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Wang H, Kim SJ, Lei Y, Wang S, Wang H, Huang H, Zhang H, Tsung A. Neutrophil extracellular traps in homeostasis and disease. Signal Transduct Target Ther 2024; 9:235. [PMID: 39300084 PMCID: PMC11415080 DOI: 10.1038/s41392-024-01933-x] [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: 02/24/2024] [Revised: 06/25/2024] [Accepted: 07/16/2024] [Indexed: 09/22/2024] Open
Abstract
Neutrophil extracellular traps (NETs), crucial in immune defense mechanisms, are renowned for their propensity to expel decondensed chromatin embedded with inflammatory proteins. Our comprehension of NETs in pathogen clearance, immune regulation and disease pathogenesis, has grown significantly in recent years. NETs are not only pivotal in the context of infections but also exhibit significant involvement in sterile inflammation. Evidence suggests that excessive accumulation of NETs can result in vessel occlusion, tissue damage, and prolonged inflammatory responses, thereby contributing to the progression and exacerbation of various pathological states. Nevertheless, NETs exhibit dual functionalities in certain pathological contexts. While NETs may act as autoantigens, aggregated NET complexes can function as inflammatory mediators by degrading proinflammatory cytokines and chemokines. The delineation of molecules and signaling pathways governing NET formation aids in refining our appreciation of NETs' role in immune homeostasis, inflammation, autoimmune diseases, metabolic dysregulation, and cancer. In this comprehensive review, we delve into the multifaceted roles of NETs in both homeostasis and disease, whilst discussing their potential as therapeutic targets. Our aim is to enhance the understanding of the intricate functions of NETs across the spectrum from physiology to pathology.
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Affiliation(s)
- Han Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Susan J Kim
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA
| | - Yu Lei
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Shuhui Wang
- Department of Gastroenterology, Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hui Wang
- Department of Medical Genetics, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China
| | - Hai Huang
- Feinstein Institutes for Medical Research, Manhasset, NY, USA
| | - Hongji Zhang
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA.
| | - Allan Tsung
- Department of Surgery, School of Medicine, University of Virginia, Charlottesville, VA, USA.
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Yamamoto H, Nakanishi Y, Mitsuhashi T, Hatanaka Y, Hatanaka K, Nange A, Yoshida Y, Ino N, Go M, Okamura K, Tsuchikawa T, Nakamura T, Noji T, Asano T, Matsui A, Tanaka K, Murakami S, Ebihara Y, Kurashima Y, Shichinohe T, Hirano S. Impact of Neutrophil Extracellular Traps Identified by Citrullinated Histone H3 Immunohistochemistry for Postoperative Prognosis in Patients with Extrahepatic Cholangiocarcinomas. Ann Surg Oncol 2024; 31:2090-2100. [PMID: 38052736 DOI: 10.1245/s10434-023-14638-2] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2023] [Accepted: 11/07/2023] [Indexed: 12/07/2023]
Abstract
BACKGROUND Neutrophil extracellular traps (NETs) are extracellular chromatin structures composed of cytoplasmic, granular, and nuclear components of neutrophils. Recently, NETs have received much attention for their role in tumor biology; however, their impact on the postoperative prognosis of patients with extrahepatic cholangiocarcinomas (EHCCs) remains unclear. The purpose of this study was to clarify the impact of NETs identified by immunohistochemical citrullinated histone H3 (Cit-H3) staining on postoperative overall survival (OS) in patients with perihilar cholangiocarcinoma (PHCC) and distal cholangiocarcinoma (DCC). METHODS This study included 318 patients with EHCC (PHCC, n = 192; DCC, n = 126) who underwent surgical resection with curative intent. Neutrophils and NETs were identified by immunohistochemistry using antibodies against CD15 and Cit-H3, respectively. Based on the distribution of CD15 and Cit-H3 expression in the tumor bed, the patients were classified into four groups: one negative group and three subgroups of the positive group (diffuse, intermediate, and focal subgroups). RESULTS No significant difference was found in the postoperative OS rate depending on the distribution of CD15 expression in patients with PHCC or DCC. However, the three subgroups with positive Cit-H3 expression had significantly poorer OS than the negative group for both PHCC and DCC. Moreover, positive Cit-H3 was an independent OS factor in the multivariable analyses of PHCC (hazard ratio [HR] 1.69, 95% confidence interval [CI] 1.11-2.59, P = 0.0115) and DCC (HR 2.03; 95% CI 1.21-3.42, P = 0.0057). CONCLUSIONS The presence of NETs in the tumor microenvironment may have adverse prognostic effects in patients with EHCCs.
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Affiliation(s)
- Hiroyuki Yamamoto
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yoshitsugu Nakanishi
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan.
