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Liu L, Luo H, Xie Y, Wang Y, Ren S, Sun H, Xin Z, Li D. Endogenous IL-33 inhibits apoptosis in non-small cell lung cancer cells by regulating BCL2/BAX via the ERK1/2 pathway. Sci Rep 2025; 15:6422. [PMID: 39984631 PMCID: PMC11845513 DOI: 10.1038/s41598-025-91202-w] [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: 10/15/2024] [Accepted: 02/18/2025] [Indexed: 02/23/2025] Open
Abstract
Lung cancer remains a leading cause of cancer-related mortality worldwide, with non-small cell lung cancer (NSCLC) accounting for 85% of cases. Although targeted therapies have improved treatment outcomes, drug resistance poses a significant challenge, underscoring the need for novel therapeutic strategies. Interleukin-33 (IL-33), a member of the IL-1 superfamily, functions both as a nuclear protein and a cytokine, binding to its receptor, ST2. While IL-33 is known to promote tumour cell migration and metastasis, its role in regulating apoptosis remains incompletely understood. In this study, we focused on endogenous IL-33, employing lentiviral transfection to overexpress both the full-length and mature forms of IL-33 in lung cancer cells. We examined its effects on apoptosis in vitro and investigated the underlying molecular mechanisms. Our findings reveal that endogenous IL-33 inhibits apoptosis in lung cancer cells by modulating the expression of BCL2 and BAX via the ERK1/2 pathway in an autocrine manner. These results uncover a novel mechanism of IL-33-mediated tumour survival and provide a foundation for the development of IL-33/ST2-targeted therapies in NSCLC.
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Affiliation(s)
- Liping Liu
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Haoge Luo
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Yingdong Xie
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Ying Wang
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Shiying Ren
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Haiyang Sun
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China
| | - Zhuoyuan Xin
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China.
| | - Dong Li
- Key Laboratory of Pathobiology, Ministry of Education, College of Basic Medical Sciences, Jilin University, Changchun, China.
- Department of Immunology, College of Basic Medical Sciences, Jilin University, Changchun, China.
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2
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Sheng F, Li M, Yu JM, Yang SY, Zou L, Yang GJ, Zhang LL. IL-33/ST2 axis in diverse diseases: regulatory mechanisms and therapeutic potential. Front Immunol 2025; 16:1533335. [PMID: 39925809 PMCID: PMC11802536 DOI: 10.3389/fimmu.2025.1533335] [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: 11/23/2024] [Accepted: 01/02/2025] [Indexed: 02/11/2025] Open
Abstract
Interleukin-33 (IL-33) is a nuclear factor and member of the IL-1 cytokine family. IL-33 is mainly expressed by epithelial and endothelial cells and exerts its function through interaction with various immune cells, and binding to its receptor can form the IL-33/Suppression of tumorigenicity 2 (ST2) signaling pathway. While most cytokines are actively synthesized within cells, IL-33 is produced passively in response to tissue damage or cell necrosis, indicating its role as a signaling molecule following cellular infection, stress, or trauma. IL-33/ST2 signaling pathway has been proved to play diverse role in the pathological process of central nervous system disorders, cancer, fibrosis, autoimmune diseases, etc. Although research on the IL-33/ST2 signaling pathway has deepened recently, relevant treatment strategies have been proposed, and even targeted drugs are in the preclinical stage; further research on the effect of the IL-33/ST2 signaling pathway in different diseases is still necessary, to provide a clearer understanding of the different roles of IL-33/ST2 in disease progression and to develop new drugs and treatment strategies. Because IL-33/ST2 plays an important role in the occurrence and progression of diseases, the study of therapeutic drugs targeting this pathway is also necessary. This review focused on recent studies on the positive or negative role of IL-33/ST2 in different diseases, as well as the current related drugs targeting IL-33/ST2 in the preclinical and clinical stage. The mechanism of IL-33/ST2 in different diseases and its mediating effect on different immune cells have been summarized, as well as the antibody drugs targeting IL-33 or ST2, natural compounds with a mediating effect, and small molecule substances targeting relative pathway. We aim to provide new ideas and treatment strategies for IL-33/ST2-related drugs to treat different diseases.
