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Guan X, Guan X, Zhao Z, Yan H. NETs: Important players in cancer progression and therapeutic resistance. Exp Cell Res 2024; 441:114191. [PMID: 39094902 DOI: 10.1016/j.yexcr.2024.114191] [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: 04/21/2024] [Revised: 07/19/2024] [Accepted: 07/28/2024] [Indexed: 08/04/2024]
Abstract
Neutrophil extracellular traps (NETs) are web-like structures composed of cytoplasmic contents, DNA chromatin and various granular proteins released by neutrophils in response to viruses, bacteria, immune complexes and cytokines. Studies have shown that NETs can promote the occurrence, development and metastasis of tumors. In this paper, the mechanism underlying the formation and degradation of NETs and the malignant biological behaviors of NETs, such as the promotion of tumor cell proliferation, epithelial mesenchymal transition, extracellular matrix remodeling, angiogenesis, immune evasion and tumor-related thrombosis, are described in detail. NETs are being increasingly studied as therapeutic targets for tumors. We have summarized strategies for targeting NETs or interfering with NET-cancer cell interactions and explored the potential application value of NETs as biomarkers in cancer diagnosis and treatment, as well as the relationship between NETs and therapeutic resistance.
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Affiliation(s)
- Xiaoying Guan
- Pathology Department, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Xiaoli Guan
- General Medicine Department, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Zhiqiang Zhao
- Pathology Department, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China
| | - Hong Yan
- Pathology Department, The Second Hospital & Clinical Medical School, Lanzhou University, Lanzhou, 730030, Gansu, China.
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Targeting TRAIL Death Receptors in Triple-Negative Breast Cancers: Challenges and Strategies for Cancer Therapy. Cells 2022; 11:cells11233717. [PMID: 36496977 PMCID: PMC9739296 DOI: 10.3390/cells11233717] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2022] [Revised: 11/11/2022] [Accepted: 11/18/2022] [Indexed: 11/23/2022] Open
Abstract
The tumor necrosis factor (TNF) superfamily member TNF-related apoptosis-inducing ligand (TRAIL) induces apoptosis in cancer cells via death receptor (DR) activation with little toxicity to normal cells or tissues. The selectivity for activating apoptosis in cancer cells confers an ideal therapeutic characteristic to TRAIL, which has led to the development and clinical testing of many DR agonists. However, TRAIL/DR targeting therapies have been widely ineffective in clinical trials of various malignancies for reasons that remain poorly understood. Triple negative breast cancer (TNBC) has the worst prognosis among breast cancers. Targeting the TRAIL DR pathway has shown notable efficacy in a subset of TNBC in preclinical models but again has not shown appreciable activity in clinical trials. In this review, we will discuss the signaling components and mechanisms governing TRAIL pathway activation and clinical trial findings discussed with a focus on TNBC. Challenges and potential solutions for using DR agonists in the clinic are also discussed, including consideration of the pharmacokinetic and pharmacodynamic properties of DR agonists, patient selection by predictive biomarkers, and potential combination therapies. Moreover, recent findings on the impact of TRAIL treatment on the immune response, as well as novel strategies to address those challenges, are discussed.
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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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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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