| | - Tomoko Mitsuhashi
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yutaka Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Kanako Hatanaka
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Ayae Nange
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Yusuke Yoshida
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Norito Ino
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Masaru Go
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
- Department of Surgical Pathology, Hokkaido University Hospital, Sapporo, Japan
| | - Keisuke Okamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Takahiro Tsuchikawa
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Toru Nakamura
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Takehiro Noji
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Toshimichi Asano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Aya Matsui
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Kimitaka Tanaka
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Soichi Murakami
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Yuma Ebihara
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Yo Kurashima
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Toshiaki Shichinohe
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
| | - Satoshi Hirano
- Department of Gastroenterological Surgery II, Hokkaido University Faculty of Medicine, Sapporo, Hokkaido, Japan
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Wang B, Ling D, Li L, Zhang J, Xu J. Impact of preoperative white blood cell count on outcomes in different stage colorectal cancer patients undergoing surgical resection: a single-institution retrospective cohort study. BMC Cancer 2024; 24:242. [PMID: 38383340 PMCID: PMC10882932 DOI: 10.1186/s12885-024-11983-7] [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: 12/11/2023] [Accepted: 02/08/2024] [Indexed: 02/23/2024] Open
Abstract
PURPOSE To explore the association between preoperative WBC count and the long-term survival outcomes and clinical outcomes in different stage patients who underwent surgical resection for colorectal cancer (CRC). PATIENTS AND METHODS A cohort of 8121 Chinese patients who underwent surgical resection for CRC from January 1, 2008 to December 31, 2014 were enrolled as part of the retrospective cohort were retrospectively analyzed. Based on that the preoperative WBC optimal cut-off value was 7*109/L (7,000/µL), the high preoperative WBC group and the low preoperative WBC group was defined. Inverse probability of treatment weighting (IPTW) using the propensity score was used to reduce confounding. The impact of preoperative WBC count on overall survival (OS) and disease-free survival (DFS) was investigated using the Kaplan-Meier method and Univariate Cox proportional hazards models in different stage subgroup respectively. RESULTS After IPTW, the clinical characters in the high preoperative WBC count group and the low preoperative WBC count group were balanced. Kaplan-Meier analysis showed that the 5-year OS rate were significantly lower in the high preoperative WBC count group overall, in stage II and IV. The 5-year DFS rate was significantly lower overall, in stage II and III in the high preoperative WBC count group. High preoperative WBC count was associated with poorer OS overall in stage II and stage IV. CONCLUSIONS This study suggests that preoperative WBC count is an independent risk factor for survival in patients undergoing colorectal surgery and may need to consider the stage of cancer when applied to predict long-term adverse outcome prognosis.
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Affiliation(s)
- Bei Wang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Dandan Ling
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Lihong Li
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Jun Zhang
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, China
| | - Jianghui Xu
- Department of Anesthesiology, Fudan University Shanghai Cancer Center, 200032, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, 200032, Shanghai, 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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Kästle S, Stechele MR, Richter L, Schinner R, Öcal E, Alunni-Fabbroni M, De Toni E, Corradini S, Seidensticker M, Goldberg SN, Ricke J, Wildgruber M, Kimm MA. Peripheral blood-based cell signature indicates response to interstitial brachytherapy in primary liver cancer. J Cancer Res Clin Oncol 2023; 149:9777-9786. [PMID: 37247078 PMCID: PMC10423129 DOI: 10.1007/s00432-023-04875-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: 04/25/2023] [Accepted: 05/19/2023] [Indexed: 05/30/2023]
Abstract
PURPOSE Biomarkers are essential to implement personalized therapies in cancer treatment options. As primary liver tumors are increasing and treatment is coupled to liver function and activation of systemic cells of the immune system, we investigated blood-based cells for their ability to predict response to local ablative therapy. METHODS We analyzed peripheral blood cells in 20 patients with primary liver cancer at baseline and following brachytherapy. In addition to platelets, leukocytes, lymphocytes, monocytes, neutrophils and most common ratios PLR, LMR, NMR and NLR, we investigated T cell and NKT cell populations of 11 responders and 9 non-responders using flow cytometry. RESULTS We have found a peripheral blood cell signature that differed significantly between responders and non-responders treated with interstitial brachytherapy (IBT). At baseline, non-responders featured higher numbers of platelets, monocytes and neutrophils, a higher platelet-to-lymphocyte ratio and an increase in the NKT cell population with a concurrent reduction in CD16 + NKT cells. Simultaneously, a lower percentage of CD4 + T cells was present in non-responders, as also reflected in a lower CD4/8 ratio. CD45RO + memory cells were lower in both, CD4 + and CD8 + T cell populations whereas PD-1 + T cells were only present in the CD4 + T cell population. CONCLUSION Baseline blood-based cell signature may function as a biomarker to predict response following brachytherapy in primary liver cancer.
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Affiliation(s)
- Sophia Kästle
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | | | - Lisa Richter
- Core Facility Flow Cytometry, Biomedical Center Munich, Ludwig-Maximilians-Universität München, Planegg-Martinsried, Germany
| | - Regina Schinner
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Elif Öcal
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | | | - Enrico De Toni
- Department of Medicine II, University Hospital, LMU Munich, Munich, Germany
| | - Stefanie Corradini
- Department of Radiation Oncology, University Hospital, LMU Munich, Munich, Germany
| | - Max Seidensticker
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - S Nahum Goldberg
- Goldyne Savad Institute of Gene Therapy, Hadassah Hebrew University Hospital, Jerusalem, Israel
- Laboratory for Minimally Invasive Tumor Therapies, Department of Radiology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
- Division of Image-Guided Therapy and Interventional Oncology, Department of Radiology, Hadassah Hebrew University Hospital, Jerusalem, Israel
| | - Jens Ricke
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Moritz Wildgruber
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany
| | - Melanie A Kimm
- Department of Radiology, University Hospital, LMU Munich, Munich, Germany.
