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Veronez LC, Silveira DSCD, Lopes-Júnior LC, Dos Santos JC, Barbisan LF, Pereira-da-Silva G. Jacalin Attenuates Colitis-Associated Colorectal Carcinogenesis by Inhibiting Tumor Cell Proliferation and Intestinal Inflammation. Inflamm Bowel Dis 2025; 31:1344-1354. [PMID: 39745886 DOI: 10.1093/ibd/izae303] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/28/2024] [Indexed: 01/04/2025]
Abstract
BACKGROUND Colorectal cancer (CRC) remains a significant cause of morbidity and mortality worldwide. In patients with inflammatory bowel disease, who have twice the risk of developing CRC, chronic inflammation has been recognized to contribute to colitis-associated cancer (CAC) development. Jacalin, a lectin extracted from jackfruit seeds, has been shown to recognize altered glycosylation and to exert antiproliferative and cytotoxic effects in CRC. However, its activity in CAC remains unknown. Herein, we sought to investigate the effects of jacalin in CAC progression using the dextran sulfate sodium (DSS) and azoxymethane (AOM) mouse model. METHODS Colitis-associated cancer induction was performed in male C57BL/6 mice by an intraperitoneal injection of AOM, followed by 3 cycles of 2.5% DSS diluted in drinking water for 7 days, intercalated by 2 weeks of normal drinking water. After 1 week of daily pretreatment, mice were orally treated with phosphate-buffered saline (control group), 100 or 500 µg of jacalin three times a week for an additional 11 weeks. RESULTS We showed that jacalin-treated mice presented tumors with reduced volumes and mean size compared to the control group. In addition, both doses of jacalin reduced the number of proliferating cells (Ki-67 positive cells) in tumor tissues, while the higher dose (500 µg) showed also a similar effect in "normal-appearing" colonic crypts. Jacalin treatment attenuated the clinical scores of inflammations, which was accompanied by a reduction of intestinal and/or tumoral production of IL-1β, IL-23, and IL-17. CONCLUSIONS Collectively, our findings demonstrated that jacalin suppresses CAC development, highlighting its anti-inflammatory and antitumoral role in the AOM/DSS-induced model.
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Affiliation(s)
- Luciana Chain Veronez
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Denise Sayuri Calheiros da Silveira
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Luis Carlos Lopes-Júnior
- Nursing Department, Health Sciences Center, Federal University of Espírito Santo, Vitória, Espírito Santo, Brazil
| | - Jéssica Cristina Dos Santos
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
| | - Luis Fernando Barbisan
- Structural and Functional Biology Department, São Paulo State University (UNESP), Institute of Biosciences, Botucatu, São Paulo 18618-689, Brazil
| | - Gabriela Pereira-da-Silva
- Graduate Program in Basic and Applied Immunology, Biochemistry and Immunology Department, Ribeirão Preto Medical School, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
- Maternal-Infant and Public Health Nursing Department, Ribeirão Preto School of Nursing, University of São Paulo, Ribeirão Preto, São Paulo 14040-902, Brazil
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Silinskaite U, Valciukiene J, Jakubauskas M, Poskus T. The Immune Environment in Colorectal Adenoma: A Systematic Review. Biomedicines 2025; 13:699. [PMID: 40149674 PMCID: PMC11940254 DOI: 10.3390/biomedicines13030699] [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: 02/10/2025] [Accepted: 02/28/2025] [Indexed: 03/29/2025] Open
Abstract
Background/Objectives: Research on colorectal adenoma is significantly less comprehensive compared to studies on colorectal carcinoma. Although colorectal adenoma is a precursor of the majority of sporadic colorectal cancers, not all adenomas develop into carcinomas. The complex interaction of immune responses in the premalignant tumor microenvironment might be a factor for that. Methods: In this systematic review, we aim to provide a thorough analysis of the current research examining the immune infiltration patterns in sporadic colorectal adenoma tissues in the context of immune cell-based, cytokine-based, and other immunological factor-related changes along the conventional adenoma-carcinoma sequence. The articles included in the review extend up to December 2024 in PubMed and Web of Science databases. Results: Most included studies have shown significant differences in immune cell counts, densities, and cytokine expression levels associated with premalignant colorectal lesions (and/or colorectal cancer). No consensus on the immune-related tendencies concerning CD4+T cells and CD8+T cells was reached. Decreasing expression of mDCs and plasma and naïve B cells were detected along the ACS. The increased density of tissue eosinophils in the adenoma tissue dramatically diminishes after the transition to carcinoma. As the adenoma progresses, the increasing expression of IL-1α, IL-4, IL-6, IL-8, IL-10, IL-17A, IL-21, IL-23, IL-33, and TGF-β and decreasing levels of IL-12A, IL-18, IFN-γ, and TNFα cytokines in the invasive carcinoma stage is being detected. The over-expression of COX-2, PD-1/PD-L1, CTLA-4, and ICOS/ICOSLG in the colorectal adenomatous and cancerous tissues was also observed. Conclusions: Further studies are needed for a better understanding of the whole picture of colorectal adenoma-associated immunity and its impact on precancerous lesion's potential to progress.
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Che K, Li J, Chen Z, Li Q, Wen Q, Wang C, Yang Z. IL-33 in cancer immunotherapy: Pleiotropic functions and biological strategies. Cytokine Growth Factor Rev 2024:S1359-6101(24)00093-5. [PMID: 39638672 DOI: 10.1016/j.cytogfr.2024.11.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/03/2024] [Revised: 11/17/2024] [Accepted: 11/18/2024] [Indexed: 12/07/2024]
Abstract
Interleukin-33 (IL-33) belongs to the IL-1 cytokine superfamily and plays a critical role in regulating immune responses and maintaining host homeostasis. IL-33 is essential for driving and enhancing type 2 immune responses and is closely associated with the pathogenesis of various inflammatory diseases, infections, and the progression and metastasis of cancers. This study aimed to provide an overview of the anti-tumor effects of IL-33 by examining its complex immunomodulatory functions within the tumor microenvironment and how it regulates immune cells to mediate these effects. We also provided perspectives on the pleiotropic roles of IL-33 in immunomodulation, its potential use in cancer immunotherapies, and possible adverse effects associated with its therapeutic application. Understanding these mechanisms is crucial for developing more effective IL-33-based diagnostic and therapeutic strategies.
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Affiliation(s)
- Keying Che
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Jinyu Li
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Zheng Chen
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Li
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Qiang Wen
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China
| | - Chuanxi Wang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
| | - Zhe Yang
- Tumor Research and Therapy Center, Shandong Provincial Hospital Affiliated to Shandong First Medical University, Jinan, China.
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4
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He R, Huang S, Lu J, Su L, Gao X, Chi H. Unveiling the immune symphony: decoding colorectal cancer metastasis through immune interactions. Front Immunol 2024; 15:1362709. [PMID: 38415252 PMCID: PMC10897008 DOI: 10.3389/fimmu.2024.1362709] [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: 12/28/2023] [Accepted: 01/29/2024] [Indexed: 02/29/2024] Open
Abstract
Colorectal cancer (CRC), known for its high metastatic potential, remains a leading cause of cancer-related death. This review emphasizes the critical role of immune responses in CRC metastasis, focusing on the interaction between immune cells and tumor microenvironment. We explore how immune cells, through cytokines, chemokines, and growth factors, contribute to the CRC metastasis cascade, underlining the tumor microenvironment's role in shaping immune responses. The review addresses CRC's immune evasion tactics, especially the upregulation of checkpoint inhibitors like PD-1 and CTLA-4, highlighting their potential as therapeutic targets. We also examine advanced immunotherapies, including checkpoint inhibitors and immune cell transplantation, to modify immune responses and enhance treatment outcomes in CRC metastasis. Overall, our analysis offers insights into the interplay between immune molecules and the tumor environment, crucial for developing new treatments to control CRC metastasis and improve patient prognosis, with a specific focus on overcoming immune evasion, a key aspect of this special issue.
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Affiliation(s)
- Ru He
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Shangke Huang
- Department of Oncology, The Affiliated Hospital of Southwest Medical University, Luzhou, China
| | - Jiaan Lu
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Lanqian Su
- Clinical Medical College, Southwest Medical University, Luzhou, China
| | - Xinrui Gao
- Department of Oncology, Yongchuan Hospital of Traditional Chinese Medicine, Chongqing, China
| | - Hao Chi
- Clinical Medical College, Southwest Medical University, Luzhou, China
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5
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Zhang H, Shi Y, Lin C, He C, Wang S, Li Q, Sun Y, Li M. Overcoming cancer risk in inflammatory bowel disease: new insights into preventive strategies and pathogenesis mechanisms including interactions of immune cells, cancer signaling pathways, and gut microbiota. Front Immunol 2024; 14:1338918. [PMID: 38288125 PMCID: PMC10822953 DOI: 10.3389/fimmu.2023.1338918] [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: 11/15/2023] [Accepted: 12/26/2023] [Indexed: 01/31/2024] Open
Abstract
Inflammatory bowel disease (IBD), characterized primarily by gastrointestinal inflammation, predominantly manifests as Crohn's disease (CD) and ulcerative colitis (UC). It is acknowledged that Inflammation plays a significant role in cancer development and patients with IBD have an increased risk of various cancers. The progression from inflammation to carcinogenesis in IBD is a result of the interplay between immune cells, gut microbiota, and carcinogenic signaling pathways in epithelial cells. Long-term chronic inflammation can lead to the accumulation of mutations in epithelial cells and the abnormal activation of carcinogenic signaling pathways. Furthermore, Immune cells play a pivotal role in both the acute and chronic phases of IBD, contributing to the transformation from inflammation to tumorigenesis. And patients with IBD frequently exhibit dysbiosis of the intestinal microbiome. Disruption of the gut microbiota and subsequent immune dysregulation are central to the pathogenesis of both IBD and colitis associated colorectal cancer (CAC). The proactive management of inflammation combined with regular endoscopic and tumor screenings represents the most direct and effective strategy to prevent the IBD-associated cancer.
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Affiliation(s)
- Haonan Zhang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Yulu Shi
- Department of Oncology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Chanchan Lin
- Department of Gastroenterology, Quanzhou First Hospital Affiliated to Fujian Medical University, Quanzhou, Fujian, China
| | - Chengcheng He
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Shanping Wang
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Qingyuan Li
- Guangdong Provincial Key Laboratory of Gastroenterology, Department of Gastroenterology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, China
| | - Yan Sun
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
| | - Mingsong Li
- Inflammatory Bowel Diseases Research Center, Department of Gastroenterology, Guangdong Provincial Key Laboratory of Major Obstetric Diseases, Guangdong Provincial Clinical Research Center for Obstetrics and Gynecology, The Third Affiliated Hospital of Guangzhou Medical University, Guangzhou, China
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Salvioli S, Basile MS, Bencivenga L, Carrino S, Conte M, Damanti S, De Lorenzo R, Fiorenzato E, Gialluisi A, Ingannato A, Antonini A, Baldini N, Capri M, Cenci S, Iacoviello L, Nacmias B, Olivieri F, Rengo G, Querini PR, Lattanzio F. Biomarkers of aging in frailty and age-associated disorders: State of the art and future perspective. Ageing Res Rev 2023; 91:102044. [PMID: 37647997 DOI: 10.1016/j.arr.2023.102044] [Citation(s) in RCA: 23] [Impact Index Per Article: 11.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2023] [Revised: 08/24/2023] [Accepted: 08/25/2023] [Indexed: 09/01/2023]
Abstract
According to the Geroscience concept that organismal aging and age-associated diseases share the same basic molecular mechanisms, the identification of biomarkers of age that can efficiently classify people as biologically older (or younger) than their chronological (i.e. calendar) age is becoming of paramount importance. These people will be in fact at higher (or lower) risk for many different age-associated diseases, including cardiovascular diseases, neurodegeneration, cancer, etc. In turn, patients suffering from these diseases are biologically older than healthy age-matched individuals. Many biomarkers that correlate with age have been described so far. The aim of the present review is to discuss the usefulness of some of these biomarkers (especially soluble, circulating ones) in order to identify frail patients, possibly before the appearance of clinical symptoms, as well as patients at risk for age-associated diseases. An overview of selected biomarkers will be discussed in this regard, in particular we will focus on biomarkers related to metabolic stress response, inflammation, and cell death (in particular in neurodegeneration), all phenomena connected to inflammaging (chronic, low-grade, age-associated inflammation). In the second part of the review, next-generation markers such as extracellular vesicles and their cargos, epigenetic markers and gut microbiota composition, will be discussed. Since recent progresses in omics techniques have allowed an exponential increase in the production of laboratory data also in the field of biomarkers of age, making it difficult to extract biological meaning from the huge mass of available data, Artificial Intelligence (AI) approaches will be discussed as an increasingly important strategy for extracting knowledge from raw data and providing practitioners with actionable information to treat patients.