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Affiliation(s)
- Feiya Sheng
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
| | - Mi Li
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Jia-Mei Yu
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Si-Yu Yang
- College of Pharmacy, Chengdu University, Chengdu, China
| | - Liang Zou
- Key Laboratory of Coarse Cereal Processing, Ministry of Agriculture and Rural Affairs, Chengdu University, Chengdu, China
| | - Guan-Jun Yang
- State Key Laboratory for Managing Biotic and Chemical Threats to the Quality and Safety of Agro−Products, Ningbo University, Ningbo, China
| | - Le-Le Zhang
- School of Basic Medical Sciences, Chengdu University, Chengdu, China
- State Key Laboratory of Quality Research in Chinese Medicine, Institute of Chinese Medical Sciences, University of Macau, Macao, Macao SAR, China
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3
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Basirjafar P, Jafarzadeh A, Salimian J. Leptin/LPS-treated dendritic cells reduce the expression of genes involved in tumor tissue metastasis and angiogenesis in an animal model of breast cancer. Immunol Res 2024; 73:2. [PMID: 39658676 DOI: 10.1007/s12026-024-09564-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2024] [Accepted: 11/07/2024] [Indexed: 12/12/2024]
Abstract
Leptin, an immune-regulating protein, enhances the maturation of dendritic cells (DCs). We previously demonstrated that leptin and lipopolysaccharide (LPS) promote the expression of co-stimulatory molecules on the surface of DCs. Leptin/LPS-treated DCs increased T cell responses against 4T1 breast cancer in mice. Therefore, in the present study, we investigate the effects of a DC vaccine treated with leptin and LPS on the genes involved in tumor metastasis, angiogenesis, and related cytokines in a mouse model of breast cancer. Tumor induction was achieved through subcutaneous injection of 4T1 cells into syngeneic mice. On days 12 and 19, the mouse groups received the DC vaccine treated with leptin and a combination of leptin and LPS. After sacrificing the mice on day 26, the levels of IL-6 and IL-33 in the serum were assayed using the ELISA technique, and the expression levels of the VEGF, CCL2, MMP9, and CCL5 genes in the tumors were measured by Real-Time PCR. Compared to untreated tumor-bearing mice, the leptin-treated mature DC (mDC) group exhibited a significant reduction in the expression of MMP9 (0.33-fold, p = 0.01) and CCL5 (0.81-fold, p = 0.02). The leptin-LPS-treated mDC group showed decreased expression of genes involved in metastasis and tumor growth, including VEGF (0.72-fold, p = 0.03), MMP9 (0.26-fold, p = 0.001), and CCL5 (0.3-fold, p = 0.006), indicating more efficient prevention of metastasis. The CCL2 gene expression levels in both treatment groups showed a slight decreasing trend, but these changes were not statistically significant. The leptin-treated mDC group reduced IL-6 production by approximately 16% (p = 0.02), while treatment with the leptin-LPS-treated mDC significantly decreased IL-6 production by approximately 22% (p = 0.01) and increased IL-33 production by approximately 42% (p = 0.03). The findings of the present study indicate that the leptin-LPS-treated mDC vaccine group reduced the expression of genes and cytokines involved in metastasis and angiogenesis, demonstrating greater efficacy compared to the leptin-treated mDC vaccine group.
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Affiliation(s)
- Pedram Basirjafar
- Applied Virology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran
| | - Abdollah Jafarzadeh
- Department of Immunology, School of Medicine, Rafsanjan University of Medical Sciences, Rafsanjan, Iran
- Department of Immunology, School of Medicine, Kerman University of Medical Sciences, Kerman, Iran
| | - Jafar Salimian
- Applied Virology Research Center, Biomedicine Technologies Institute, Baqiyatallah University of Medical Sciences, Tehran, Iran.