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Varela S, Puentes H, Moya A, Kazim SF, Couldwell WT, Schmidt MH, Bowers CA. Preoperative Laboratory Values Are Predictive of Adverse Postoperative Outcomes in Patients Older Than 65 Years Undergoing Brain Tumor Resection: A National Surgical Quality Improvement Program Study. World Neurosurg 2023; 176:e49-e59. [PMID: 36972900 DOI: 10.1016/j.wneu.2023.03.086] [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: 01/11/2023] [Revised: 03/20/2023] [Accepted: 03/21/2023] [Indexed: 03/29/2023]
Abstract
OBJECTIVE In this study, we used a large national database to assess the effect of preoperative laboratory value (PLV) derangements on postoperative outcomes in patients older than 65 years undergoing brain tumor resection. METHODS Data was collected for patients >65 years old undergoing brain tumor resection from 2015 to 2019 (N = 10,525). Univariate and multivariate analysis were performed for 11 PLVs and 6 postoperative outcomes. RESULTS Hypernatremia (odds ratio [OR], 4.707; 95% confidence interval [CI], 1.695-13.071; P < 0.01) and increased creatinine level (OR, 2.556; 95% CI, 1.291-5.060; P < 0.01) were the most significant predictors of 30-day mortality. The most significant predictor of Clavien-Dindo grade IV complications was increased creatinine level (OR, 1.667; 95% CI, 1.064-2.613; P < 0.05), whereas, significant predictors of major complications were hypoalbuminemia (OR, 1.426; 95% CI, 1.132-1.796; P < 0.05) and leukocytosis (OR, 1.347; 95% CI, 1.075-1.688; P < 0.05). Predictors of readmission were anemia (OR, 1.326; 95% CI, 1.047-1.680; P < 0.05) and thrombocytopenia (OR, 1.387; 95% CI, 1.037-1.856; P < 0.05), whereas, hypoalbuminemia (OR, 1.787; 95% CI, 1.280-2.495; P < 0.001) was predictive of reoperation. Increased partial thromboplastin time and hypoalbuminemia were predictors of extended length of stay (OR, 2.283, 95% CI, 1.360-3.834, P < 0.01 and OR, 1.553, 95% CI, 1.553-1.966, P < 0.001, respectively). Hypernatremia (OR, 2.115; 95% CI, 1.181-3.788; P < 0.05) and hypoalbuminemia (OR, 1.472; 95% CI, 1.239-1.748; P < 0.001) were the most significant predictors of NHD. Seven of 11 PLVs were associated with adverse postoperative outcomes. CONCLUSIONS PLV derangements were significantly associated with adverse postoperative outcomes in patients older than 65 years undergoing brain tumor resection. The most significant predictors of adverse postoperative outcomes were hypoalbuminemia and leukocytosis.
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Affiliation(s)
- Samantha Varela
- School of Medicine, University of New Mexico (UNM), Albuquerque, New Mexico, USA
| | - Hansell Puentes
- Burrell College of Osteopathic Medicine, Las Cruces, New Mexico, USA
| | - Addi Moya
- School of Medicine, University of New Mexico (UNM), Albuquerque, New Mexico, USA
| | - Syed Faraz Kazim
- Department of Neurosurgery, University of New Mexico Hospital (UNMH), Albuquerque, New Mexico, USA
| | - William T Couldwell
- Department of Neurosurgery, Clinical Neurosciences Center, University of Utah, Salt Lake City, Utah, USA
| | - Meic H Schmidt
- Department of Neurosurgery, University of New Mexico Hospital (UNMH), Albuquerque, New Mexico, USA
| | - Christian A Bowers
- Department of Neurosurgery, University of New Mexico Hospital (UNMH), Albuquerque, New Mexico, USA.
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Li R, Huang B, Tian H, Sun Z. Immune evasion in esophageal squamous cell cancer: From the perspective of tumor microenvironment. Front Oncol 2023; 12:1096717. [PMID: 36698392 PMCID: PMC9868934 DOI: 10.3389/fonc.2022.1096717] [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: 11/12/2022] [Accepted: 12/19/2022] [Indexed: 01/12/2023] Open
Abstract
Esophageal cancer (EC) is one of the most life-threatening malignancies worldwide. Esophageal squamous cell carcinoma (ESCC) is the dominant subtype, accounting for approximately 90% of new incident EC each year. Although multidisciplinary treatment strategies have advanced rapidly, patients with ESCC are often diagnosed at advanced stage and the long-term prognosis remains unsatisfactory. In recent decades, immunotherapy, such as immune checkpoint inhibitors (ICIs), tumor vaccines, and chimeric antigen receptor T-cell (CAR-T) therapy, has been successfully used in clinical practice as a novel therapy for treating tumors, bringing new hope to ESCC patients. However, only a small fraction of patients achieved clinical benefits due to primary or acquired resistance. Immune evasion plays a pivotal role in the initiation and progression of ESCC. Therefore, a thorough understanding of the mechanisms by which ESCC cells escape from anti-tumor immunity is necessary for a more effective multidisciplinary treatment strategy. It has been widely recognized that immune evasion is closely associated with the crosstalk between tumor cells and the tumor microenvironment (TME). TME is a dynamic complex and comprehensive system including not only cellular components but also non-cellular components, which influence hallmarks and fates of tumor cells from the outside. Novel immunotherapy targeting tumor-favorable TME represents a promising strategy to achieve better therapeutic responses for patients with ESCC. In this review, we provide an overview of immune evasion in ESCC, mainly focusing on the molecular mechanisms that underlie the role of TME in immune evasion of ESCC. In addition, we also discuss the challenges and opportunities of precision therapy for ESCC by targeting TME.