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Affiliation(s)
- Stefano Salvioli
- Department of Medical and Surgical Science, University of Bologna, Bologna, Italy; IRCCS Azienda Ospedaliero-Universitaria di Bologna, Bologna, Italy.
| | | | - Leonardo Bencivenga
- Department of Translational Medical Sciences, University of Naples Federico II, Napoli, Italy
| | - Sara Carrino
- Department of Medical and Surgical Science, University of Bologna, Bologna, Italy
| | - Maria Conte
- Department of Medical and Surgical Science, University of Bologna, Bologna, Italy
| | - Sarah Damanti
- IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milano, Italy
| | - Rebecca De Lorenzo
- IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milano, Italy
| | - Eleonora Fiorenzato
- Parkinson's Disease and Movement Disorders Unit, Center for Rare Neurological Diseases (ERN-RND), Department of Neurosciences, University of Padova, Padova, Italy
| | - Alessandro Gialluisi
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Pozzilli, Italy; EPIMED Research Center, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Assunta Ingannato
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
| | - Angelo Antonini
- Parkinson's Disease and Movement Disorders Unit, Center for Rare Neurological Diseases (ERN-RND), Department of Neurosciences, University of Padova, Padova, Italy; Center for Neurodegenerative Disease Research (CESNE), Department of Neurosciences, University of Padova, Padova, Italy
| | - Nicola Baldini
- IRCCS Istituto Ortopedico Rizzoli, Bologna, Italy; Department of Biomedical and Neuromotor Sciences, University of Bologna, Bologna, Italy
| | - Miriam Capri
- Department of Medical and Surgical Science, University of Bologna, Bologna, Italy
| | - Simone Cenci
- IRCCS Ospedale San Raffaele and Vita-Salute San Raffaele University, Milano, Italy
| | - Licia Iacoviello
- Department of Epidemiology and Prevention, IRCCS NEUROMED, Pozzilli, Italy; EPIMED Research Center, Department of Medicine and Surgery, University of Insubria, Varese, Italy
| | - Benedetta Nacmias
- Department of Neuroscience, Psychology, Drug Research and Child Health, University of Florence, Florence, Italy; IRCCS Fondazione Don Carlo Gnocchi, Florence, Italy
| | - Fabiola Olivieri
- Department of Clinical and Molecular Sciences, Università Politecnica Delle Marche, Ancona, Italy; Clinic of Laboratory and Precision Medicine, IRCCS INRCA, Ancona, Italy
| | - Giuseppe Rengo
- Department of Translational Medical Sciences, University of Naples Federico II, Napoli, Italy; Istituti Clinici Scientifici Maugeri IRCCS, Scientific Institute of Telese Terme, Telese Terme, Italy
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7
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Molfetta R, Lecce M, Milito ND, Putro E, Pietropaolo G, Marangio C, Scarno G, Moretti M, De Smaele E, Santini T, Bernardini G, Sciumè G, Santoni A, Paolini R. SCF and IL-33 regulate mouse mast cell phenotypic and functional plasticity supporting a pro-inflammatory microenvironment. Cell Death Dis 2023; 14:616. [PMID: 37730723 PMCID: PMC10511458 DOI: 10.1038/s41419-023-06139-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2023] [Revised: 08/31/2023] [Accepted: 09/08/2023] [Indexed: 09/22/2023]
Abstract
Mast cells (MCs) are multifaceted innate immune cells often present in the tumor microenvironment (TME). Several recent findings support their contribution to the transition from chronic inflammation to cancer. However, MC-derived mediators can either favor tumor progression, inducing the spread of the tumor, or exert anti-tumorigenic functions, limiting tumor growth. This apparent controversial role likely depends on the plastic nature of MCs that under different microenvironmental stimuli can rapidly change their phenotype and functions. Thus, the exact effect of unique MC subset(s) during tumor progression is far from being understood. Using a murine model of colitis-associated colorectal cancer, we initially characterized the MC population within the TME and in non-lesional colonic areas, by multicolor flow cytometry and confocal microscopy. Our results demonstrated that tumor-associated MCs harbor a main connective tissue phenotype and release high amounts of Interleukin (IL)-6 and Tumor Necrosis Factor (TNF)-α. This MC phenotype correlates with the presence of high levels of Stem Cell Factor (SCF) and IL-33 inside the tumor. Thus, we investigated the effect of SCF and IL-33 on primary MC cultures and underscored their ability to shape MC phenotype eliciting the production of pro-inflammatory cytokines. Our findings support the conclusion that during colonic transformation a sustained stimulation by SCF and IL-33 promotes the accumulation of a prevalent connective tissue-like MC subset that through the secretion of IL-6 and TNF-α maintains a pro-inflammatory microenvironment.
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Affiliation(s)
- Rosa Molfetta
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy.
| | - Mario Lecce
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
- Leibniz Institute for Immunotherapy-Division of functional immune cell modulation, Franz-Josef-Strausse, D-93053, Regensburg, Germany
| | - Nadia D Milito
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
| | - Erisa Putro
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
| | - Giuseppe Pietropaolo
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
| | - Caterina Marangio
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
| | - Gianluca Scarno
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
- Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY, 10065, USA
| | - Marta Moretti
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Enrico De Smaele
- Department of Experimental Medicine, Sapienza University of Rome, Viale Regina Elena 324, 00161, Rome, Italy
| | - Tiziana Santini
- Department of Biology and Biotechnologies "Charles Darwin", Sapienza University of Rome, Rome, Italy
| | - Giovanni Bernardini
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
| | - Giuseppe Sciumè
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
| | - Angela Santoni
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy
- IRCCS Neuromed, Pozzilli, 86077, Isernia, Italy
| | - Rossella Paolini
- Department of Molecular Medicine, Laboratory affiliated to Istituto Pasteur Italia - Fondazione Cenci Bolognetti, Sapienza University of Rome, 00161, Rome, Italy.
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Pisani LF, Teani I, Vecchi M, Pastorelli L. Interleukin-33: Friend or Foe in Gastrointestinal Tract Cancers? Cells 2023; 12:1481. [PMID: 37296602 PMCID: PMC10252908 DOI: 10.3390/cells12111481] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/05/2023] [Revised: 05/18/2023] [Accepted: 05/22/2023] [Indexed: 06/12/2023] Open
Abstract
Accumulating evidence suggests that Interleukin-33 (IL-33), a member of the IL-1 family, has crucial roles in tissue homeostasis and repair, type 2 immunity, inflammation, and viral infection. IL-33 is a novel contributing factor in tumorigenesis and plays a critical role in regulating angiogenesis and cancer progression in a variety of human cancers. The partially unraveled role of IL-33/ST2 signaling in gastrointestinal tract cancers is being investigated through the analysis of patients' samples and by studies in murine and rat models. In this review, we discuss the basic biology and mechanisms of release of the IL-33 protein and its involvement in gastrointestinal cancer onset and progression.
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Affiliation(s)
- Laura Francesca Pisani
- Gastroenterology and Endoscopy Unit, IRCCS Policlinico San Donato, 20097 San Donato Milanese, Italy
- Immunology and Functional Genomics Unit, Centro Cardiologico Monzino, IRCCS, 20138 Milan, Italy
| | - Isabella Teani
- Department of Medicine, University of Verona, 37129 Verona, Italy;
| | - Maurizio Vecchi
- Gastroenterology and Endoscopy Unit, Fondazione IRCCS Ca’ Granda Ospedale Maggiore Policlinico, 20122 Milan, Italy
- Department of Pathophysiology and Transplantation, University of Milan, 20122 Milan, Italy
| | - Luca Pastorelli
- Department of Health Sciences, University of Milan, 20122 Milan, Italy
- Gastroenterology and Liver Unit, ASST Santi Paolo e Carlo, 20142 Milan, Italy
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Akimoto M, Susa T, Okudaira N, Koshikawa N, Hisaki H, Iizuka M, Okinaga H, Takenaga K, Okazaki T, Tamamori-Adachi M. Hypoxia induces downregulation of the tumor-suppressive sST2 in colorectal cancer cells via the HIF-nuclear IL-33-GATA3 pathway. Proc Natl Acad Sci U S A 2023; 120:e2218033120. [PMID: 37094129 PMCID: PMC10160999 DOI: 10.1073/pnas.2218033120] [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: 10/22/2022] [Accepted: 03/30/2023] [Indexed: 04/26/2023] Open
Abstract
As a decoy receptor, soluble ST2 (sST2) interferes with the function of the inflammatory cytokine interleukin (IL)-33. Decreased sST2 expression in colorectal cancer (CRC) cells promotes tumor growth via IL-33-mediated bioprocesses in the tumor microenvironment. In this study, we discovered that hypoxia reduced sST2 expression in CRC cells and explored the associated molecular mechanisms, including the expression of key regulators of ST2 gene transcription in hypoxic CRC cells. In addition, the effect of the recovery of sST2 expression in hypoxic tumor regions on malignant progression was investigated using mouse CRC cells engineered to express sST2 in response to hypoxia. Our results indicated that hypoxia-dependent increases in nuclear IL-33 interfered with the transactivation activity of GATA3 for ST2 gene transcription. Most importantly, hypoxia-responsive sST2 restoration in hypoxic tumor regions corrected the inflammatory microenvironment and suppressed tumor growth and lung metastasis. These results indicate that strategies targeting sST2 in hypoxic tumor regions could be effective for treating malignant CRC.
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Affiliation(s)
- Miho Akimoto
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Takao Susa
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Noriyuki Okudaira
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Nobuko Koshikawa
- Department of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Nitona, Chuoh-ku, Chiba260-8717, Japan
| | - Harumi Hisaki
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Masayoshi Iizuka
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
- Medical Education Center, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Hiroko Okinaga
- Department of Internal Medicine, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Keizo Takenaga
- Department of Innovative Cancer Therapeutics, Chiba Cancer Center Research Institute, Nitona, Chuoh-ku, Chiba260-8717, Japan
| | - Tomoki Okazaki
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
| | - Mimi Tamamori-Adachi
- Department of Biochemistry, Teikyo University School of Medicine, Kaga, Itabashi-ku, Tokyo173-8605, Japan
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10
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Liu X, Li Z, Ren J, Cui G. IL-33-expressing microvascular endothelial cells in human esophageal squamous cell carcinoma: Implications for pathological features and prognosis. Microvasc Res 2023; 147:104506. [PMID: 36792028 DOI: 10.1016/j.mvr.2023.104506] [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: 10/24/2022] [Revised: 02/09/2023] [Accepted: 02/10/2023] [Indexed: 02/15/2023]
Abstract
Accumulating evidence suggests that interleukin (IL)-33 plays a critical role in regulating angiogenesis and cancer progression. In this study, we characterized the pathological importance of IL-33 deployed by tumor microvascular endothelial cells (ECs) in human esophageal squamous cell carcinoma (ESCC). The expression of IL-33 in microvascular ECs in 80 cases of ESCC was examined with immunohistochemistry (IHC) and double immunofluorescence. IHC results showed that strong IL-33-immunoreactivity (IR) in microvessels, which were confirmed to be ECs by double immunofluorescence staining with IL-33/CD31 antibodies. Moreover, high proliferative activity was shown in IL-33-positive ECs, and the IL-33 functional receptor ST2 was expressed in microvascular ECs. Clinicopathological analysis revealed that IL-33-positive microvessel density (MVD) was positively correlated with node involvement in patients with ESCC. A log rank test showed a highly significant inverse correlation between the densities of IL-33-positive MVDs and overall survival rate, and patients with higher IL-33-positive MVDs tended to have a lower survival rate (both p < 0.05). Therefore, we concluded that IL-33 deployed by microvascular ECs correlates with advanced pathological features and the long-term survival rate, which provides new insights into the regulatory mechanisms of tumor angiogenesis in the tumor microenvironment and might serve as a promising target in patients with ESCC.
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Affiliation(s)
- Xia Liu
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Zhenfeng Li
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jingli Ren
- Department of Pathology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Guanglin Cui
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Faculty of Health Science, Nord University, Campus Levanger, Norway.
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11
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Maryam S, Krukiewicz K, Haq IU, Khan AA, Yahya G, Cavalu S. Interleukins (Cytokines) as Biomarkers in Colorectal Cancer: Progression, Detection, and Monitoring. J Clin Med 2023; 12:jcm12093127. [PMID: 37176567 PMCID: PMC10179696 DOI: 10.3390/jcm12093127] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2023] [Revised: 04/18/2023] [Accepted: 04/20/2023] [Indexed: 05/15/2023] Open
Abstract
Cancer is the primary cause of death in economically developed countries and the second leading cause in developing countries. Colorectal cancer (CRC) is the third most common cause of cancer-related deaths worldwide. Risk factors for CRC include obesity, a diet low in fruits and vegetables, physical inactivity, and smoking. CRC has a poor prognosis, and there is a critical need for new diagnostic and prognostic biomarkers to reduce related deaths. Recently, studies have focused more on molecular testing to guide targeted treatments for CRC patients. The most crucial feature of activated immune cells is the production and release of growth factors and cytokines that modulate the inflammatory conditions in tumor tissues. The cytokine network is valuable for the prognosis and pathogenesis of colorectal cancer as they can aid in the cost-effective and non-invasive detection of cancer. A large number of interleukins (IL) released by the immune system at various stages of CRC can act as "biomarkers". They play diverse functions in colorectal cancer, and include IL-4, IL-6, IL-8, IL-11, IL-17A, IL-22, IL-23, IL-33, TNF, TGF-β, and vascular endothelial growth factor (VEGF), which are pro-tumorigenic genes. However, there are an inadequate number of studies in this area considering its correlation with cytokine profiles that are clinically useful in diagnosing cancer. A better understanding of cytokine levels to establish diagnostic pathways entails an understanding of cytokine interactions and the regulation of their various biochemical signaling pathways in healthy individuals. This review provides a comprehensive summary of some interleukins as immunological biomarkers of CRC.