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4
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Park JH, Mortaja M, Son HG, Zhao X, Sloat LM, Azin M, Wang J, Collier MR, Tummala KS, Mandinova A, Bardeesy N, Semenov YR, Mino-Kenudson M, Demehri S. Statin prevents cancer development in chronic inflammation by blocking interleukin 33 expression. Nat Commun 2024; 15:4099. [PMID: 38816352 PMCID: PMC11139893 DOI: 10.1038/s41467-024-48441-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2023] [Accepted: 04/24/2024] [Indexed: 06/01/2024] Open
Abstract
Chronic inflammation is a major cause of cancer worldwide. Interleukin 33 (IL-33) is a critical initiator of cancer-prone chronic inflammation; however, its induction mechanism by environmental causes of chronic inflammation is unknown. Herein, we demonstrate that Toll-like receptor (TLR)3/4-TBK1-IRF3 pathway activation links environmental insults to IL-33 induction in the skin and pancreas inflammation. An FDA-approved drug library screen identifies pitavastatin to effectively suppress IL-33 expression by blocking TBK1 membrane recruitment/activation through the mevalonate pathway inhibition. Accordingly, pitavastatin prevents chronic pancreatitis and its cancer sequela in an IL-33-dependent manner. The IRF3-IL-33 axis is highly active in chronic pancreatitis and its associated pancreatic cancer in humans. Interestingly, pitavastatin use correlates with a significantly reduced risk of chronic pancreatitis and pancreatic cancer in patients. Our findings demonstrate that blocking the TBK1-IRF3-IL-33 signaling axis suppresses cancer-prone chronic inflammation. Statins present a safe and effective prophylactic strategy to prevent chronic inflammation and its cancer sequela.
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Affiliation(s)
- Jong Ho Park
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Department of Anatomy, School of Medicine, Keimyung University, Daegu, South Korea
| | - Mahsa Mortaja
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Heehwa G Son
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Xutu Zhao
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Lauren M Sloat
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Marjan Azin
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Jun Wang
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Michael R Collier
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Krishna S Tummala
- Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
- Quantitative Biosciences, Merck Research Laboratories, Boston, MA, USA
| | - Anna Mandinova
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Nabeel Bardeesy
- Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Center for Regenerative Medicine, Massachusetts General Hospital, Boston, MA, USA
- Department of Medicine, Harvard Medical School, Boston, MA, USA
- Cancer Program, Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA, USA
| | - Yevgeniy R Semenov
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
- Laboratory of Systems Pharmacology, Harvard Program in Therapeutic Science, Harvard Medical School, Boston, USA
| | - Mari Mino-Kenudson
- Department of Pathology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA
| | - Shadmehr Demehri
- Center for Cancer Immunology, Krantz Family Center for Cancer Research, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Cutaneous Biology Research Center, Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
- Department of Dermatology, Massachusetts General Hospital and Harvard Medical School, Boston, MA, USA.
