19-1020] [Citation(s) in RCA: 104] [Impact Index Per Article: 20.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Revised: 03/25/2020] [Accepted: 05/01/2020] [Indexed: 12/27/2022]
Abstract
Multiple myeloma is a plasma cell malignancy, which grows in the bone marrow (BM). The major population of cells in the BM is represented by neutrophils and they can form neutrophil extracellular traps (NET). Here, we investigated whether multiple myeloma cells induce NET formation and whether targeting this process would delay multiple myeloma progression. We demonstrated that murine and human multiple myeloma cells stimulate citrullination of histone H3 and NET formation by neutrophils and that this process is abrogated by pharmacological targeting of peptidylarginine deiminase 4 (PAD4) with a novel-specific small molecule inhibitor BMS-P5. Administration of BMS-P5 to multiple myeloma-bearing mice delays appearance of symptoms and disease progression. Taken together, our data demonstrate that targeting PAD4 may be beneficial for treatment of multiple myeloma.
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Affiliation(s)
- Marina Li
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Cindy Lin
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | - Hui Deng
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania
| | | | - Luca Bernabei
- Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | - Dan T Vogl
- Division of Hematology/Oncology, Abramson Cancer Center, University of Pennsylvania, Philadelphia, Pennsylvania
| | | | - Yulia Nefedova
- Immunology, Microenvironment and Metastasis Program, The Wistar Institute, Philadelphia, Pennsylvania.
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45
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Zhou J, Jiang S, Wang W, Liu R. [Research Progress of Tumor-Associated Neutrophils and Lung Cancer]. ZHONGGUO FEI AI ZA ZHI = CHINESE JOURNAL OF LUNG CANCER 2020; 22:727-731. [PMID: 31771743 PMCID: PMC6885416 DOI: 10.3779/j.issn.1009-3419.2019.11.07] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
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。
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Affiliation(s)
- Jinhua Zhou
- Jining No.1 People's Hospital, Jining 272000, China
| | | | - Wei Wang
- The Second Hospital of Shandong University, Jinan 250033, China
| | - Ruijuan Liu
- Jining No.1 People's Hospital, Jining 272000, China
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Carroll GM, Burns GL, Petit JA, Walker MM, Mathe A, Smith SR, Keely S, Pockney PG. Does postoperative inflammation or sepsis generate neutrophil extracellular traps that influence colorectal cancer progression? A systematic review. Surg Open Sci 2020; 2:57-69. [PMID: 32754708 PMCID: PMC7391903 DOI: 10.1016/j.sopen.2019.12.005] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2019] [Revised: 12/17/2019] [Accepted: 12/31/2019] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Colorectal cancer is the third most common cancer worldwide. Almost half of those that have a potentially curative resection go on to develop metastatic disease. A recognized risk for recurrence is perioperative systemic inflammation and sepsis. Neutrophil extracellular traps have been implicated as promotors of tumor progression. We aimed to examine the evidence in the literature for an association between neutrophil extracellular traps and postoperative metastasis in colorectal cancer. MATERIALS AND METHODS Studies published between 2000 and December 2018 that examined the role of neutrophil extracellular traps in sepsis and inflammation in colorectal cancer and in relation to tumor-related outcomes were identified through a database search of Cochrane, CINAHL, and MEDLINE. Quality and bias assessment was carried out by 2 reviewers. RESULTS Of 8,940 screened and of the 30 studies included, 21 were observational, 5 were in vivo experimental, 1 was in vitro, and 3 used a combination of these approaches. CONCLUSION There is clear evidence from the literature that presence of a preoperative systemic inflammatory response predicts cancer recurrence following potentially curative resection, but the evidence for association of sepsis and progression is lacking. There is robust experimental evidence in murine models showing that neutrophil extracellular traps are present in sepsis and are associated with cancer progression. Some human observational studies corroborate the prognostic significance of neutrophil extracellular traps in progression of colorectal cancer. Further human studies are needed to translate the experimental evidence and to definitively associate sepsis and neutrophil extracellular traps with poor colorectal cancer-specific outcomes.