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Affiliation(s)
- Sajida Maryam
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
| | - Katarzyna Krukiewicz
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland
- Centre for Organic and Nanohybrid Electronics, Silesian University of Technology, Konarskiego 22B, 44-100 Gliwice, Poland
| | - Ihtisham Ul Haq
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
- Department of Physical Chemistry and Technology of Polymers, Silesian University of Technology, M. Strzody 9, 44-100 Gliwice, Poland
- Joint Doctoral School, Silesian University of Technology, Akademicka 2A, 44-100 Gliwice, Poland
| | - Awal Ayaz Khan
- Department of Biosciences, COMSATS University Islamabad (CUI), Islamabad 44000, Pakistan
| | - Galal Yahya
- Department of Microbiology and Immunology, Faculty of Pharmacy, Zagazig University, Zagazig 44519, Al Sharqia, Egypt
- Department of Molecular Genetics, Faculty of Biology, Technical University of Kaiserslautern, Paul-Ehrlich Str. 24, 67663 Kaiserslautern, Germany
| | - Simona Cavalu
- Faculty of Medicine and Pharmacy, University of Oradea, P-ta 1 Decembrie 10, 410087 Oradea, Romania
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12
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Cui G, Yuan A, Pang Z, Florholmen J. Differential profile of protumor immunological factors between the tumor site and the tumor-free site - predictive potential of IL-8 and COX2 for colorectal cancer and metastasis. Int Immunopharmacol 2023; 118:110089. [PMID: 37023696 DOI: 10.1016/j.intimp.2023.110089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2023] [Revised: 03/21/2023] [Accepted: 03/22/2023] [Indexed: 04/08/2023]
Abstract
To study the role of host immune surveillance in the initiation and progression of colorectal cancer (CRC), a set of protumor immunological factors was determined by quantitative real-time PCR (q-PCR) between the primary tumor and the adjacent tumor-free site tissues in 63 patients with colorectal neoplasms. Results showed that expression levels of interleukin (IL)-1β, IL-6, IL-8, IL-17A, IL-23, and cyclooxygenase 2 (COX2) mRNAs, except transforming growth factor beta (TGFβ), in adenoma tissues were significantly higher than that in relative adjacent tissues. Difference of immunological factor levels between adenoma and adjacent tissues (Δ values) was in an order of ΔIL-8 > ΔIL-6 > ΔIL-17A > ΔIL-1β > ΔCOX2 > ΔIL-23; Analysis showed that the value of ΔCOX2 correlated to the grade of dysplastic degree in patients with adenoma. Notably, levels of all these immunological factors in CRC tissues were continuously increased, the order of values of Δ immunological factors was ΔIL-8 > ΔCOX2 > ΔIL-6 > ΔIL-1β > ΔIL-17A > ΔIL-23 > ΔTGFβ. Further analysis revealed that increased value of Δ IL-1β was associated with advanced TNM stage, a higher value of Δ COX2 tended to predicate a deeper degree of tumor invasion; and higher values of Δ IL-1β, IL-6 and COX2 closely correlated to lymph node metastasis in patients with CRC. In addition, the ratio of ΔIL-8/ΔTGFβ was most obvious changed factor and associated with node metastasis in patients with CRC. Therefore, we concluded that the difference of protumor immunological factor levels between the primary tumor site and tumor-free site along the adenoma-carcinoma sequence reflects the change of protumor/antitumor force balance, which is associated with CRC initiation and invasion.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China; Faculty of Health Science, Nord University, Campus Levanger, Levanger, Norway.
| | - Aping Yuan
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Zhigang Pang
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan Province, China.
| | - Jon Florholmen
- Department of Gastroenterology, University Hospital of North Norway, University of Tromsø, Tromsø, Norway.
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13
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Stricker E, Peckham-Gregory EC, Scheurer ME. HERVs and Cancer-A Comprehensive Review of the Relationship of Human Endogenous Retroviruses and Human Cancers. Biomedicines 2023; 11:936. [PMID: 36979914 PMCID: PMC10046157 DOI: 10.3390/biomedicines11030936] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/13/2023] [Revised: 03/03/2023] [Accepted: 03/10/2023] [Indexed: 03/30/2023] Open
Abstract
Genomic instability and genetic mutations can lead to exhibition of several cancer hallmarks in affected cells such as sustained proliferative signaling, evasion of growth suppression, activated invasion, deregulation of cellular energetics, and avoidance of immune destruction. Similar biological changes have been observed to be a result of pathogenic viruses and, in some cases, have been linked to virus-induced cancers. Human endogenous retroviruses (HERVs), once external pathogens, now occupy more than 8% of the human genome, representing the merge of genomic and external factors. In this review, we outline all reported effects of HERVs on cancer development and discuss the HERV targets most suitable for cancer treatments as well as ongoing clinical trials for HERV-targeting drugs. We reviewed all currently available reports of the effects of HERVs on human cancers including solid tumors, lymphomas, and leukemias. Our review highlights the central roles of HERV genes, such as gag, env, pol, np9, and rec in immune regulation, checkpoint blockade, cell differentiation, cell fusion, proliferation, metastasis, and cell transformation. In addition, we summarize the involvement of HERV long terminal repeat (LTR) regions in transcriptional regulation, creation of fusion proteins, expression of long non-coding RNAs (lncRNAs), and promotion of genome instability through recombination.
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Affiliation(s)
- Erik Stricker
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77047, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77047, USA
| | | | - Michael E. Scheurer
- Department of Molecular Virology and Microbiology, Baylor College of Medicine, Houston, TX 77047, USA
- Department of Pediatrics, Baylor College of Medicine, Houston, TX 77047, USA
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14
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Cui G, Liu H, Laugsand JB. Endothelial cells-directed angiogenesis in colorectal cancer: Interleukin as the mediator and pharmacological target. Int Immunopharmacol 2023; 114:109525. [PMID: 36508917 DOI: 10.1016/j.intimp.2022.109525] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2022] [Revised: 11/22/2022] [Accepted: 11/27/2022] [Indexed: 12/14/2022]
Abstract
Enhanced angiogenesis is a cancer hallmark and critical for colorectal cancer (CRC) invasion and metastasis. Upon exposure to proangiogenic factors, therefore, targeting tumor-associated proangiogenic factors/receptors hold great promise as a therapeutic modality to treat CRC, particularly metastatic CRC. Accumulating evidence from numerous studies suggests that tumor endothelial cells (ECs) are not only the target of proangiogenic factors, but also function as the cellular source of proangiogenic factors. Studies showed that ECs can produce different proangiogenic factors to participate in the regulation of angiogenesis process, in which ECs-derived interleukins (ILs) show a potential stimulatory effect on angiogenesis via either an direct action on their receptors expressed on progenitor of ECs or an indirect way through enhanced production of other proangiogenic factors. Although a great deal of attention is given to the effects of tumor-derived and immune cell-derived ILs, few studies describe the potential effects of vascular ECs-derived ILs on the tumor angiogenesis process. This review provides an updated summary of available information on proangiogenic ILs, such as IL-1, IL-6, IL-8, IL-17, IL-22, IL-33, IL-34, and IL-37, released by microvascular ECs as potential drivers of the tumor angiogenesis process and discusses their potential as a novel candidate for antiangiogenic target for the treatment of CRC patients.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Faculty of Health Science, Nord University, Campus Levanger, Norway.
| | - Hanzhe Liu
- School of Stomatology, Wuhan University, Wuhan, China.
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15
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Cui G, Wang Z, Liu H, Pang Z. Cytokine-mediated crosstalk between cancer stem cells and their inflammatory niche from the colorectal precancerous adenoma stage to the cancerous stage: Mechanisms and clinical implications. Front Immunol 2022; 13:1057181. [PMID: 36466926 PMCID: PMC9714270 DOI: 10.3389/fimmu.2022.1057181] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/29/2022] [Accepted: 11/03/2022] [Indexed: 10/15/2023] Open
Abstract
The majority of colorectal cancers (CRCs) are thought to arise from precancerous adenomas. Upon exposure to diverse microenvironmental factors, precancerous stem cells (pCSCs) undergo complex genetic/molecular changes and gradually progress to form cancer stem cells (CSCs). Accumulative evidence suggests that the pCSC/CSC niche is an inflammatory dominated milieu that contains different cytokines that function as the key communicators between pCSCs/CSCs and their niche and have a decisive role in promoting CRC development, progression, and metastasis. In view of the importance and increasing data about cytokines in modulating pCSCs/CSC stemness properties and their significance in CRC, this review summarizes current new insights of cytokines, such as interleukin (IL)-4, IL-6, IL-8, IL-17A, IL-22, IL-23, IL-33 and interferon (IFN)-γ, involving in the modulation of pCSC/CSC properties and features in precancerous and cancerous lesions and discusses the possible mechanisms of adenoma progression to CRCs and their therapeutic potential.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Faculty of Health Science, Nord University, Levanger, Norway
| | - Ziqi Wang
- College of Medical Imaging, Mudanjiang Medical University, Mudanjiang, China
| | - Hanzhe Liu
- School of Stomatology, Wuhan University, Wuhan, China
| | - Zhigang Pang
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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16
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Johnsen KM, Florholmen J, Moe ØK, Gundersen M, Beilfuss J, Kileng H, Sørbye SW, Goll R. Prediction of long-term remission in patients following discontinuation of anti-TNF therapy in ulcerative colitis: a 10 year follow up study. BMC Gastroenterol 2022; 22:459. [PMID: 36384477 PMCID: PMC9667633 DOI: 10.1186/s12876-022-02522-4] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 05/02/2022] [Accepted: 09/23/2022] [Indexed: 11/17/2022] Open
Abstract
BACKGROUND The long-term outcomes of Ulcerative colitis (UC) after discontinuation of biological therapy are largely unknown. There is also a lack of accurate and validated markers that can predict outcome after withdrawal accurately. The aims of this study were to describe the long-term outcomes in UC patients following cessation of anti-TNF therapy and explore potential biomarkers as an approach towards precision medicine. METHODS Seventy-five patients with moderate to severe UC treated to remission with anti-tumor necrosis factor (TNF) were included in the study. This is a follow-up of previously reported UC outcomes. The patients were categorized as either "Remission" or "Relapse". The "Relapse" group was divided into subgroups determined by the highest treatment level needed to obtain remission the last 3 years of observation: non-biological therapy, biological therapy or colectomy. Remission were divided in long term remission (LTR), those using immunomodulating drugs (LTR + imids) and those using only 5-amino-salicylate (5-ASA) treatment (LTR) for the past 3 years. Analyses of mucosal gene expression by real-time PCR were performed. RESULTS The median (IQR) observation time of all patients included was 121 (111-137) months. Of the 75 patients, 46 (61%) did not receive biological therapy, including 23 (31%) in LTR ± imids. Of these 23 patients, 16 (21%) were defined as LTR with a median observation time of (IQR) 95 (77-113) months. In total 14 patients (19%) underwent colectomy during the 10 years after first remission. Mucosal TNF copies/µg mRNA < 10 000 at anti-TNF discontinuation predicted long-term remission, biological free remission and lower risk of colectomy with a HR 0.36 (0.14-0.92) for long-term remission, HR 0.17 (0.04-0.78) for biological free remission and HR 0.12 (0.01-0.91) for colectomy. IL1RL1 was normalized in LTR phenotype and higher in relapsing UC. CONCLUSION In this 10-year follow-up of UC of patients with moderate to severe disease, 61% of patients experience an altered phenotype to a milder disease course without need of biological therapy. Twenty-one percent of the patients were LTR without any medication except of 5-ASA. Mucosal TNF gene expression and IL1RL1- transcripts may be of clinical utility for long term prognosis in development of precision medicine in UC.
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Affiliation(s)
- Kay-Martin Johnsen
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway.
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway.
| | - Jon Florholmen
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway
| | - Øystein K Moe
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway
| | - Mona Gundersen
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway
| | - Julia Beilfuss
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway
| | - Hege Kileng
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway
| | - Sveinung W Sørbye
- Department of Clinical Pathology, University Hospital of North Norway, Tromsö, Norway
| | - Rasmus Goll
- Research Group of Gastroenterology and Nutrition, Department of Clinical Medicine, UiT The Arctic University of Norway, Tromsö, Norway
- Division of Internal Medicine, Department of Gastroenterology, University Hospital of North Norway, Tromsö, Norway
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17
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Guo H, Bossila EA, Ma X, Zhao C, Zhao Y. Dual Immune Regulatory Roles of Interleukin-33 in Pathological Conditions. Cells 2022; 11:cells11203237. [PMID: 36291105 PMCID: PMC9600220 DOI: 10.3390/cells11203237] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2022] [Revised: 10/07/2022] [Accepted: 10/11/2022] [Indexed: 11/20/2022] Open
Abstract
Interleukin-33 (IL-33), a member of the IL-1 cytokine family and a multifunctional cytokine, plays critical roles in maintaining host homeostasis and in pathological conditions, such as allergy, infectious diseases, and cancer, by acting on multiple types of immune cells and promoting type 1 and 2 immune responses. IL-33 is rapidly released by immune and non-immune cells upon stimulation by stress, acting as an “alarmin” by binding to its receptor, suppression of tumorigenicity 2 (ST2), to trigger downstream signaling pathways and activate inflammatory and immune responses. It has been recognized that IL-33 displays dual-functioning immune regulatory effects in many diseases and has both pro- and anti-tumorigenic effects, likely depending on its primary target cells, IL-33/sST2 expression levels, cellular context, and the cytokine microenvironment. Herein, we summarize our current understanding of the biological functions of IL-33 and its roles in the pathogenesis of various conditions, including inflammatory and autoimmune diseases, infections, cancers, and cases of organ transplantation. We emphasize the nature of context-dependent dual immune regulatory functions of IL-33 in many cells and diseases and review systemic studies to understand the distinct roles of IL-33 in different cells, which is essential to the development of more effective diagnoses and therapeutic approaches for IL-33-related diseases.