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Okamoto M, Mizuno R, Kawada K, Itatani Y, Kiyasu Y, Hanada K, Hirata W, Nishikawa Y, Masui H, Sugimoto N, Tamura T, Inamoto S, Sakai Y, Obama K. Neutrophil Extracellular Traps Promote Metastases of Colorectal Cancers through Activation of ERK Signaling by Releasing Neutrophil Elastase. Int J Mol Sci 2023; 24:ijms24021118. [PMID: 36674635 PMCID: PMC9867023 DOI: 10.3390/ijms24021118] [Citation(s) in RCA: 21] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/06/2022] [Revised: 12/30/2022] [Accepted: 01/04/2023] [Indexed: 01/11/2023] Open
Abstract
Neutrophil extracellular traps (NETs) play important roles in host immunity, as there is increasing evidence of their contribution to the progression of several types of cancers even though their role in colorectal cancers (CRCs) remains unclear. To investigate the clinical relevance of NETs in CRCs, we examined the expression of citrullinated histone H3 using immunohistochemistry and preoperative serum myeloperoxidase-DNA complexes in CRC patients using an enzyme-linked immunosorbent assay. High expression of intratumoral or systemic NETs was found to correlate with poor relapse-free survival (RFS), for which it is an independent prognostic factor. In vitro investigations of CRC cells (HCT116, HT29) revealed that NETs did not affect their proliferation but did promote the migration of CRC cells mediated by neutrophil elastase (NE) released during NETosis to increase extracellular signal-regulated kinase (ERK) activity. In vivo experiments using nude mice (KSN/slc) revealed that NE inhibition suppressed liver metastases in CRC cells, although it did not affect the growth of subcutaneously implanted tumors. Taken together, these results suggest that NET formation correlates with poor prognoses of patients with CRC and that the inhibition of NE could be a potential therapy for CRC metastases.
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Affiliation(s)
- Michio Okamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Rei Mizuno
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Uji-Tokushukai Medical Center, Kyoto 611-0041, Japan
- Correspondence: ; Tel.: +81-75-751-3445
| | - Kenji Kawada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Kurashiki Central Hospital, Okayama 710-8602, Japan
| | - Yoshiro Itatani
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Yoshiyuki Kiyasu
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Rogel Cancer Center, University of Michigan, Ann Arbor, MI 48109, USA
| | - Keita Hanada
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Wataru Hirata
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Yasuyo Nishikawa
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Hideyuki Masui
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Naoko Sugimoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Takuya Tamura
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
| | - Susumu Inamoto
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Japanese Red Cross Osaka Hospital, Osaka 543-8555, Japan
| | - Yoshiharu Sakai
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
- Department of Surgery, Japanese Red Cross Osaka Hospital, Osaka 543-8555, Japan
| | - Kazutaka Obama
- Department of Surgery, Graduate School of Medicine, Kyoto University, Kyoto 606-8501, Japan
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Liang L, Liu F, Yang W, Yang W, Chen L, He Y, Liu Z, Zhang L, Zhang F, Cai F, Xu H, Lin M, Liu M, Pan Y, Liu Y, Hu Z, Chen H, He Z, Ke Y. Combined Mean Corpuscular Hemoglobin, Fibrinogen, and Albumin (MF-A) Is a Novel Prognostic Marker in Patients with Resectable Esophageal Squamous Cell Carcinoma. Ann Surg Oncol 2022; 29:5626-5633. [PMID: 35181817 DOI: 10.1245/s10434-022-11415-5] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/20/2021] [Accepted: 01/18/2022] [Indexed: 02/05/2023]
Abstract
BACKGROUND The aim was to systematically select blood markers routinely tested in clinical settings, which are independently associated with overall survival (OS) and are able to stratify prognosis of esophageal squamous cell carcinoma (ESCC) patients undergoing esophagectomy. METHODS We selected optimal blood markers for prognostic stratification from 60 candidates in a clinical cohort of 1819 consecutive patients with resectable ESCC in China. Selection was carried out using two-step multivariable Cox proportional hazards regression adjusted for multifaceted confounders. A composite index was developed by multiplying risk factors and dividing them by protective factors. RESULTS With a median follow-up of 48.07 months, 641 deaths occurred in the 1819 patients and the 5-year OS was 56.30%. Two risk factors (mean corpuscular hemoglobin, fibrinogen) and a protective factor (albumin), all dichotomized and assigned values 1 and 2, were used to construct the composite index marker "MF-A". Three risk groups were created based on the MF-A score including low- (0.5), moderate- (1), and high-risk groups (2 and 4). Compared with patients in the low-risk group (1184/1778, 66.59%), those in the moderate- (488, 27.45%), and high-risk (106, 5.96%) groups were at elevated risk of death (adjusted HR: 1.32, 95% CI: 1.11-1.57; adjusted HR: 2.08, 95% CI: 1.56-2.75; Ptrend < 10-7). Within each TNM stage grouping, OS also trended to be significantly worse as the MF-A score increased. CONCLUSIONS "MF-A" is a novel independent predictor which may be used to estimate and stratify prognosis for ESCC patients undergoing esophagectomy.