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Affiliation(s)
- Georgia M. Carroll
- Division of Surgery, John Hunter Hospital, New South Wales, Australia
- School of Medicine and Public Health, University of Newcastle, New South Wales, Australia
- Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Grace L. Burns
- Hunter Medical Research Institute, Newcastle, New South Wales, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia
| | - Joel A. Petit
- Division of Surgery, John Hunter Hospital, New South Wales, Australia
- School of Medicine and Public Health, University of Newcastle, New South Wales, Australia
- Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Marjorie M. Walker
- School of Medicine and Public Health, University of Newcastle, New South Wales, Australia
- Hunter Medical Research Institute, Newcastle, New South Wales, Australia
| | - Andrea Mathe
- Hunter Medical Research Institute, Newcastle, New South Wales, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia
| | - Stephen R. Smith
- Division of Surgery, John Hunter Hospital, New South Wales, Australia
- School of Medicine and Public Health, University of Newcastle, New South Wales, Australia
| | - Simon Keely
- Hunter Medical Research Institute, Newcastle, New South Wales, Australia
- School of Biomedical Sciences and Pharmacy, University of Newcastle, New South Wales, Australia
| | - Peter G. Pockney
- Division of Surgery, John Hunter Hospital, New South Wales, Australia
- School of Medicine and Public Health, University of Newcastle, New South Wales, Australia
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Shang A, Gu C, Zhou C, Yang Y, Chen C, Zeng B, Wu J, Lu W, Wang W, Sun Z, Li D. Exosomal KRAS mutation promotes the formation of tumor-associated neutrophil extracellular traps and causes deterioration of colorectal cancer by inducing IL-8 expression. Cell Commun Signal 2020; 18:52. [PMID: 32228650 PMCID: PMC7106821 DOI: 10.1186/s12964-020-0517-1] [Citation(s) in RCA: 87] [Impact Index Per Article: 17.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/25/2019] [Accepted: 01/29/2020] [Indexed: 12/28/2022] Open
Abstract
Background Colorectal cancer (CRC) remains one of the leading causes of cancer-related death. The current study aimed to elucidate the mechanism by which exosomes carrying KRAS mutant contribute to neutrophil recruitment as well as the formation of the neutrophil extracellular trap (NET) in CRC. Methods APC-WT and APC-KRASG12D mouse models were initially developed. Peripheral blood, spleen, bone marrow (BM) and mesenteric lymph nodes (mLN) were isolated to detect neutrophil content. Then, APC-WT and APC-KRASG12D mice were injected with exosomes isolated from APC-WT and APC-KRASG12D mice. The ratio of neutrophils, NETs formation and IL-8 protein content were subsequently quantified in colon tissues. DKs-8 (wild type) and DKO-1 (KRAS mutant) cells were employed for in vitro experimentation. Then, DKs-8 cells were cultured with exosome-treated PMA stimulated neutrophil-forming NETs culture medium, with cell viability, invasion, migration, and adhesion evaluated. Results Compared with APC-WT mice, the numbers of polyps and neutrophils in the peripheral blood, spleen and mLNs were increased in APC-KRASG12D mice, accompanied with increased NET formation, IL-8 expression and exosomes. Meanwhile, IL-8 upregulation, neutrophil recruitment and NET formation were observed in the mice injected with exosomes derived from APC-KRASG12D. The in vitro investigation results revealed that more NETs were formed in the presence of DKO-1-Exos, which were inhibited by DNAse. In addition, DKs-8- and DKO-1 cells-derived exosomes could adhere to NETs under static conditions in vitro. Exosomal KRAS mutants were noted to exert stimulatory effects on the IL-8 production and NET formation to promote the growth of CRC cells. Conclusion The results provide evidence suggesting that exosomes may transfer mutant KRAS to recipient cells and trigger increases in IL-8 production, neutrophil recruitment and formation of NETs, eventually leading to the deterioration of CRC.