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Affiliation(s)
- Han Guo
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Elhusseny A. Bossila
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Biotechnology Department, Faculty of Agriculture Al-Azhar University, Cairo 11311, Egypt
| | - Xinran Ma
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Chenxu Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
| | - Yong Zhao
- State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
- University of Chinese Academy of Sciences, Beijing 101499, China
- Beijing Institute for Stem Cell and Regeneration, Beijing 100101, China
- Correspondence: ; Tel.: +86-10-64807302; Fax: +86-10-64807313
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18
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Jou E, Rodriguez-Rodriguez N, McKenzie ANJ. Emerging roles for IL-25 and IL-33 in colorectal cancer tumorigenesis. Front Immunol 2022; 13:981479. [PMID: 36263033 PMCID: PMC9573978 DOI: 10.3389/fimmu.2022.981479] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/29/2022] [Accepted: 09/15/2022] [Indexed: 12/31/2022] Open
Abstract
Colorectal cancer (CRC) is the second leading cause of cancer-related death worldwide, and is largely refractory to current immunotherapeutic interventions. The lack of efficacy of existing cancer immunotherapies in CRC reflects the complex nature of the unique intestinal immune environment, which serves to maintain barrier integrity against pathogens and harmful environmental stimuli while sustaining host-microbe symbiosis during homeostasis. With their expression by barrier epithelial cells, the cytokines interleukin-25 (IL-25) and IL-33 play key roles in intestinal immune responses, and have been associated with inappropriate allergic reactions, autoimmune diseases and cancer pathology. Studies in the past decade have begun to uncover the important roles of IL-25 and IL-33 in shaping the CRC tumour immune microenvironment, where they may promote or inhibit tumorigenesis depending on the specific CRC subtype. Notably, both IL-25 and IL-33 have been shown to act on group 2 innate lymphoid cells (ILC2s), but can also stimulate an array of other innate and adaptive immune cell types. Though sometimes their functions can overlap they can also produce distinct phenotypes dependent on the differential distribution of their receptor expression. Furthermore, both IL-25 and IL-33 modulate pathways previously known to contribute to CRC tumorigenesis, including angiogenesis, tumour stemness, invasion and metastasis. Here, we review our current understanding of IL-25 and IL-33 in CRC tumorigenesis, with specific focus on dissecting their individual function in the context of distinct subtypes of CRC, and the potential prospects for targeting these pathways in CRC immunotherapy.
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Affiliation(s)
- Eric Jou
- MRC Laboratory of Molecular Biology, Cambridge, United Kingdom
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19
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Warner K, Ghaedi M, Chung DC, Jacquelot N, Ohashi PS. Innate lymphoid cells in early tumor development. Front Immunol 2022; 13:948358. [PMID: 36032129 PMCID: PMC9411809 DOI: 10.3389/fimmu.2022.948358] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/19/2022] [Accepted: 07/26/2022] [Indexed: 12/20/2022] Open
Abstract
Innate and adaptive immune cells monitor, recognize, and eliminate transformed cells. Innate lymphoid cells (ILCs) are innate counterparts of T cells that play a key role in many facets of the immune response and have a profound impact on disease states, including cancer. ILCs regulate immune responses by responding and integrating a wide range of signals within the local microenvironment. As primarily tissue-resident cells, ILCs are ideally suited to sense malignant transformation and initiate anti-tumor immunity. However, as ILCs have been associated with anti-tumor and pro-tumor activities in established tumors, they could potentially have dual functions during carcinogenesis by promoting or suppressing the malignant outgrowth of premalignant lesions. Here we discuss emerging evidence that shows that ILCs can impact early tumor development by regulating immune responses against transformed cells, as well as the environmental cues that potentially induce ILC activation in premalignant lesions.
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Affiliation(s)
- Kathrin Warner
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Maryam Ghaedi
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Douglas C. Chung
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
| | - Nicolas Jacquelot
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
| | - Pamela S. Ohashi
- Princess Margaret Cancer Centre, University Health Network, University of Toronto, Toronto, ON, Canada
- Department of Immunology, University of Toronto, Toronto, ON, Canada
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20
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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21
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Yi XM, Lian H, Li S. Signaling and functions of interleukin-33 in immune regulation and diseases. CELL INSIGHT 2022; 1:100042. [PMID: 37192860 PMCID: PMC10120307 DOI: 10.1016/j.cellin.2022.100042] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Revised: 05/31/2022] [Accepted: 06/03/2022] [Indexed: 05/18/2023]
Abstract
Interleukin-33 (IL-33) which belongs to the interleukin-1 (IL-1) family is an alarmin cytokine with critical roles in tissue homeostasis, pathogenic infection, inflammation, allergy and type 2 immunity. IL-33 transmits signals through its receptor IL-33R (also called ST2) which is expressed on the surface of T helper 2 (Th2) cells and group 2 innate lymphoid cells (ILC2s), thus inducing transcription of Th2-associated cytokine genes and host defense against pathogens. Moreover, the IL-33/IL-33R axis is also involved in development of multiple types of immune-related diseases. In this review, we focus on current progress on IL-33-trigggered signaling events, the important functions of IL-33/IL-33R axis in health and diseases as well as the promising therapeutic implications of these findings.
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Affiliation(s)
- Xue-Mei Yi
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan University, Wuhan, 430071, China
| | - Huan Lian
- Department of Microbial Pathogenesis, Yale University School of Medicine, New Haven, CT, 06536, USA
| | - Shu Li
- Department of Infectious Diseases, Zhongnan Hospital of Wuhan University, Medical Research Institute, Frontier Science Center for Immunology and Metabolism, Research Unit of Innate Immune and Inflammatory Diseases, Chinese Academy of Medical Sciences, Wuhan University, Wuhan, 430071, China
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22
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The Role of Inflammatory Cytokines in the Pathogenesis of Colorectal Carcinoma—Recent Findings and Review. Biomedicines 2022; 10:biomedicines10071670. [PMID: 35884974 PMCID: PMC9312930 DOI: 10.3390/biomedicines10071670] [Citation(s) in RCA: 31] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/26/2022] [Revised: 07/04/2022] [Accepted: 07/05/2022] [Indexed: 11/17/2022] Open
Abstract
The inflammatory process plays a significant role in the development of colon cancer (CRC). Intestinal cytokine networks are critical mediators of tissue homeostasis and inflammation but also impact carcinogenesis at all stages of the disease. Recent studies suggest that inflammation is of greater importance in the serrated pathway than in the adenoma-carcinoma pathway. Interleukins have gained the most attention due to their potential role in CRC pathogenesis and promising results of clinical trials. Malignant transformation is associated with the pro-tumorigenic and anti-tumorigenic cytokines. The harmony between proinflammatory and anti-inflammatory factors is crucial to maintaining homeostasis. Immune cells in the tumor microenvironment modulate immune sensitivity and facilitate cancer escape from immune surveillance. Therefore, clarifying the role of underlying cytokine pathways and the effects of their modulation may be an important step to improve the effectiveness of cancer immunotherapy.
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23
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Obata-Ninomiya K, de Jesus Carrion S, Hu A, Ziegler SF. Emerging role for thymic stromal lymphopoietin-responsive regulatory T cells in colorectal cancer progression in humans and mice. Sci Transl Med 2022; 14:eabl6960. [PMID: 35584230 DOI: 10.1126/scitranslmed.abl6960] [Citation(s) in RCA: 18] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Recruitment of regulatory T cells (Tregs) to tumors is a hallmark of cancer progression. Tumor-derived factors, such as the cytokine thymic stromal lymphopoietin (TSLP), can influence Treg function in tumors. In our study, we identified a subset of Tregs expressing the receptor for TSLP (TSLPR+ Tregs) that were increased in colorectal tumors in humans and mice and largely absent in adjacent normal colon. This Treg subset was also found in the peripheral blood of patients with colon cancer but not in the peripheral blood of healthy control subjects. Mechanistically, we found that this Treg subset coexpressed the interleukin-33 (IL-33) receptor [suppressor of tumorigenicity 2 (ST2)] and had high programmed cell death 1 (PD-1) and cytotoxic lymphocyte-associated antigen 4 (CTLA-4) expression, regulated in part by the transcription factor Mef2c. Treg-specific deletion of TSLPR, but not ST2, was associated with a reduction in tumor number and size with concomitant increase in TH1 cells in tumors in chemically induced mouse models of colorectal cancer. Therapeutic blockade of TSLP using TSLP-specific monoclonal antibodies effectively inhibited the progression of colorectal tumors in this mouse model. Collectively, these data suggest that TSLP controls the progression of colorectal cancer through regulation of tumor-specific Treg function and represents a potential therapeutic target that requires further investigation.
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Affiliation(s)
| | | | - Alex Hu
- Center for Systems Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
| | - Steven F Ziegler
- Center for Fundamental Immunology, Benaroya Research Institute, Seattle, WA 98101, USA
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24
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GEINDREAU M, BRUCHARD M, VEGRAN F. Role of Cytokines and Chemokines in Angiogenesis in a Tumor Context. Cancers (Basel) 2022; 14:cancers14102446. [PMID: 35626056 PMCID: PMC9139472 DOI: 10.3390/cancers14102446] [Citation(s) in RCA: 47] [Impact Index Per Article: 15.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2022] [Revised: 05/10/2022] [Accepted: 05/11/2022] [Indexed: 01/02/2023] Open
Abstract
Simple Summary Tumor growth in solid cancers requires adequate nutrient and oxygen supply, provided by blood vessels created by angiogenesis. Numerous studies have demonstrated that this mechanism plays a crucial role in cancer development and appears to be a well-defined hallmark of cancer. This process is carefully regulated, notably by cytokines with pro-angiogenic or anti-angiogenic features. In this review, we will discuss the role of cytokines in the modulation of angiogenesis. In addition, we will summarize the therapeutic approaches based on cytokine modulation and their clinical approval. Abstract During carcinogenesis, tumors set various mechanisms to help support their development. Angiogenesis is a crucial process for cancer development as it drives the creation of blood vessels within the tumor. These newly formed blood vessels insure the supply of oxygen and nutrients to the tumor, helping its growth. The main factors that regulate angiogenesis are the five members of the vascular endothelial growth factor (VEGF) family. Angiogenesis is a hallmark of cancer and has been the target of new therapies this past few years. However, angiogenesis is a complex phenomenon with many redundancy pathways that ensure its maintenance. In this review, we will first describe the consecutive steps forming angiogenesis, as well as its classical regulators. We will then discuss how the cytokines and chemokines present in the tumor microenvironment can induce or block angiogenesis. Finally, we will focus on the therapeutic arsenal targeting angiogenesis in cancer and the challenges they have to overcome.
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Affiliation(s)
- Mannon GEINDREAU
- Université de Bourgogne Franche-Comté, 21000 Dijon, France; (M.G.); (M.B.)
- CRI INSERM UMR1231 ‘Lipids, Nutrition and Cancer’ Team CAdiR, 21000 Dijon, France
| | - Mélanie BRUCHARD
- Université de Bourgogne Franche-Comté, 21000 Dijon, France; (M.G.); (M.B.)
- CRI INSERM UMR1231 ‘Lipids, Nutrition and Cancer’ Team CAdiR, 21000 Dijon, France
- Centre Georges-François Leclerc, UNICANCER, 21000 Dijon, France
- LipSTIC Labex, 21000 Dijon, France
| | - Frédérique VEGRAN
- Université de Bourgogne Franche-Comté, 21000 Dijon, France; (M.G.); (M.B.)
- CRI INSERM UMR1231 ‘Lipids, Nutrition and Cancer’ Team CAdiR, 21000 Dijon, France
- Centre Georges-François Leclerc, UNICANCER, 21000 Dijon, France
- LipSTIC Labex, 21000 Dijon, France
- Correspondence:
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25
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Vaghari-Tabari M, Targhazeh N, Moein S, Qujeq D, Alemi F, Majidina M, Younesi S, Asemi Z, Yousefi B. From inflammatory bowel disease to colorectal cancer: what's the role of miRNAs? Cancer Cell Int 2022; 22:146. [PMID: 35410210 PMCID: PMC8996392 DOI: 10.1186/s12935-022-02557-3] [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: 08/24/2021] [Accepted: 03/21/2022] [Indexed: 12/27/2022] Open
Abstract
Inflammatory Bowel Disease (IBD) is a chronic inflammatory disease with relapse and remission periods. Ulcerative colitis and Crohn's disease are two major forms of the disease. IBD imposes a lot of sufferings on the patient and has many consequences; however, the most important is the increased risk of colorectal cancer, especially in patients with Ulcerative colitis. This risk is increased with increasing the duration of disease, thus preventing the progression of IBD to cancer is very important. Therefore, it is necessary to know the details of events contributed to the progression of IBD to cancer. In recent years, the importance of miRNAs as small molecules with 20-22 nucleotides has been recognized in pathophysiology of many diseases, in which IBD and colorectal cancer have not been excluded. As a result, the effectiveness of these small molecules as therapeutic target is hopefully confirmed. This paper has reviewed the related studies and findings about the role of miRNAs in the course of events that promote the progression of IBD to colorectal carcinoma, as well as a review about the effectiveness of some of these miRNAs as therapeutic targets.
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Affiliation(s)
- Mostafa Vaghari-Tabari
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Clinical Biochemistry and Laboratory Medicine, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Niloufar Targhazeh
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Soheila Moein
- Medicinal Plants Processing Research Center, Shiraz University of Medical Sciences, Shiraz, Iran.,Department of Biochemistry, Faculty of Medicine, Hormozgan University of Medical Sciences, Bandar Abbas, Iran
| | - Durdi Qujeq
- Cellular and Molecular Biology Research Center (CMBRC), Health Research Institute, Babol University of Medical Sciences, Babol, Iran.,Department of Clinical Biochemistry, Babol University of Medical Sciences, Babol, Iran
| | - Forough Alemi
- Student Research Committee, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Maryam Majidina
- Solid Tumor Research Center, Urmia University of Medical Sciences, Urmia, Iran
| | - Simin Younesi
- Schoole of Health and Biomedical Sciences, RMIT University, Melborne, VIC, Australia
| | - Zatollah Asemi
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Kashan University of Medical Sciences, Kashan, Iran.
| | - Bahman Yousefi
- Molecular Medicine Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.