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Affiliation(s)
- Linlin Liang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Fangfang Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Wenlei Yang
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Wei Yang
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Lei Chen
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Yu He
- Department of Non-Communicable Disease Epidemiology, London School of Hygiene & Tropical Medicine, London, UK
| | - Zhen Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Liqun Zhang
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Fan Zhang
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Fen Cai
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Huawen Xu
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Miaoping Lin
- Cancer Hospital of Shantou University Medical College, Shantou City, People's Republic of China
| | - Mengfei Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Yaqi Pan
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Ying Liu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Zhe Hu
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Huanyu Chen
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Zhonghu He
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
| | - Yang Ke
- Key laboratory of Carcinogenesis and Translational Research (Ministry of Education/Beijing), Laboratory of Genetics, Peking University Cancer Hospital & Institute, Beijing, People's Republic of China
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10
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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: 18] [Impact Index Per Article: 6.0] [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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11
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Weng M, Zhao W, Yue Y, Guo M, Nan K, Liao Q, Sun M, Zhou D, Miao C. High preoperative white blood cell count determines poor prognosis and is associated with an immunosuppressive microenvironment in colorectal cancer. Front Oncol 2022; 12:943423. [PMID: 35965545 PMCID: PMC9373020 DOI: 10.3389/fonc.2022.943423] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2022] [Accepted: 07/06/2022] [Indexed: 12/24/2022] Open
Abstract
Background The correlation between high white blood cell (WBC) count and poor prognosis has been identified in various types of cancer; however, the clinical significance and immune context of WBC count in colorectal cancer remains unclear. Methods Between February 2009 and November 2014, 7,433 patients at the Shanghai Cancer Center who had undergone elective surgery for colorectal cancer were enrolled in this retrospective cohort study. Patients were divided into two groups: low and high preoperative WBC groups. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan-Meier method and Cox regression analysis were used to identify independent prognostic factors in colorectal cancer patients. Tumor-infiltrating immune cells in the high and low preoperative WBC groups were compared using immunohistochemical staining. Results Of the 7,433 patients who underwent colorectal cancer surgery and were available for analysis, 5,750 were included in the low preoperative WBC group, and 1,683 were included in the high preoperative WBC group. After propensity score matching, 1,553 patients were included in each group. Kaplan-Meier survival curves showed that a high preoperative WBC count was associated with a decreased overall survival (P = 0.002) and disease-free survival (P = 0.003), and that preoperative WBC count was an independent risk factor for overall survival (hazard ratio, 1.234; 95% confidence interval, 1.068-1.426; P = 0.004) and disease-free survival (hazard ratio, 1.210; 95% confidence interval, 1.047-1.397, P = 0.01). Compared to the low preoperative WBC group, the high preoperative WBC group exhibited higher expression of regulatory T cells (P = 0.0034), CD68+ macrophages (P = 0.0071), and CD66b+ neutrophils (P = 0.0041); increased expression of programmed cell death protein 1 (P = 0.005) and programmed cell death ligand 1 (P = 0.0019); and lower expression of CD8+ T cells (P = 0.0057) in colorectal cancer patients. Conclusions Our research indicates that a high preoperative WBC count is a prognostic indicator in colorectal cancer patients and is associated with an immunosuppressive tumor microenvironment, which could aid in future risk stratification.
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Affiliation(s)
- Meilin Weng
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Wenling Zhao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Ying Yue
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Miaomiao Guo
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Ke Nan
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Qingwu Liao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Minli Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Di Zhou
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Fudan University, Shanghai, China
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12
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Weng M, Yue Y, Wu D, Zhou C, Guo M, Sun C, Liao Q, Sun M, Zhou D, Miao C. Increased MPO in Colorectal Cancer Is Associated With High Peripheral Neutrophil Counts and a Poor Prognosis: A TCGA With Propensity Score-Matched Analysis. Front Oncol 2022; 12:940706. [PMID: 35912260 PMCID: PMC9331745 DOI: 10.3389/fonc.2022.940706] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/10/2022] [Accepted: 06/09/2022] [Indexed: 12/26/2022] Open
Abstract
Background Myeloperoxidase (MPO) has been demonstrated to be a local mediator of inflammation in tissue damage in various inflammatory diseases. Given its controversial effect on colorectal cancer (CRC), there has been growing interest in investigating the role of this enzyme in CRC. The mechanism underlying MPO activity and CRC progression requires further clarification. Methods The expression and function of MPO in CRC were evaluated using TCGA analysis. TCGA, TIMER, and Human Cell Landscape analyses were used to analyze the correlation between MPO expression and neutrophil infiltration in CRC. Spearman's bivariate correlation analysis was used to verify the correlation between MPO levels in CRC and the peripheral neutrophil count. In the clinical analysis, 8,121 patients who underwent elective surgery for CRC were enrolled in this retrospective cohort study from January 2008 to December 2014. Propensity score matching was used to address the differences in baseline characteristics. The Kaplan-Meier method and Cox regression analysis were used to identify independent prognostic factors in patients with CRC. Results MPO was upregulated in CRC tissues, which is related to malignant progression and worse survival in CRC patients from TCGA analysis. MPO was significantly correlated with the infiltration level of neutrophils in CRC in TCGA, TIMER, and Human Cell Landscape analyses. MPO was positively correlated with the peripheral neutrophil count. Data of the 8,121 patients who underwent CRC surgery were available for analysis. After propensity score matching, 3,358 patients were included in each group. Kaplan-Meier survival curves showed that high preoperative neutrophil levels were associated with decreased overall survival (OS; P < 0.001) and disease-free survival (DFS; P = 0.015). The preoperative neutrophil count was an independent risk factor for OS (hazard ratio [HR], 1.157; 95% confidence interval [CI], 1.055-1.268; P = 0.002) and DFS (HR, 1.118; 95% CI, 1.009-1.238; P = 0.033). Conclusions Our research indicates that increased MPO levels in CRC are significantly correlated with high preoperative neutrophil counts, and both serve as prognostic indicators for worse survival in CRC patients. Our study suggests that neutrophils may be key players in the mechanism linking MPO levels with poor CRC outcomes.