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Affiliation(s)
- Anquan Shang
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China
| | - Chenzheng Gu
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China
| | - Chen Zhou
- Department of Pathology, The Sixth People's Hospital of Yancheng City, Yancheng, 224001, People's Republic of China
| | - Yibao Yang
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China
| | - Chen Chen
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China
| | - Bingjie Zeng
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China
| | - Junlu Wu
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China
| | - Wenying Lu
- Department of Pathology, The Sixth People's Hospital of Yancheng City, Yancheng, 224001, People's Republic of China
| | - Weiwei Wang
- Department of Pathology, The Sixth People's Hospital of Yancheng City, Yancheng, 224001, People's Republic of China
| | - Zujun Sun
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China.
| | - Dong Li
- Department of Laboratory Medicine, Shanghai Tongji Hospital, Tongji University School of Medicine, No. 389, Xincun Road, Shanghai, 200065, People's Republic of China.
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Wu L, Saxena S, Singh RK. Neutrophils in the Tumor Microenvironment. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1224:1-20. [PMID: 32036601 DOI: 10.1007/978-3-030-35723-8_1] [Citation(s) in RCA: 111] [Impact Index Per Article: 22.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Neutrophils are the first responders to inflammation, infection, and injury. As one of the most abundant leukocytes in the immune system, neutrophils play an essential role in cancer progression, through multiple mechanisms, including promoting angiogenesis, immunosuppression, and cancer metastasis. Recent studies demonstrating elevated neutrophil to lymphocyte ratios suggest neutrophil as a potential therapeutic target and biomarker for disease status in cancer. This chapter will discuss the phenotypic and functional changes in the neutrophil in the tumor microenvironment, the underlying mechanism(s) of neutrophil facilitated cancer metastasis, and clinical potential of neutrophils as a prognostic/diagnostic marker and therapeutic target.
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Affiliation(s)
- Lingyun Wu
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Sugandha Saxena
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA
| | - Rakesh K Singh
- Department of Pathology and Microbiology, University of Nebraska Medical Center, Omaha, NE, USA.
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NETosis in cancer: a critical analysis of the impact of cancer on neutrophil extracellular trap (NET) release in lung cancer patients vs. mice. Cancer Immunol Immunother 2020; 69:199-213. [PMID: 31982939 DOI: 10.1007/s00262-019-02474-x] [Citation(s) in RCA: 40] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/15/2019] [Accepted: 12/31/2019] [Indexed: 12/15/2022]
Abstract
Neutrophils play a major role in tumor biology. Among other functions, neutrophils can release extracellular traps (NETs), mesh-like structures of decondensed chromatin fibers, in a process termed NETosis. Originally characterized as an antimicrobial mechanism, NETosis has been described in cancer, but cancer-related predisposition is not clear. In the current study, we investigated the predisposition of circulating neutrophils to release NETs in lung cancer and the impact of G-CSF on this function, comparing circulating neutrophils isolated from cancer patients to the LLC and AB12 mouse models. We find that neutrophils from both healthy donors and cancer patients display high NETotic potential, with 30-60% of cells undergoing NETosis upon PMA stimulation. In contrast, neutrophils isolated from tumor-bearing mice displayed only 4-5% NETotic cells, though significantly higher than naive controls (1-2%). Despite differential mechanisms of activation described, Ionomycin and PMA mainly triggered suicidal rather than vital NETosis. G-CSF secreting tumors did not increase NETotic rates in murine neutrophils, and direct G-CSF stimulation did not promote their NET release. In contrast, human neutrophils strongly responded to G-CSF stimulation resulting also in a higher response to PMA + G-CSF stimulation. Our data show clear differences in NETotic potentials between human and murine neutrophils. We do not find a predisposition of neutrophils to release NETs in lung cancer patients compared to healthy controls, whereas cancer may modulate neutrophils' NETotic potential in mice. G-CSF secreted from tumors differentially affects murine and human NETosis in cancer. These important differences should be considered in future studies of NETosis in cancer.