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26
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Huang F, Chen WY, Ma J, He XL, Wang JW. Paradoxical role of interleukin-33/suppressor of tumorigenicity 2 in colorectal carcinogenesis: Progress and therapeutic potential. World J Clin Cases 2022; 10:23-34. [PMID: 35071502 PMCID: PMC8727260 DOI: 10.12998/wjcc.v10.i1.23] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/14/2021] [Accepted: 08/24/2021] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is presently the second most prevalent global mortality-inducing cancer. CRC carcinogenesis is a multifactorial process involving internal genetic mutations and the external environment. In addition, non-neoplastic cell activities within tumor microenvironments for CRC development have been established. However, interleukin (IL)-33, secreted by such cell types, plays a pivotal role in cancer progression due to interaction with cellular constituents within the tumor-inflammation microenvironment. IL-33 belongs to the IL-1 cytokine family and acts as binding attachments for the suppressor of tumorigenicity (ST)2 receptor. Therefore, how to coordinate tumor microenvironment, design and optimize treatment strategies suitable for CRC, based on IL-33/ST2 signal is a challenge. Even though it has established influences upon immunity-linked conditions, IL-33 effects on CRC progression and prevention and related mechanisms are still controversial. Our review depicts controversial activities for IL-33/ST2 within carcinogenesis and cancer prevention. Moreover, IL-33/ST2 signaling is a potential therapeutic target for CRC.
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Affiliation(s)
- Fang Huang
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
- Key Laboratory of Endocrine Gland Diseases of Zhejiang Province, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Wan-Yuan Chen
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Jie Ma
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Xiang-Lei He
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
| | - Jian-Wei Wang
- Department of Pathology, Laboratory Medicine Center, Zhejiang Provincial Peoples’ Hospital, Peoples’ Hospital of Hangzhou Medical College, Hangzhou 310014, Zhejiang Province, China
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27
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Qi J, Crinier A, Escalière B, Ye Y, Wang Z, Zhang T, Batista L, Liu H, Hong L, Wu N, Zhang M, Chen L, Liu Y, Shen L, Narni-Mancinelli E, Vivier E, Su B. Single-cell transcriptomic landscape reveals tumor specific innate lymphoid cells associated with colorectal cancer progression. CELL REPORTS MEDICINE 2021; 2:100353. [PMID: 34467243 PMCID: PMC8385246 DOI: 10.1016/j.xcrm.2021.100353] [Citation(s) in RCA: 57] [Impact Index Per Article: 14.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 12/22/2020] [Revised: 03/29/2021] [Accepted: 06/24/2021] [Indexed: 02/08/2023]
Abstract
Innate lymphoid cells (ILCs) are tissue-resident lymphocytes differing from conventional T lymphocytes in having no antigen-specific receptors. ILCs include natural killer (NK) cells, helper-like ILC1s, ILC2s, and ILC3s, and lymphoid tissue-inducer (LTi) cells. Tumor ILCs are frequently found in various cancers, but their roles in cancer immunity and immunotherapy remain largely unclear. We report here the single-cell characterization of blood and gut helper-like ILC subsets in healthy conditions and in colorectal cancer (CRC). The healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s. Additional tumor-specific ILC1-like and ILC2 subsets were identified in CRC patients. Signaling lymphocytic activation molecule family member 1 (SLAMF1) was found to be selectively expressed on tumor-specific ILCs, and higher levels of SLAMF1+ ILCs were observed in the blood of CRC patients. The SLAMF1-high group of CRC patients had a significantly higher survival rate than the SLAMF1-low group, suggesting that SLAMF1 is an anti-tumor biomarker in CRC.
Healthy gut contains ILC1s, ILC3s, and ILC3/NKs, but no ILC2s Blood and tumor ILCs from CRC patients have unique transcriptomic features Tumor tissue from CRC patients contains a tumor specific ILC1-like subset and ILC2s SLAMF1 is identified as an anti-tumor biomarker in CRC
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Affiliation(s)
- Jingjing Qi
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Adeline Crinier
- Aix-Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France
| | - Bertrand Escalière
- Aix-Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France
| | - Youqiong Ye
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Zhengting Wang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Tianyu Zhang
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Luciana Batista
- Innate Pharma Research Laboratories, Innate Pharma, 13009 Marseille, France
| | - Hongzhi Liu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Liwen Hong
- Department of Gastroenterology, Ruijin Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Ningbo Wu
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Mingnan Zhang
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Lei Chen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Yingbin Liu
- Department of General Surgery, Xinhua Hospital Affiliated to Shanghai Jiao Tong University School of Medicine, Shanghai 200092, China
| | - Lei Shen
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
| | - Emilie Narni-Mancinelli
- Aix-Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France
| | - Eric Vivier
- Aix-Marseille Université, CNRS, INSERM, Centre d'Immunologie de Marseille-Luminy, 13009 Marseille, France.,Innate Pharma Research Laboratories, Innate Pharma, 13009 Marseille, France.,Immunology, Marseille Immunopole, Hôpital de la Timone, Assistance Publique des Hôpitaux de 13005 Marseille, France
| | - Bing Su
- Shanghai Institute of Immunology, Department of Immunology and Microbiology, and the Ministry of Education Key Laboratory of Cell Death and Differentiation, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China.,Shanghai Jiao Tong University School of Medicine-Yale Institute for Immune Metabolism, Shanghai Jiao Tong University School of Medicine, Shanghai 200025, China
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28
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Jiang W, Lian J, Yue Y, Zhang Y. IL-33/ST2 as a potential target for tumor immunotherapy. Eur J Immunol 2021; 51:1943-1955. [PMID: 34131922 DOI: 10.1002/eji.202149175] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/15/2021] [Revised: 03/26/2021] [Accepted: 06/14/2021] [Indexed: 12/12/2022]
Abstract
IL-33, a member of the IL-1 family, was initially reported to be expressed constitutively in the nucleus of tissue-lining and structural cells. However, upon tissue damage or injury, IL-33 can be released quickly to bind with its cognate receptor ST2 in response to wound healing and inflammation and act as a DAMP. As a key regulator of Th2 responses, IL-33/ST2 signal is primarily associated with immunity and immune-related disorders. In recent years, IL-33/ST2 signaling pathway has been reported to promote the development of cancer and remodel the tumor microenvironment by expanding immune suppressive cells such as myeloid-derived suppressor cells or regulatory T cells. However, its role remains controversial in some tumor settings. IL-33 could also promote effective infiltration of immune cells such as CD8+ T and NK cells, which act as antitumor. These dual effects may limit the clinical application to target this cytokine axis. Therefore, more comprehensive exploration and deeper understanding of IL-33 are required. In this review, we summarized the IL-33/ST2 axis versatile roles in the tumor microenvironment with a focus on the IL-33-target immune cells and downstream signaling pathways. We also discuss how the IL-33/ST2 axis could be used as a potential therapeutic target for cancer immunotherapy.
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Affiliation(s)
- Wenyi Jiang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
| | - Jingyao Lian
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
| | - Ying Yue
- Clinical Laboratory, Henan Medical College Hospital Workers, Zhengzhou, Henan, China
| | - Yi Zhang
- Biotherapy Center and Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou, Henan, China
- Henan Key Laboratory for Tumor Immunology and Biotherapy, Zhengzhou, Henan, China
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29
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The expression of RIPK3 is associated with cell turnover of gastric mucosa in the mouse and human stomach. J Mol Histol 2021; 52:849-857. [PMID: 34173165 PMCID: PMC8324621 DOI: 10.1007/s10735-021-10001-5] [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: 01/12/2021] [Accepted: 06/17/2021] [Indexed: 01/10/2023]
Abstract
Necroptosis is a novel manner of programmed cell death and important for tissue development, homeostasis, damage, and repair. Activation of receptor-interacting protein kinase 3 (RIPK3), a key member of receptor-interacting protein family in contributing significantly to necroptosis, in tissues is a hallmark of cells dying by necroptosis. However, there are few studies that examine the expression of RIPK3 in the glandular cells of stomachs under physiological condition. We have therefore conducted this study to immunohistochemically characterize the key element of necroptosis, RIPK3, in the mouse and human stomach. Results showed that RIPK3 positive cells could be observed in the surface mucosal cells, granular cells, and lamina propria cells in both mouse and human stomach tissues. Ratios of PCNA/RIPK3 positive cells in the glandular cells were ~ 2.1 in mouse and ~ 4.15 in human sections respectively. Morphological and double immunofluorescence analysis confirmed that these RIPK3 positive cells were mucous, parietal and lamina propria cells. Our results indicate that the expression of RIPK3 in different cell types might contribute to cell turnover of gastric mucosa in the mouse and human stomach under physiological condition.
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30
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Cui G, Li Z, Florholmen J, Goll R. Dynamic stromal cellular reaction throughout human colorectal adenoma-carcinoma sequence: A role of TH17/IL-17A. Biomed Pharmacother 2021; 140:111761. [PMID: 34044278 DOI: 10.1016/j.biopha.2021.111761] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2021] [Revised: 05/07/2021] [Accepted: 05/20/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Accumulating data suggest that the tumour stroma rapidly undergoes dynamic mechanical and cellular changes by which creates a supportive milieu to promote disease progression and metastasis. Cytokines are reported to play a key role in the modulation of tumour stromal response. METHODS The activation of TH17/interleukin (IL)-17A network in association with tumour stromal proliferative and cellular response in samples from 50 patients with colorectal adenoma, 45 with colorectal cancer (CRCs) were elucidated with quantitative real-time PCR (q-PCR), immunohistochemistry and double immunofluorescence. RESULTS q-PCR results showed that retinoic acid-receptor-related orphan receptor-C, a critical transcriptional factor for TH17 cell differentiation, was significantly increased at the adenoma stage and slightly decreased at the CRC stage, but was still higher than that at normal controls. The level of TH17 signature cytokine IL-17A was shown in an increasing gradient throughout the adenoma-carcinoma sequence. Immunohistochemistry revealed an activated proliferative rate evaluated by Ki67 and population expansion of myofibroblasts in the adenoma/CRC stroma. Notably, densities of IL-17A-expressing cells were associated with populations of Ki67-positive cells and myofibroblasts in the adenoma/CRC stroma. Finally, CD146-positive stromal cells are an important participator for stroma remodelling, double immunofluorescence image demonstrated that IL-17 receptor C, one of the key elements for IL-17 receptor complex, was highly expressed in CD146-positive adenoma/CRC stromal cells. CONCLUSIONS An activated TH17/IL-17A network in the tumour microenvironment is significantly associated with dynamic stromal cellular response throughout the adenoma-carcinoma sequence, which might provide a supportive environment for the initiation and progression of CRC.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China; Faculty of Heath Science, Nord University at Levanger, Norway.
| | - Zhenfeng Li
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Jon Florholmen
- Research Group Gastroenterology Nutrition, Arctic University Norway, Tromsø, Norway
| | - Rasmus Goll
- Research Group Gastroenterology Nutrition, Arctic University Norway, Tromsø, Norway
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31
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Ercolano G, Gomez-Cadena A, Dumauthioz N, Vanoni G, Kreutzfeldt M, Wyss T, Michalik L, Loyon R, Ianaro A, Ho PC, Borg C, Kopf M, Merkler D, Krebs P, Romero P, Trabanelli S, Jandus C. PPARɣ drives IL-33-dependent ILC2 pro-tumoral functions. Nat Commun 2021; 12:2538. [PMID: 33953160 PMCID: PMC8100153 DOI: 10.1038/s41467-021-22764-2] [Citation(s) in RCA: 58] [Impact Index Per Article: 14.5] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/27/2020] [Accepted: 03/25/2021] [Indexed: 01/27/2023] Open
Abstract
Group 2 innate lymphoid cells (ILC2s) play a critical role in protection against helminths and in diverse inflammatory diseases by responding to soluble factors such as the alarmin IL-33, that is often overexpressed in cancer. Nonetheless, regulatory factors that dictate ILC2 functions remain poorly studied. Here, we show that peroxisome proliferator-activated receptor gamma (PPARγ) is selectively expressed in ILC2s in humans and in mice, acting as a central functional regulator. Pharmacologic inhibition or genetic deletion of PPARγ in ILC2s significantly impair IL-33-induced Type-2 cytokine production and mitochondrial fitness. Further, PPARγ blockade in ILC2s disrupts their pro-tumoral effect induced by IL-33-secreting cancer cells. Lastly, genetic ablation of PPARγ in ILC2s significantly suppresses tumor growth in vivo. Our findings highlight a crucial role for PPARγ in supporting the IL-33 dependent pro-tumorigenic role of ILC2s and suggest that PPARγ can be considered as a druggable pathway in ILC2s to inhibit their effector functions. Hence, PPARγ targeting might be exploited in cancer immunotherapy and in other ILC2-driven mediated disorders, such as asthma and allergy.
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Affiliation(s)
- Giuseppe Ercolano
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Alejandra Gomez-Cadena
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Nina Dumauthioz
- Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland
| | - Giulia Vanoni
- Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland
| | - Mario Kreutzfeldt
- Department of Pathology and Immunology, Division of Clinical Pathology, University and University Hospitals of Geneva, Geneva, Switzerland
| | - Tania Wyss
- Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland
| | - Liliane Michalik
- Center for Integrative Genomics, University of Lausanne, Lausanne, Switzerland
| | - Romain Loyon
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,University Hospital of Besançon, Department of Medical Oncology, Besançon, France
| | - Angela Ianaro
- Department of Pharmacy, University of Naples Federico II, Naples, Italy
| | - Ping-Chih Ho
- Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland
| | - Christophe Borg
- Univ. Bourgogne Franche-Comté, INSERM, EFS BFC, UMR1098, Interactions Hôte-Greffon-Tumeur/Ingénierie Cellulaire et Génique, Besançon, France.,University Hospital of Besançon, Department of Medical Oncology, Besançon, France
| | - Manfred Kopf
- Institute of Molecular Health Sciences, ETH Zürich, Zürich, Switzerland
| | - Doron Merkler
- Department of Pathology and Immunology, Division of Clinical Pathology, University and University Hospitals of Geneva, Geneva, Switzerland
| | - Philippe Krebs
- Institute of Pathology, University of Bern, Bern, Switzerland
| | - Pedro Romero
- Department of Oncology UNIL CHUV, University of Lausanne, Lausanne, Switzerland
| | - Sara Trabanelli
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland.,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland
| | - Camilla Jandus
- Department of Pathology and Immunology, University of Geneva, Geneva, Switzerland. .,Ludwig Institute for Cancer Research, Lausanne Branch, Lausanne, Switzerland.