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Affiliation(s)
- Meilin Weng
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Department of Anesthesiology, Shanghai Cancer Center, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Ying Yue
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Dan Wu
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Changming Zhou
- Department of Cancer Prevention, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Miaomiao Guo
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Caihong Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Qingwu Liao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Minli Sun
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Di Zhou
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Changhong Miao
- Department of Anesthesiology, Zhongshan Hospital, Fudan University, Shanghai, China
- Shanghai Key Laboratory of Perioperative Stress and Protection, Zhongshan Hospital, Fudan University, Shanghai, China
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13
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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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14
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Shen XT, Xie SZ, Xu J, Yang LY, Qin LX. Pan-Cancer Analysis Reveals a Distinct Neutrophil Extracellular Trap-Associated Regulatory Pattern. Front Immunol 2022; 13:798022. [PMID: 35432310 PMCID: PMC9009150 DOI: 10.3389/fimmu.2022.798022] [Citation(s) in RCA: 24] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2021] [Accepted: 03/09/2022] [Indexed: 12/12/2022] Open
Abstract
Background Neutrophils form extracellular net-like structures called neutrophil extracellular traps (NETs). Emerging evidence has shown that cancer can induce NET formation; however, it is not fully understood how NETs influence cancer biology, and no consensus has been reached on their pro- or antitumor effects. A comprehensive analysis of the global NET-associated gene regulatory network is currently unavailable and is urgently needed. Methods We systematically explored and discussed NET enrichment, NET-associated gene regulatory patterns, and the prognostic implications of NETs in approximately 8,000 patients across 22 major human cancer types. We identified NET-associated regulatory gene sets that we then screened for NET-associated regulatory patterns that might affect patient survival. We functionally annotated the NET-associated regulatory patterns to compare the biological differences between NET-related survival subgroups. Results A gene set variation analysis (GSVA) based on 23 major component genes was used to calculate a metric called the NET score. We found that the NET score was closely associated with many important cancer hallmarks, particularly inflammatory responses and epithelial-to-mesenchymal transition (EMT)-induced metastasis. Higher NET scores were related to poor immunotherapy response. Survival analysis revealed that NETs had diverse prognostic impacts among various cancer types. The NET-associated regulatory patterns linked to shorter or longer cancer patient survival were distinct from each other. Functional analysis revealed that more of the NET-associated regulatory genes linked to poor cancer survival were associated with extracellular matrix (ECM) remodeling and pan-cancerous risk factors. SPP1 was found to be highly expressed and correlated with NET formation in cancers with poor survival. We also found that the co-upregulation of NET formation and SPP1 expression was closely linked to increased EMT and poor survival, that SPP1 influenced NET-induced malignant capacity, and that SPP1 overproduction induced a robust formation of metastatic-promoting NETs. Conclusion NETs were common across cancers but displayed a diverse regulatory pattern and outcome readouts in different cancer types. SPP1 is potentially the key to NET-related poor outcomes.
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Affiliation(s)
- Xiao-Tian Shen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Sun-Zhe Xie
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Jing Xu
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
| | - Lu-Yu Yang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
- *Correspondence: Lun-Xiu Qin, ; Lu-Yu Yang,
| | - Lun-Xiu Qin
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
- Cancer Metastasis Institute, Fudan University, Shanghai, China
- *Correspondence: Lun-Xiu Qin, ; Lu-Yu Yang,
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15
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De Meo ML, Spicer JD. The role of neutrophil extracellular traps in cancer progression and metastasis. Semin Immunol 2022; 57:101595. [DOI: 10.1016/j.smim.2022.101595] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/25/2021] [Revised: 01/05/2022] [Accepted: 01/18/2022] [Indexed: 02/08/2023]
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16
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Wolach O, Martinod K. Casting a NET on cancer: the multiple roles for neutrophil extracellular traps in cancer. Curr Opin Hematol 2022; 29:53-62. [PMID: 34854835 DOI: 10.1097/moh.0000000000000690] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
PURPOSE OF REVIEW The role of the innate immune system has become widely appreciated in cancer and cancer-associated disorders. Neutrophils, the most abundant circulating leukocytes, have prognostic value in determining cancer progression and survival. One of the ways by which neutrophils negatively impact outcome is by formation of neutrophil extracellular traps (NETs) which result in release of nuclear chromatin and bioactive proteins into the extracellular space. Here, we review the evidence for NETs contributions to cancer progression, metastasis, and cancer-associated thrombosis (CAT). RECENT FINDINGS NETs are increased across several cancer types and predict progression and adverse outcome. Several preclinical and clinical observations implicate NETs in promoting tumor growth, angiogenesis and metastasis via distinct pathways. Furthermore, NETs are shown to contribute to resistance to immunotherapy. NETs also emerge as key players in the prothrombotic phenotype associated with cancer that can result in potentially life-threatening arterial and venous thrombosis. Recent mechanistic insights expose several potential targets to inhibit NET formation and disrupt the interaction between NETs and tumor cells. SUMMARY Clinical and translational insights highlight the central role of NETs in cancer progression and metastasis, disease resistance and CAT. Targeting NETs and NET-associated pathways may represent a novel approach to treat cancer.