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Posabella A, Köhn P, Lalos A, Wilhelm A, Mechera R, Soysal S, Muenst S, Güth U, Stadlmann S, Terracciano L, Droeser RA, Zeindler J, Singer G. High density of CD66b in primary high-grade ovarian cancer independently predicts response to chemotherapy. J Cancer Res Clin Oncol 2020; 146:127-136. [PMID: 31853662 DOI: 10.1007/s00432-019-03108-6] [Citation(s) in RCA: 20] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/22/2019] [Accepted: 12/11/2019] [Indexed: 12/18/2022]
Abstract
PURPOSE Ovarian carcinoma (OC) is the most lethal female genital cancer. After a primary curative surgical approach followed by chemotherapy, a fraction of the patients recur with chemoresistant disease. Data indicate a favorable therapeutic effect of tumor-infiltrating neutrophils (TIN) in OC. Our aim was to investigate the prognostic role of CD66b expression, corresponding to neutrophilic infiltration for recurrence-free survival (RFS) and overall survival (OS) in patients with OC. METHODS A collective of 47 primary serous ovarian carcinoma and their matching recurrences were processed and stained with CD66b using immunohistochemistry. Tumors from patients with RFS of more than 6 months were defined as chemosensitive. Statistical analysis of CD66b expression was performed to assess the clinical endpoints. RESULTS High density of CD66b expressing neutrophils in primary carcinoma was associated with chemosensitivity (p = 0.014) and longer RFS (p = 0.001). Univariate analysis identified high density of CD66b expressing neutrophils as a predictor for favorable RFS (HR 0.41, 95% CI 0.22-0.76, p < 0.005). Residual disease > 2 cm (HR 3.67, 95% CI 1.62-8.31, p < 0.002) and higher number of chemotherapy cycles (HR 1.28, 95% CI 1.05-1.55, p < 0.013) were associated with worse RFS. Multivariate analysis showed that high density of CD66b expressing neutrophils (HR 0.22, 95% CI 0.10-0.48, p < 0.001) and residual disease > 2 cm (HR 3.69, 95% CI 1.43-9.53, p < 0.007) were independent predictors of RFS but had no impact on OS. CONCLUSION High CD66b neutrophil density in primary high-grade OC predicts good response to initial chemotherapy and longer recurrence-free survival independent of known risk factors.
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Affiliation(s)
- Alberto Posabella
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Philipp Köhn
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Alexandros Lalos
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Alexander Wilhelm
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Robert Mechera
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Savas Soysal
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Simone Muenst
- Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland
| | - Uwe Güth
- Brustzentrum Zürich, Seefeldstrasse 214, 8008, Zurich, Switzerland
- Department of Gynecology and Obstetrics, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Sylvia Stadlmann
- Department of Gynecology and Obstetrics, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland
- Institute of Pathology, Kantonsspital Baden AG, Im Ergel 1, 5404, Baden, Switzerland
| | - Luigi Terracciano
- Institute of Pathology, University Hospital Basel, Schönbeinstrasse 40, 4031, Basel, Switzerland
| | - Raoul A Droeser
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland.
| | - Jasmin Zeindler
- University Center for Gastrointestinal and Liver Diseases (Clarunis), University of Basel, Spitalstrasse 21, 4031, Basel, Switzerland
| | - Gad Singer
- Department of Gynecology and Obstetrics, University Hospital Basel, Spitalstrasse 21, 4031, Basel, Switzerland
- Institute of Pathology, Kantonsspital Baden AG, Im Ergel 1, 5404, Baden, Switzerland
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