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Cui G. The Mechanisms Leading to Distinct Responses to PD-1/PD-L1 Blockades in Colorectal Cancers With Different MSI Statuses. Front Oncol 2021; 11:573547. [PMID: 33763344 PMCID: PMC7982849 DOI: 10.3389/fonc.2021.573547] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/30/2020] [Accepted: 01/25/2021] [Indexed: 12/15/2022] Open
Abstract
Current clinical studies showed distinct therapeutic outcomes, in which CRC patients with mismatch repair-deficient (dMMR)/microsatellite instability high (MSI-H) seem to be relatively more "sensitive" in response to anti-programmed death-1 receptor (PD-1)/programmed death-1 receptor ligand 1 (PD-L1) therapy than those with mismatch repair-proficient (pMMR)/microsatellite instability-low (MSI-L). The mechanisms by which the same PD-1/PD-L1 blockades lead to two distinct therapeutic responses in CRC patients with different MSI statuses remain poorly understood and become a topic of great interest in both basic research and clinical practice. In this review of the potential mechanisms for the distinct response to PD-1/PD-L1 blockades between dMMR/MSI-H CRCs and pMMR/MSI-L CRCs, relevant references were electronically searched and collected from databases PubMed, MEDLINE, and Google scholar. Sixty-eight articles with full text and 10 articles by reference-cross search were included for final analysis after eligibility selection according to the guidelines of PRISMA. Analysis revealed that multiple factors e.g. tumor mutation burden, immune cell densities and types in the tumor microenvironment, expression levels of PD-1/PD-L1 and cytokines are potential determinants of such distinct response to PD-1/PD-L1 blockades in CRC patients with different MSI statuses which might help clinicians to select candidates for anti-PD-1/PD-L1 therapy and improve therapeutic response in patients with CRC.
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Affiliation(s)
- Guanglin Cui
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China.,Faculty of Health Science, Nord University, Bodø, Norway
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Increased IL-33 and IL-17 in Colorectal Carcinoma Patients with Severe Disease. SERBIAN JOURNAL OF EXPERIMENTAL AND CLINICAL RESEARCH 2020. [DOI: 10.2478/sjecr-2018-0034] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/19/2023] Open
Abstract
Abstract
Colorectal cancer (CRC) represents one of the most common cancers. It is frequently diagnosed at advanced stages, indicating on need for new diagnostic markers. The aim of this study was to determine systemic and fecal values of IL-17 and IL-33 in patients with CRC and the relationship with clinicopathological aspects of disease.
The blood samples and feces liquid fraction of 50 patients with CRC were analyzed. Serum and fecal levels of IL-33 and IL-17 were measured using sensitive enzyme-linked immunosorbent assay (ELISA) kits.
Fecal levels of Il-33 and IL-17 were increased in CRC patients with poor tumor tissue differentiation. Serum IL-33 and fecal IL-17 were increased in patients with presence of lung/liver metastasis or peritoneal carcinomatosis, respectively, while enhanced fecal IL-33 was detected only in patients with peritoneal carcinomatosis.
Positive correlation between IL-33 and IL-17 values in sera and feces, respectively was also observed.
We believe that increased local values of IL-33 and IL-17, reflected trough higher fecal concentration, in CRC patients with poor tumor tissue differentiation and with presence of lung/liver metastasis or peritoneal carcinomatosis may be considered as a sign of the tumor’s malignant progression and, consequently, of a poor prognosis for patients.
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Yu J, Zhang Y, Qian J. Endoscopic submucosal dissection in the treatment of patients with early colorectal carcinoma and precancerous lesions. J Gastrointest Oncol 2020; 11:911-917. [PMID: 33209487 PMCID: PMC7657837 DOI: 10.21037/jgo-20-393] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/31/2020] [Accepted: 10/12/2020] [Indexed: 12/25/2022] Open
Abstract
BACKGROUND Our study aims to explore the indications and clinical efficacy of endoscopic submucosal dissection (ESD) on the early colorectal carcinoma and precancerous lesions. METHODS The clinical data of 29 patients with early colorectal carcinoma and precancerous lesions who were treated with ESD at Nantong First People's Hospital between January 2018 and December 2019 were collected. Then the endoscopic morphology, postoperative pathological classification, tumor resection rate, postoperative complications, and follow-up outcomes were analyzed. RESULTS Colorectal carcinoma lesions were distributed in the left colon, accounting for 89.6%. There were 14 cases (48.3%) with protuberant endoscopic tumors, accounting for the highest proportion, while 2 cases (6.9%) of the flat tumors, accounting for the lowest proportion. The average operation time for ESD was 123 minutes, and en-bloc resection was 100% while the curative resection rate was 89.6%. There were 3 cases (10.3%) with delayed hemorrhage after ESD, and 1 case with persistent hemorrhage during the operation was transferred to surgical treatment. No cases with infection or perforation after ESD. For postoperative pathological classification, villous-tubular adenoma with low-grade epithelioma accounted for 31%; tubular adenoma with high-grade epithelioma only accounted for 3.4%. There was no recurrence in the follow-up for 1-20 months. CONCLUSIONS Control of surgical indications strictly, improvement of operation skills, attention to postoperative pathological feedback, and close follow-up are necessary guarantees to improve the clinical effectiveness of ESD.
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Affiliation(s)
- Jing Yu
- Department of Gastroenterology, the Second Affiliated Hospital of Nantong University, Nantong, China
| | - Yan Zhang
- Department of Gastroenterology, the Second Affiliated Hospital of Nantong University, Nantong, China
| | - Junbo Qian
- Department of Gastroenterology, the Second Affiliated Hospital of Nantong University, Nantong, China
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35
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Zhang X, Chen W, Zeng P, Xu J, Diao H. The Contradictory Role of Interleukin-33 in Immune Cells and Tumor Immunity. Cancer Manag Res 2020; 12:7527-7537. [PMID: 32904627 PMCID: PMC7457384 DOI: 10.2147/cmar.s262745] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2020] [Accepted: 08/02/2020] [Indexed: 12/29/2022] Open
Abstract
Interleukin (IL)-33 is a member of the IL-1 superfamily and is a crucial cytokine playing the role of a dual-function molecule. IL-33 mediates its function by interacting with its receptor suppression of tumorigenicity 2 (ST2), which is constitutively expressed on T helper (Th)1 cells, Th2 cells, and other immune cells. Previously, we summarized findings on IL-33 and performed an intensive study of the correlation between IL-33 and tumor. IL-33 enables anti-tumor immune responses through Th1 cells and natural killer (NK) cells and plays a role in tumor immune escape in cancers via Th2 cells and regulatory T cells. Herein, we discuss the contradictory role of IL-33 in immune cells in different cancer, and our summaries may be helpful for better understanding of the development of research on IL-33 and tumor immunity.
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Affiliation(s)
- Xujun Zhang
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Wenbiao Chen
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Ping Zeng
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Jia Xu
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
| | - Hongyan Diao
- State Key Laboratory for Diagnosis and Treatment of Infectious Diseases, National Clinical Research Center for Infectious Diseases, Collaborative Innovation Center for Diagnosis and Treatment of Infectious Diseases, The First Affiliated Hospital, College of Medicine, Zhejiang University, Hangzhou 310003, People's Republic of China
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36
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Eissmann MF, Buchert M, Ernst M. IL33 and Mast Cells-The Key Regulators of Immune Responses in Gastrointestinal Cancers? Front Immunol 2020; 11:1389. [PMID: 32719677 PMCID: PMC7350537 DOI: 10.3389/fimmu.2020.01389] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/14/2020] [Accepted: 05/29/2020] [Indexed: 12/13/2022] Open
Abstract
The Interleukin (IL-)1 family IL33 is best known for eliciting type 2 immune responses by stimulating mast cells (MCs), regulatory T-cells (Tregs), innate lymphoid cells (ILCs) and other immune cells. MCs and IL33 provide critical control of immunological and epithelial homeostasis in the gastrointestinal (GI) tract. Meanwhile, the role of MCs in solid malignancies appears tissue-specific with both pro and anti-tumorigenic activities. Likewise, IL33 signaling significantly shapes immune responses in the tumor microenvironment, but these effects remain often dichotomous when assessed in experimental models of cancer. Thus, the balance between tumor suppressing and tumor promoting activities of IL33 are highly context dependent, and most likely dictated by the mixture of cell types responding to IL33. Adding to this complexity is the promiscuous nature by which MCs respond to cytokines other than IL33 and release chemotactic factors that recruit immune cells into the tumor microenvironment. In this review, we integrate the outcomes of recent studies on the role of MCs and IL33 in cancer with our own observations in the GI tract. We propose a working model where the most abundant IL33 responsive immune cell type is likely to dictate an overall tumor-supporting or tumor suppressing outcome in vivo. We discuss how these opposing responses affect the therapeutic potential of targeting MC and IL33, and highlight the caveats and challenges facing our ability to effectively harness MCs and IL33 biology for anti-cancer immunotherapy.
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Affiliation(s)
- Moritz F Eissmann
- Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Michael Buchert
- Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Matthias Ernst
- Olivia Newton-John Cancer Research Institute, and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
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37
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Jevtovic A, Pantic J, Jovanovic I, Milovanovic M, Stanojevic I, Vojvodic D, Arsenijevic N, Lukic ML, Radosavljevic GD. Interleukin-33 pretreatment promotes metastatic growth of murine melanoma by reducing the cytotoxic capacity of CD8 + T cells and enhancing regulatory T cells. Cancer Immunol Immunother 2020; 69:1461-1475. [PMID: 32285171 DOI: 10.1007/s00262-020-02522-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/27/2018] [Accepted: 02/15/2020] [Indexed: 01/08/2023]
Abstract
Interleukin-33 (IL-33) regulates innate and acquired immune response to pathogens, self-antigens and tumors. IL-33 effects on tumors depend on the dose and mode of administration along with the type of malignancy. We studied the effects of IL-33 on the development of primary and metastatic melanoma induced by B16-F1 cell line in C57BL/6 mice. Intraperitoneally applied IL-33 restricts primary tumor growth. When administered intranasally 3 days prior to the intravenous injection of the tumor cells, IL-33 promoted growth of B16-F1 melanoma metastases, while B16-F10 gave massive metastases independently of IL-33. To mimic natural dissemination, we next used a limited number (5 × 104) of B16-F1 cells intravenously followed by application of IL-33 intraperitoneally. IL-33 increased the size of metastases (10.96 ± 3.96 mm2) when compared to the control group (0.86 ± 0.39 mm2), without changing incidence and number of metastases. IL-33 increased expression of ST2 on both tumor and immune cells in metastases. Also, IL-33 enhanced eosinophils and anti-tumor NK cells in the lung. The striking finding was reduced cytotoxicity of CD8+ T cells derived from metastatic lung of IL-33 injected mice. IL-33 reduced the percentage of TNF-α+ and IFN-γ+ CD8+ T cells while increasing the frequency of CD8+ T cells that express inhibitory molecules (PD-1, KLRG-1 and CTLA-4). There was a significant accumulation of CD11b+Gr-1+ myeloid suppressor cells and FoxP3+, IL-10+ and CTLA-4+ regulatory T cells in the metastatic lung of IL-33 injected mice. The relevance of IL-33 for melanoma metastases was also documented in a significantly increased level of serum IL-33 in stage III melanoma patients.
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Affiliation(s)
- Andra Jevtovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia.,Department of Otorhinolaryngology, Faculty of Medical Sciences, University of Kragujevac, Kragujevac, Serbia
| | - Jelena Pantic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Ivan Jovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Marija Milovanovic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Ivan Stanojevic
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Danilo Vojvodic
- Institute for Medical Research, Military Medical Academy, Belgrade, Serbia
| | - Nebojsa Arsenijevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia
| | - Miodrag L Lukic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia.
| | - Gordana D Radosavljevic
- Center for Molecular Medicine and Stem Cell Research, Faculty of Medical Sciences, University of Kragujevac, 69 Svetozara Markovica Street, 34000, Kragujevac, Serbia.
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Cui G, Yuan A, Li Z, Goll R, Florholmen J. ST2 and regulatory T cells in the colorectal adenoma/carcinoma microenvironment: implications for diseases progression and prognosis. Sci Rep 2020; 10:5892. [PMID: 32246094 PMCID: PMC7125220 DOI: 10.1038/s41598-020-62502-0] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2019] [Accepted: 03/13/2020] [Indexed: 02/07/2023] Open
Abstract
ST2 (also known as IL1RL1) is the critical functional receptor for interleukin (IL)-33 in stimulating regulatory T cell (Treg) expansion and function in physiological and pathological conditions. We examined the correlation between ST2 cell expression and FoxP3 positive Tregs in both colorectal adenoma and cancer (CRC) microenvironment by real-time PCR, immunohistochemistry (IHC) and double immunofluorescences. The clinicopathological and prognostic significance of cellular ST2-positive cells and FoxP3-positive Tregs in patients with adenoma and CRC were evaluated. Real-time PCR results revealed increased expression levels of ST2 and FoxP3 mRNAs in both adenoma and CRC tissues as compared with control tissues. IHC analysis confirmed increased densities of ST2-positive cells in both the adenoma/CRC epithelium and stroma, which show a close positive linear association with the densities of FoxP3-positive Tregs in respective compartments. Pathological feature analysis showed that densities of ST2-positive cells in the tumor stroma were notably associated with degree of dysplastic grading in patients with adenoma, and disease stages and lymph node metastasis in patients with CRC. Kaplan-Meier survival curves suggested that CRC patients with high densities of ST2-positive cells in the stroma tend to have a shorter overall survival. We therefore concluded that increased densities of ST2-postive cells relate to Treg accumulation within the adenoma/CRC microenvironment, suggesting the IL-33/ST2 pathway as a potential contributor for immunosuppressive milieu formation that impact disease stage and prognosis in patients with CRC.