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Affiliation(s)
- Ofir Wolach
- Institute of Hematology, Davidoff Cancer Center, Rabin Medical Center, Petah-Tikva
- Sackler Faculty of Medicine, Tel-Aviv University, Tel Aviv, Israel
| | - Kimberly Martinod
- Center for Molecular and Vascular Biology, Department of Cardiovascular Sciences, KU Leuven, Leuven, Belgium
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17
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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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18
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Ramirez MF, Cata JP. Anesthetic care influences long-term outcomes: What is the evidence? Best Pract Res Clin Anaesthesiol 2021; 35:491-505. [PMID: 34801212 DOI: 10.1016/j.bpa.2021.01.004] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/21/2021] [Accepted: 01/27/2021] [Indexed: 10/22/2022]
Abstract
Despite advances in cancer therapy surgery remains one of the most important treatments for solid tumors; however, even with the development of better and less invasive surgical techniques, surgery is characterized by the increased risk of tumor metastasis, accelerated growth of pre-existing micrometastasis and cancer recurrence. Total intravenous anesthesia (TIVA) and regional anesthesia have been proposed to improve long-term outcomes after cancer surgery by different mechanisms, including attenuation of the neuroendocrine response, immunosuppression, decreased opioid requirements (opioids promote angiogenesis and tumor growth) and avoidance of volatile inhalational agents. Much of the data that support these ideas originate from laboratory studies, while there is no clear consensus from the retrospective cohort studies to date. Several randomized controlled trials (RCTs) are in progress and may provide a better understanding regarding the role of the anesthesiologist in cancer surgery. The purpose of this review is to summarize the experimental and human data regarding the effect of anesthesia agents and anesthesia techniques on cancer outcomes.
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Affiliation(s)
- M F Ramirez
- Department of Anesthesiology and Perioperative Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA
| | - J P Cata
- Department of Anesthesiology and Perioperative Medicine, The University of Texas, MD Anderson Cancer Center, Houston, TX, USA; Anesthesiology and Surgical Oncology Research Group, Houston, TX, USA.
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19
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Chu ZQ, Zhang KC, Chen L. Neutrophil extracellular traps in gastrointestinal cancer. World J Gastroenterol 2021; 27:5474-5487. [PMID: 34588746 PMCID: PMC8433615 DOI: 10.3748/wjg.v27.i33.5474] [Citation(s) in RCA: 14] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 04/06/2021] [Accepted: 08/11/2021] [Indexed: 02/06/2023] Open
Abstract
Gastrointestinal (GI) cancer is a high-risk malignancy and is characterized by high mortality and morbidity worldwide. Neutrophil extracellular traps (NETs), a weblike structure consisting of chromatin DNA with interspersed cytoplasmic and granule proteins, are extruded by activated neutrophils to entrap and kill bacteria and fungi. However, accumulating evidence shows that NETs are related to the progression and metastasis of cancer. In clinical studies, NETs infiltrate primary GI cancer tissues and are even more abundant in metastatic lesions. The quantity of NETs in peripheral blood is revealed to be associated with ascending clinical tumour stages, indicating the role of NETs as a prognostic markers in GI cancer. Moreover, several inhibitors of NETs or NET-related proteins have been discovered and used to exert anti-tumour effects in vitro or in vivo, suggesting that NETs can be regarded as targets in the treatment of GI cancer. In this review, we will focus on the role of NETs in gastric cancer and colorectal cancer, generalizing their effects on tumour-related thrombosis, invasion and metastasis. Recent reports are also listed to show the latest evidences of how NETs affect GI cancer. Additionally, notwithstanding the scarcity of systematic studies elucidating the underlying mechanisms of the interaction between NETs and cancer cells, we highlight the potential importance of NETs as biomarkers and anti-tumour therapeutic targets.
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Affiliation(s)
- Zi-Qiang Chu
- Graduate School, Chinese PLA General Hospital, Beijing 100853, China
- Institute of Basic Medical Sciences, Chinese PLA General Hospital, Beijing 100853, China
| | - Ke-Cheng Zhang
- Department of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing 100853, China
| | - Lin Chen
- Department of General Surgery, Chinese PLA General Hospital First Medical Center, Beijing 100853, China
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Raigon Ponferrada A, Guerrero Orriach JL, Molina Ruiz JC, Romero Molina S, Gómez Luque A, Cruz Mañas J. Breast Cancer and Anaesthesia: Genetic Influence. Int J Mol Sci 2021; 22:7653. [PMID: 34299272 PMCID: PMC8307639 DOI: 10.3390/ijms22147653] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/28/2021] [Revised: 07/05/2021] [Accepted: 07/06/2021] [Indexed: 12/20/2022] Open
Abstract
Breast cancer is the leading cause of mortality in women. It is a heterogeneous disease with a high degree of inter-subject variability even in patients with the same type of tumor, with individualized medicine having acquired significant relevance in this field. The clinical and morphological heterogeneity of the different types of breast tumors has led to a diversity of staging and classification systems. Thus, these tumors show wide variability in genetic expression and prognostic biomarkers. Surgical treatment is essential in the management of these patients. However, the perioperative period has been found to significantly influence survival and cancer recurrence. There is growing interest in the pro-tumoral effect of different anaesthetic and analgesic agents used intraoperatively and their relationship with metastatic progression. There is cumulative evidence of the influence of anaesthetic techniques on the physiopathological mechanisms of survival and growth of the residual neoplastic cells released during surgery. Prospective randomized clinical trials are needed to obtain quality evidence on the relationship between cancer and anaesthesia. This document summarizes the evidence currently available about the effects of the anaesthetic agents and techniques used in primary cancer surgery and long-term oncologic outcomes, and the biomolecular mechanisms involved in their interaction.