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Affiliation(s)
- Guanglin Cui
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Henan, China. .,Faculty of Health Science, Nord University at Campus Levanger, Levanger, Norway.
| | - Aping Yuan
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Henan, China
| | - Zhenfeng Li
- Department of Gastroenterology, the Second Affiliated Hospital of Zhengzhou University, Henan, China
| | - Rasmus Goll
- Department of Gastroenterology & Nutrition, University Hospital of North Norway, Tromsø, University of Tromsø, Tromsø, Norway
| | - Jon Florholmen
- Department of Gastroenterology & Nutrition, University Hospital of North Norway, Tromsø, University of Tromsø, Tromsø, Norway
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Zhang X, Yuan A, Zhao X, Li Z, Cui G. Tumoral Expression of CD166 in Human Esophageal Squamous Cell Carcinoma: Implications for Cancer Progression and Prognosis. Cancer Biother Radiopharm 2020; 35:214-222. [PMID: 32196367 DOI: 10.1089/cbr.2019.3089] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Accumulating data showed that cancer stem cells (CSCs) identified by cell surface markers contribute to the initiation, progression, and prognosis of human cancers. In this study, the expression of CSC candidates CD166, CD44, and Lgr5 in 65 cases of esophageal squamous cell carcinoma (ESCC) and 16 cases of control esophageal tissues were examined with immunohistochemistry (IHC). The correlation between tumoral expression levels of these CSC candidates and clinicopathological variables was analyzed. IHC results showed that the expression of CD166 in esophageal control tissues was completely negative, but it was in 87.69% (57/65) ESCC tissues. The expression of CD44 and Lgr5 did not differ between esophageal control tissues and ESCC tissues (p > 0.05). In addition, there were not correlations found among the expression levels of CD166, CD44, and Lgr5 in ESCC tissues. Clinicopathological analysis revealed that the tumoral expression level of CD166 correlated with lymph node involvement and TNM staging in patients with ESCC, and lower tumoral expression of CD44 was found in patients with advanced TNM staging. Kaplan-Meier survival curves suggested that expression level of CD166 appeared to have a negative impact on overall survival rate after surgery in patients with ESCC. Such impact was not found in other two CSC candidates. The authors therefore conclude that CD166 is a potential prognostic biomarker and correlates with advanced progression features in patients with ESCC.
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Affiliation(s)
- Xiaoshan Zhang
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.,The Academy of Medical Science, Zhengzhou University, Zhengzhou, China
| | - Aping Yuan
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.,Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
| | - Xueru Zhao
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Zhenfeng Li
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China
| | - Guanglin Cui
- Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital, Zhengzhou University, Zhengzhou, China.,Faculty of Health Science, Nord University, Campus Levanger, Levanger, Norway
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A Functional Polymorphism in the Promoter Region of Interleukin-12B Increases the Risk of Colorectal Cancer. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2091781. [PMID: 32149085 PMCID: PMC7054766 DOI: 10.1155/2020/2091781] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 11/15/2019] [Accepted: 01/31/2020] [Indexed: 01/05/2023]
Abstract
Objective To investigate whether the polymorphisms of interleukin-12B (IL-12B) were associated with the risk of developing colorectal cancer (CRC). Patients and Methods. Genotypes of rs17860508 and rs3212227 were determined by polymerase chain reaction with a direct sequencing method in 329 CRC patients and 342 matched healthy control subjects. The expression of IL-12B) were associated with the risk of developing colorectal cancer (CRC). Results Compared with TTAGAG/TTAGAG genotype of rs17860508, the GC/GC and TTAGAG/GC genotypes may significantly increase the risk of CRC (OR = 1.81, 95% CI = 1.18-2.78; OR = 1.46, 95% CI = 1.01-2.12, respectively). Furthermore, the mRNA levels of IL-12B) were associated with the risk of developing colorectal cancer (CRC). P=0.009) and TTAGAG/TTAGAG (P=0.009) and TTAGAG/TTAGAG (. Conclusion These data suggested that the rs17860508 GC/GC genotype might upregulate IL-12B expression at the transcriptional level and thus increase the risk of CRC.IL-12B) were associated with the risk of developing colorectal cancer (CRC).
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IL33 activates CD8+T and NK cells through MyD88 pathway to suppress the lung cancer cell growth in mice. Biotechnol Lett 2020; 42:1113-1121. [PMID: 32140881 DOI: 10.1007/s10529-020-02815-2] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2019] [Accepted: 01/06/2020] [Indexed: 12/12/2022]
Abstract
OBJECTIVE In this study, we observed the effects of IL-33 on tumor immune response in lung cancer-bearing mice using wild type and MyD88-/- mice respectively. METHODS Wild C57BL/6 (C57BL/6WT), MyD88 knockout C57BL/6 mice (C57BL/6 MyD88-/-) and Lewis cells were used in this study. Cell proliferation, cytokine release and cytotoxicity were detected. RESULTS IL-33 could significantly up-regulate specific cellular immunity, inhibit tumor growth and improve survival time in wild type mice group, and it had dose dependent effect. However, IL-33 had no effect on cell immunity and tumor growth in MyD88-/- mice group. Compared with MyD88-/- mice, IL-33 could significantly increase the ratio of CD8+T cells to neutrophils in wild type mice, while the percentage of tumor infiltrating CD11b+ cells, Mo-MDSC, F4/80+ macrophages and mDC cells decreased significantly in wild type mice group. IL-33 could upregulate the expression of CD107a and IFN-γ in CD8+T cells and NK cells of wild type mice, while IL-33 could not upregulate them in MyD88-/- mice. IL-33 could upregulate the expression of CD40, CD80, CD86 and CD205 in DC cells in wild type mice, induce T cells to differentiate into Th1 cells and enhance tumor cell immunity. CONCLUSIONS IL-33 could promote differentiation and maturation of DC cells through MyD88 pathway, up-regulate the tumor immunity of CD8+T cells and NK cells, and inhibit the proliferation of lung cancer cells.
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Yue Y, Lian J, Wang T, Luo C, Yuan Y, Qin G, Zhang B, Zhang Y. Interleukin-33-nuclear factor-κB-CCL2 signaling pathway promotes progression of esophageal squamous cell carcinoma by directing regulatory T cells. Cancer Sci 2020; 111:795-806. [PMID: 31883400 PMCID: PMC7060484 DOI: 10.1111/cas.14293] [Citation(s) in RCA: 41] [Impact Index Per Article: 8.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2019] [Revised: 12/18/2019] [Accepted: 12/20/2019] [Indexed: 12/12/2022] Open
Abstract
Esophageal cancer is currently one of the most fatal cancers. However, there is no effective treatment. Increasing evidence suggests that interleukin (IL)-33 has a significant role in tumor progression and metastasis. Currently, the underlying cellular and molecular mechanism of IL-33 in promoting esophageal squamous cell carcinoma (ESCC) remains unclear. In this study, we investigated whether IL-33 could induce the epithelial-mesenchymal transition (EMT) in ESCC. Interleukin-33 expression was examined in ESCC and corresponding adjacent normal tissues by immunohistochemistry and quantitative real-time PCR experiments. Elevated IL-33 levels were observed in ESCC tissues. Further in vitro experiments were undertaken to elucidate the effect of IL-33 on migration and invasion in KYSE-450 and Eca-109 esophageal cancer cells. Knockdown of IL-33 decreased the metastasis and invasion capacity in esophageal cancer cells, whereas IL-33 overexpression showed the opposite effect. We then screened CCL2 which is a downstream molecule of IL-33, and proved that IL-33 could promote tumor development and metastasis by recruiting regulatory T cells (Tregs) through CCL2, and IL-33 regulated the expression of CCL2 through transforming growth factor-β in Treg cells. Knockdown of IL-33 decreased the development of human ESCC xenografts in BALB/c nude mice. Collectively, we found that the IL-33/nuclear factor-κB/CCL2 pathway played an essential role in human ESCC progress. Hence, IL-33 should be considered as an effective therapy target for ESCC.
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Affiliation(s)
- Ying Yue
- Biotherapy CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Clinical LaboratoryThe Seventh People's Hospital of ZhengzhouZhengzhouChina
| | - Jingyao Lian
- Biotherapy CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Tian Wang
- Biotherapy CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Chenghan Luo
- Biotherapy CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Yiqiang Yuan
- Clinical LaboratoryThe Seventh People's Hospital of ZhengzhouZhengzhouChina
| | - Guohui Qin
- Biotherapy CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
| | - Bin Zhang
- Department of Hematology/OncologySchool of MedicineNorthwestern UniversityChicagoILUSA
| | - Yi Zhang
- Biotherapy CenterThe First Affiliated Hospital of Zhengzhou UniversityZhengzhouChina
- Henan Key Laboratory for Tumor Immunology and BiotherapyZhengzhouChina
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43
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Landskron G, De la Fuente López M, Dubois-Camacho K, Díaz-Jiménez D, Orellana-Serradell O, Romero D, Sepúlveda SA, Salazar C, Parada-Venegas D, Quera R, Simian D, González MJ, López-Köstner F, Kronberg U, Abedrapo M, Gallegos I, Contreras HR, Peña C, Díaz-Araya G, Roa JC, Hermoso MA. Interleukin 33/ST2 Axis Components Are Associated to Desmoplasia, a Metastasis-Related Factor in Colorectal Cancer. Front Immunol 2019; 10:1394. [PMID: 31281317 PMCID: PMC6598075 DOI: 10.3389/fimmu.2019.01394] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2018] [Accepted: 06/03/2019] [Indexed: 12/24/2022] Open
Abstract
In colorectal cancer (CRC), cancer-associated fibroblasts (CAFs) are the most abundant component from the tumor microenvironment (TM). CAFs facilitate tumor progression by inducing angiogenesis, immune suppression and invasion, thus altering the organization/composition of the extracellular matrix (i.e., desmoplasia) and/or activating epithelial-mesenchymal transition (EMT). Soluble factors from the TM can also contribute to cell invasion through secretion of cytokines and recently, IL-33/ST2 pathway has gained huge interest as a protumor alarmin, promoting progression to metastasis by inducing changes in TM. Hence, we analyzed IL-33 and ST2 content in tumor and healthy tissue lysates and plasma from CRC patients. Tissue localization and distribution of these molecules was evaluated by immunohistochemistry (using localization reference markers α-smooth muscle actin or α-SMA and E-cadherin), and clinical/histopathological information was obtained from CRC patients. In vitro experiments were conducted in primary cultures of CAFs and normal fibroblasts (NFs) isolated from tumor and healthy tissue taken from CRC patients. Additionally, migration and proliferation analysis were performed in HT29 and HCT116 cell lines. It was found that IL-33 content increases in left-sided CRC patients with lymphatic metastasis, with localization in tumor epithelia associated with abundant desmoplasia. Although ST2 content showed similarities between tumor and healthy tissue, a decreased immunoreactivity was observed in left-sided tumor stroma, associated to metastasis related factors (advanced stages, abundant desmoplasia, and presence of tumor budding). A principal component analysis (including stromal and epithelial IL-33/ST2 and α-SMA immunoreactivity with extent of desmoplasia) allowed us to distinguish clusters of low, intermediate and abundant desmoplasia, with potential to develop a diagnostic signature with benefits for further therapeutic targets. IL-33 transcript levels from CAFs directly correlated with CRC cell line migration induced by CAFs conditioned media, with rhIL-33 inducing a mesenchymal phenotype in HT29 cells. These results indicate a role of IL-33/ST2 in tumor microenvironment, specifically in the interaction between CAFs and epithelial tumor cells, thus contributing to invasion and metastasis in left-sided CRC, most likely by activating desmoplasia.