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Affiliation(s)
- Aida Raigon Ponferrada
- Institute of Biomedical Research in Malaga (IBIMA), 29010 Malaga, Spain; (A.R.P.); (A.G.L.)
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
| | - Jose Luis Guerrero Orriach
- Institute of Biomedical Research in Malaga (IBIMA), 29010 Malaga, Spain; (A.R.P.); (A.G.L.)
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
- Department of Pharmacology and Pediatrics, School of Medicine, University of Malaga, 29010 Malaga, Spain
| | - Juan Carlos Molina Ruiz
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
| | - Salvador Romero Molina
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
| | - Aurelio Gómez Luque
- Institute of Biomedical Research in Malaga (IBIMA), 29010 Malaga, Spain; (A.R.P.); (A.G.L.)
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
- Department of Pharmacology and Pediatrics, School of Medicine, University of Malaga, 29010 Malaga, Spain
| | - Jose Cruz Mañas
- Department of Anaesthesiology, Virgen de la Victoria University Hospital, 29010 Malaga, Spain; (J.C.M.R.); (S.R.M.); (J.C.M.)
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Abu-Zaid A, Alomar O, Baradwan S, Abuzaid M, Alshahrani MS, Allam HS, Alqarni SMS, Nazer A, Salem H, Al-Badawi IA. Preoperative leukocytosis correlates with unfavorable pathological and survival outcomes in endometrial carcinoma: A systematic review and meta-analysis. Eur J Obstet Gynecol Reprod Biol 2021; 264:88-96. [PMID: 34298450 DOI: 10.1016/j.ejogrb.2021.07.022] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2021] [Revised: 07/08/2021] [Accepted: 07/10/2021] [Indexed: 12/24/2022]
Abstract
AIM To meta-analytically examine the frequency and prognostic impact of preoperative leukocytosis in endometrial carcinoma (EC). METHODS Five major databases were searched till 01-February-2021. Studies that evaluated the frequency of preoperative leukocytosis or its correlation with pathological and survival outcomes in EC patients were included. Data were pooled as mean differences (MD), odds ratios (OR), or hazard ratios (HR) with 95% confidence intervals. RESULTS Nine retrospective studies, with low risk of bias, were included. The pooled prevalence of preoperative leukocytosis was 11.2% (95% CI: 8.2-14.3). There was a significant correlation between preoperative leukocytosis and FIGO stage III-IV (OR = 2.10, 95% CI: 1.60-2.75), ≥50% myometrial invasion (OR = 1.32, 95% CI: 1.02-1.72), lymph node involvement (OR = 1.83, 95% CI: 1.29-2.59), cervical involvement (OR = 2.29, 95% CI: 1.68-3.13), adnexal involvement (OR = 2.17, 95% CI: 1.42-3.31), and tumor size (MD = 1.10 cm, 95% CI: 0.63-1.58). However, preoperative leukocytosis did not significantly correlate with tumor grade II-III, non-endometrioid histology, peritoneal cytology, and lympho-vascular space involvement (p > 0.05). Additionally, preoperative leukocytosis correlated with higher rates of death (OR = 2.85, 95% CI: 2.03-4.00), tumor recurrence (OR = 2.36, 95% CI: 1.21-4.61), and worse overall survival at univariate and multivariate analyses (HR = 2.90, 95% CI: 2.24-3.75 and HR = 2.16, 95% CI: 1.59-2.94, respectively). As for disease-free survival, preoperative leukocytosis emerged as an independent prognostic factor on univariate (HR = 1.27, 95% CI: 1.16-1.39) but not multivariate (HR = 1.08, 95% CI: 1.00-1.18) analyses. CONCLUSIONS Preoperative leukocytosis is common and correlates with poor pathological and survival outcomes in EC patients.
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Affiliation(s)
- Ahmed Abu-Zaid
- Department of Obstetrics and Gynecology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; College of Graduate Health Sciences, University of Tennessee Health Science Center, Memphis, TN, USA.
| | - Osama Alomar
- Department of Obstetrics and Gynecology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Saeed Baradwan
- Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Jeddah, Saudi Arabia
| | - Mohammed Abuzaid
- Department of Obstetrics and Gynecology, King Fahad Medical City, Riyadh, Saudi Arabia
| | - Majed Saeed Alshahrani
- Department of Obstetrics and Gynecology, Faulty of Medicine, Najran University, Najran, Saudi Arabia
| | - Hassan Saleh Allam
- Department of Obstetrics and Gynecology, Prince Sultan Military Medical City, Riyadh, Saudi Arabia; Department of Obstetrics and Gynecology, Faculty of Medicine in Rabigh, King Abdulaziz University, Rabigh, Saudi Arabia.
| | - Saad Mohammed S Alqarni
- Department of Obstetrics and Gynecology, Abha Maternity and Children Hospital, Abha, Saudi Arabia
| | - Ahmed Nazer
- Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
| | - Hany Salem
- Department of Obstetrics and Gynecology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia.
| | - Ismail Abdulrahman Al-Badawi
- Department of Obstetrics and Gynecology, College of Medicine, Alfaisal University, Riyadh, Saudi Arabia; Department of Obstetrics and Gynecology, King Faisal Specialist Hospital and Research Centre, Riyadh, Saudi Arabia
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