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Affiliation(s)
- Glauben Landskron
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
| | - Marjorie De la Fuente López
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile.,Research Sub-direction, Academic Direction, Clinica Las Condes, Santiago, Chile
| | - Karen Dubois-Camacho
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
| | - David Díaz-Jiménez
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
| | - Octavio Orellana-Serradell
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
| | - Diego Romero
- Pathology Department, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Santiago A Sepúlveda
- Pathology Department, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Christian Salazar
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
| | - Daniela Parada-Venegas
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
| | - Rodrigo Quera
- Inflammatory Bowel Disease Program, Gastroenterology Department, Clinica Las Condes, Santiago, Chile
| | - Daniela Simian
- Research Sub-direction, Academic Direction, Clinica Las Condes, Santiago, Chile
| | - María-Julieta González
- Cell and Molecular Biology Program, Faculty of Medicine, Institute of Biomedical Sciences, Universidad de Chile, Santiago, Chile
| | | | - Udo Kronberg
- Coloproctology Department, Clinica Las Condes, Santiago, Chile
| | - Mario Abedrapo
- Coloproctology Department, Clinica Las Condes, Santiago, Chile.,Coloproctology Surgery Department, Hospital Clinico Universidad de Chile, Santiago, Chile
| | - Iván Gallegos
- Pathology Department, Hospital Clinico Universidad de Chile, Santiago, Chile
| | - Héctor R Contreras
- Department of Basic and Clinic Oncology, Faculty of Medicine, Universidad de Chile, Santiago, Chile
| | - Cristina Peña
- Medical Oncology Department, Ramon y Cajal University Hospital, IRYCIS, CIBERONC, Madrid, Spain
| | - Guillermo Díaz-Araya
- Molecular Pharmacology Laboratory, Faculty of Chemical Pharmaceutical Sciences, Universidad de Chile, Santiago, Chile
| | - Juan Carlos Roa
- Pathology Department, Faculty of Medicine, Pontificia Universidad Catolica de Chile, Santiago, Chile
| | - Marcela A Hermoso
- Immunology Program, Innate Immunity Laboratory, Faculty of Medicine, Biomedical Sciences Institute, Universidad de Chile, Santiago, Chile
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Li ZH, Han BW, Zhang XF. A functional polymorphism in the promoter region of IL-33 is associated with the reduced risk of colorectal cancer. Biomark Med 2019; 13:567-575. [PMID: 31140826 DOI: 10.2217/bmm-2018-0249] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/31/2022] Open
Abstract
Aim: We aimed to investigate IL-33 polymorphisms with risk of colorectal cancer (CRC). Materials & methods: IL-33 rs7025417 and rs1332290 were genotyped using a quantitative allelic Taqman assay. The expression of IL-33 mRNA was determined by real-time PCR and promoter activity was assayed using the Dual-Luciferase Reporter Assay. Results: The IL-33 rs7025417 CC genotype and C allele may decrease CRC risk. The IL-33 rs1332290 AC carriers had an increased risk of developing clinical Stage III-IV CRC. Lower levels of IL-33 mRNA were present in individuals with the rs7025417 CC genotype. Moreover, the rs7025417 C allele suppressed promoter activity of IL-33. Conclusion: These data suggest that the rs7025417 CC genotype may downregulate IL-33 mRNA and subsequently reduce the risk of CRC.
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Affiliation(s)
- Zhao-Hui Li
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China.,Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471003, PR China
| | - Bao-Wei Han
- Department of Gastrointestinal Surgery, Luoyang Central Hospital Affiliated to Zhengzhou University, Luoyang, Henan 471003, PR China
| | - Xie-Fu Zhang
- Department of Gastrointestinal Surgery, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan 450052, PR China
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45
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Interleukin-33 Involvement in Nonsmall Cell Lung Carcinomas: An Update. Biomolecules 2019; 9:biom9050203. [PMID: 31130612 PMCID: PMC6572046 DOI: 10.3390/biom9050203] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/17/2019] [Revised: 05/13/2019] [Accepted: 05/22/2019] [Indexed: 12/11/2022] Open
Abstract
Lung carcinogenesis is a multistep process involving genetic mutations and epigenetic changes, with the acquisition of a malignant phenotype characterized by apoptosis resistance, unregulated proliferation and differentiation, invasion, and metastatic abilities. However, neoplastic development and progression seem to be aided by non-neoplastic cells; the molecules they produced can either promote the immune response or, alternatively, support tumor pathogenesis. Consequently, the relative contribution of tumor-associated inflammatory pathways to cancer development has become crucial information. Interleukin-33 (IL-33) is an IL-1-like alarmin, and it is a ligand for the suppressor of tumorigenicity 2 (ST2) receptor. IL-33 functions as a dual role cytokine with the ability to induce T-helper-type 2 (Th2) immune cells and translocate into the nucleus, suppressing gene transcription. Although its function in immunity- and immune-related disorders is well known, its role in tumorigenesis is still debated. The IL-33/ST2 axis is emerging as a powerful modulator of the tumor microenvironment (TME) by recruiting immune cells, able to modify the TME, supporting malignant proliferation or improving antitumor immunity. In the present review, we discuss IL-33′s potential role in lung carcinogenesis and its possible application as a therapeutic target.
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46
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Cui G, Li Z, Ren J, Yuan A. IL-33 in the tumor microenvironment is associated with the accumulation of FoxP3-positive regulatory T cells in human esophageal carcinomas. Virchows Arch 2019; 475:579-586. [DOI: 10.1007/s00428-019-02579-9] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2019] [Revised: 04/07/2019] [Accepted: 04/18/2019] [Indexed: 12/13/2022]
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Kaleta-Richter M, Kawczyk-Krupka A, Aebisher D, Bartusik-Aebisher D, Czuba Z, Cieślar G. The capability and potential of new forms of personalized colon cancer treatment: Immunotherapy and Photodynamic Therapy. Photodiagnosis Photodyn Ther 2019; 25:253-258. [PMID: 30611864 DOI: 10.1016/j.pdpdt.2019.01.004] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/06/2018] [Revised: 12/19/2018] [Accepted: 01/02/2019] [Indexed: 02/07/2023]
Abstract
INTRODUCTION PDT can interfere with cytokine-mediated responses that play an important role in the processes of cancer progression, tumor angiogenesis and metastasis. Therefore, based on the identification of these cancer biomarkers, the therapy of combining various forms of treatment, including immunotherapy and PDT, may be a justified strategy for colorectal cancer treatment that focuses on individualized comprehensive therapy. METHOD We reviewed the major approaches on the use of immunotherapy in colorectal cancer, with the special regard to photodynamic therapy, its immunological effect and new oncological treatment directions, connected with adjuvant immunotherapy including use of nanoparticles. Databases such as PubMed, ScienceDirect and Springer were utilized to search the literature for relevant articles. PURPOSE To review studies of the immunotherapy in colon cancer and immune response to PDT. CONCLUSION Based on the identification of immunological cancer biomarkers, the therapy of combining various forms of treatment, including immunotherapy and PDT, may be a justified strategy for colorectal cancer treatment that focuses on individualized comprehensive therapy.
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Affiliation(s)
- Marta Kaleta-Richter
- School of Medicine with the Division of Dentistry in Zabrze, Department of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego Street 15, 41-902 Bytom, Poland; School of Medicine with the Division of Dentistry in Zabrze, Department of Internal Medicine, Dermatology and Allergology, Medical University of Silesia in Katowice, Marii Curie - Skłodowskiej Street 10, 41-800 Zabrze, Poland.
| | - Aleksandra Kawczyk-Krupka
- School of Medicine with the Division of Dentistry in Zabrze, Department of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego Street 15, 41-902 Bytom, Poland.
| | - David Aebisher
- Department of Photomedicine and Physical Chemistry, Faculty of Medicine, University of Rzeszów, Tadeusza Rejtana Avenue 16 C, 35-310 Rzeszów, Poland.
| | - Dorota Bartusik-Aebisher
- Department of Biochemistry and General Chemistry, Faculty of Medicine, University of Rzeszów, Tadeusza Rejtana Avenue 16 C, 35-310 Rzeszów, Poland.
| | - Zenon Czuba
- School of Medicine with the Division of Dentistry in Zabrze, Department of Microbiology and Immunology, Medical University of Silesia in Katowice, 19 Jordana St., 41- 808 Zabrze, Poland.
| | - Grzegorz Cieślar
- School of Medicine with the Division of Dentistry in Zabrze, Department of Internal Diseases, Angiology and Physical Medicine, Center for Laser Diagnostics and Therapy, Medical University of Silesia in Katowice, Batorego Street 15, 41-902 Bytom, Poland.
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48
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Huang Q, Cao W, Mielke LA, Seillet C, Belz GT, Jacquelot N. Innate Lymphoid Cells in Colorectal Cancers: A Double-Edged Sword. Front Immunol 2019; 10:3080. [PMID: 32010138 PMCID: PMC6974476 DOI: 10.3389/fimmu.2019.03080] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2019] [Accepted: 12/17/2019] [Indexed: 12/22/2022] Open
Abstract
The immune system plays a fundamental role at mucosal barriers in maintaining tissue homeostasis. This is particularly true for the gut where cells are flooded with microbial-derived signals and antigens, which constantly challenge the integrity of the intestinal barrier. Multiple immune cell populations equipped with both pro- and anti-inflammatory functions reside in the gut tissue and these cells tightly regulate intestinal health and functions. Dysregulation of this finely tuned system can progressively lead to autoimmune disease and inflammation-driven carcinogenesis. Over the last decade, the contribution of the adaptive immune system in controlling colorectal cancer has been studied in detail, but the role of the innate system, particularly innate lymphoid cells (ILCs), have been largely overlooked. By sensing their microenvironment, ILCs are essential in supporting gut epithelium repair and controling bacterial- and helminth-mediated intestinal infections, highlighting their important role in maintaining tissue integrity. Accumulating evidence also suggests that they may play an important role in carcinogenesis including intestinal cancers. In this review, we will explore the current knowledge about the pro- and anti-tumor functions of ILCs in colorectal cancer.
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Affiliation(s)
- Qiutong Huang
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Wang Cao
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Lisa Anna Mielke
- Olivia Newton-John Cancer Research Institute and La Trobe University School of Cancer Medicine, Heidelberg, VIC, Australia
| | - Cyril Seillet
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
| | - Gabrielle T. Belz
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
- The University of Queensland Diamantina Institute, The University of Queensland, Brisbane, QLD, Australia
- *Correspondence: Gabrielle T. Belz
| | - Nicolas Jacquelot
- Walter and Eliza Hall Institute of Medical Research, Parkville, VIC, Australia
- Department of Medical Biology, University of Melbourne, Parkville, VIC, Australia
- Nicolas Jacquelot
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49
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Cui G, Ren J, Xu G, Li Z, Zheng W, Yuan A. Cellular and clinicopathological features of the IL-33/ST2 axis in human esophageal squamous cell carcinomas. Cancer Cell Int 2018; 18:203. [PMID: 30559604 PMCID: PMC6290492 DOI: 10.1186/s12935-018-0700-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 12/06/2018] [Indexed: 12/14/2022] Open
Abstract
Background Emerging evidence has suggested that interleukin (IL)-33 and its primary functional receptor ST2 are involved in the pathogenesis of tumorigenesis. Methods Using immunohistochemistry (IHC) and double immunofluorescence staining, we characterized the cellular and clinicopathological features of the IL-33/ST2 axis in different compartments in human esophageal squamous cell carcinoma (ESCC) surgical specimens. Results IHC data revealed an increased expression of IL-33-immunoreactivity (IR) and ST2-IR located in both ESCC cells and tumor stromal cells; which were associated with advanced clinicopathological features such as TNM stages and node involvement. However, the Kaplan–Meier analysis showed that densities of neither IL-33 positive nor ST2 positive cells in both the ESCC mass and stroma were associated with the overall survival rate in patients with ESCC. Double immunofluorescence staining for cellular feature analysis demonstrated that these IL-33 positive and ST2 positive cells in ESCCs were with a high proliferation rate, and IL-33-IR was frequently co-expressed with ST2-IR in both ESCC and stromal cells. Conclusion Significant altered cellular features of the IL-33/ST2 axis in ESCCs were associated with advanced clinicopathological variables. The data suggest that the IL-33/ST2 axis might be involved in the progression of human ESCCs.
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Affiliation(s)
- Guanglin Cui
- 1Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China.,2Faculty of Health Science, Nord University, Campus Levanger, Levanger, Norway
| | - Jingli Ren
- 3Department of Pathology, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Gang Xu
- 1Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Zhenfeng Li
- 1Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Wei Zheng
- 1Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China
| | - Aping Yuan
- 1Research Group of Gastrointestinal Diseases, the Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan China.,4Faculty of Chemistry, Biotechnology and Food Science, Norwegian University of Life Sciences, Ås, Norway
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50
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Zhou Y, Ji Y, Wang H, Zhang H, Zhou H. IL-33 Promotes the Development of Colorectal Cancer Through Inducing Tumor-Infiltrating ST2L + Regulatory T Cells in Mice. Technol Cancer Res Treat 2018; 17:1533033818780091. [PMID: 29950152 PMCID: PMC6048617 DOI: 10.1177/1533033818780091] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023] Open
Abstract
Colorectal cancer, one of the most commonly diagnosed and lethal cancers worldwide, is accompanied by the disorders of immune system. However, the underlying mechanism is still not fully understood. In this study, our goal was to determine whether interleukin 33 promotes tumorigenesis and progression of colorectal cancer through increased recruitment of tumor-infiltrating ST2+ regulatory T cells in CT26 tumor-bearing mice. We found that the mRNA or protein levels of interleukin 33, soluble ST2, and membrane ST2 were elevated in the serum of tumor-bearing mice when compared to WT mice. The mRNA levels of interleukin 33, soluble ST2, and membrane ST2 were also elevated in the tissue of tumor-bearing mice when compared to surrounding nontumor muscular tissues. In addition, the frequency of ST2L+ regulatory T cells was significantly increased in both tumor tissue and spleen of tumor-bearing mice. Higher protein levels of interleukin-4, -10, and -13 were also observed in the serum or the tumor homogenates of tumor-bearing mice. We found exogenously administered recombinant mouse interleukin 33 promoted tumor size and induced tumor-infiltrating ST2L+ regulatory T cells in tumor-bearing mice while neutralizing interleukin-33 or ST2L inhibited tumor size and decreased ST2L+ regulatory T cells. Furthermore, ST2L+ regulatory T cells from tumor tissue were also able to suppress CD4+CD25-T cell proliferation and interferon γ production. Altogether, our findings demonstrate the critical roles of interleukin 33 in promoting colorectal cancer development through inducing tumor-infiltrating ST2L+ regulatory T cells, and inhibition of interleukin-33/ST2L signaling maybe a potential target for the prevention of colorectal cancer.
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Affiliation(s)
- Yaxing Zhou
- 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China
| | - Yong Ji
- 2 Department of Cardiothoracic Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Nanjing, China
| | - Honggang Wang
- 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China
| | - Hai Zhang
- 3 Department of Hepatobiliary Surgery, Affiliated Hospital of Jiangsu University, Zhenjiang, China
| | - Haihua Zhou
- 1 Department of Hepatobiliary Surgery, the Fifth Affiliated Hospital of Medical School of Nantong University, Nantong, China
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