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5
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Perri G, Vilas Boas VG, Nogueira MRS, Mello Júnior EJF, Coelho AL, Posadas EM, Hogaboam C, Cavassani KA, Campanelli AP. Interleukin 33 supports squamous cell carcinoma growth via a dual effect on tumour proliferation, migration and invasion, and T cell activation. Cancer Immunol Immunother 2024; 73:110. [PMID: 38662248 PMCID: PMC11045681 DOI: 10.1007/s00262-024-03676-8] [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: 10/30/2023] [Accepted: 03/14/2024] [Indexed: 04/26/2024]
Abstract
Interleukin (IL)-33 is an important cytokine in the tumour microenvironment; it is known to promote the growth and metastasis of solid cancers, such as gastric, colorectal, ovarian and breast cancer. Our group demonstrated that the IL-33/ST2 pathway enhances the development of squamous cell carcinoma (SCC). Conversely, other researchers have reported that IL-33 inhibits tumour progression. In addition, the crosstalk between IL-33, cancer cells and immune cells in SCC remains unknown. The aim of this study was to investigate the effect of IL-33 on the biology of head and neck SCC lines and to evaluate the impact of IL-33 neutralisation on the T cell response in a preclinical model of SCC. First, we identified epithelial and peritumoural cells as a major local source of IL-33 in human SCC samples. Next, in vitro experiments demonstrated that the addition of IL-33 significantly increased the proliferative index, motility and invasiveness of SCC-25 cells, and downregulated MYC gene expression in SCC cell lines. Finally, IL-33 blockade significantly delayed SCC growth and led to a marked decrease in the severity of skin lesions. Importantly, anti-IL-33 monoclonal antibody therapy increase the percentage of CD4+IFNγ+ T cells and decreased CD4+ and CD8+ T cells secreting IL-4 in tumour-draining lymph nodes. Together, these data suggest that the IL-33/ST2 pathway may be involved in the crosstalk between the tumour and immune cells by modulating the phenotype of head and neck SCC and T cell activity. IL-33 neutralisation may offer a novel therapeutic strategy for SCC.
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Affiliation(s)
- Graziela Perri
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, Bauru, SP, 17012-901, Brazil
| | - Vanessa Garcia Vilas Boas
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, Bauru, SP, 17012-901, Brazil
| | - Maria Renata Sales Nogueira
- Research and Teaching Division, State Department of Health, Instituto Lauro de Souza Lima, Bauru, SP, Brazil
| | | | - Ana Lucia Coelho
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Edwin M Posadas
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Cory Hogaboam
- Department of Medicine, Division of Pulmonary and Critical Care Medicine, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Karen A Cavassani
- Samuel Oschin Comprehensive Cancer Institute, Cedars-Sinai Medical Center, Los Angeles, CA, 90048, USA
| | - Ana Paula Campanelli
- Department of Biological Sciences, Bauru School of Dentistry, University of São Paulo, Al. Dr. Octávio Pinheiro Brisolla, Bauru, SP, 17012-901, Brazil.
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6
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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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7
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Chatterjee A, Azevedo-Martins JM, Stachler MD. Interleukin-33 as a Potential Therapeutic Target in Gastric Cancer Patients: Current Insights. Onco Targets Ther 2023; 16:675-687. [PMID: 37583706 PMCID: PMC10424681 DOI: 10.2147/ott.s389120] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2023] [Accepted: 08/06/2023] [Indexed: 08/17/2023] Open
Abstract
Gastric cancer is a significant global health problem as it is the fifth most prevalent cancer worldwide and the fourth leading cause of cancer-related mortality. While cytotoxic chemotherapy remains the primary treatment for advanced GC, response rates are limited. Recent progresses, focused on molecular signalling within gastric cancer, have ignited new hope for potential therapeutic targets that may improve survival and/or reduce the toxic effects of traditional therapies. Carcinomas are generally initiated when critical regulatory genes get mutated, but the progression to malignancy is usually supported by the non-neoplastic cells that create a conducive environment for transformation and progression to occur. Interleukin 33 (IL-33) functions as a dual activity cytokine as it is also a nuclear factor. IL-33 is usually present in the nuclei of the cells. Upon tissue damage, it is released into the extracellular space and binds to its receptor, suppression of tumorigenicity 2 (ST2) L, which is expressed on the membranes of the target cells. IL-33 signalling activates the T Helper 2 (Th2) immune response among other responses. Although the studies on the role of IL-33 in gastric cancer are still in the early stages, they have revealed potentially important (though sometimes conflicting) functions or roles in cancer development and progression. The pro-tumorigenic roles include induction and the recruitment of tumor-associated immune cells, promoting metaplasia progression, and inducing stem cell like and EMT properties in gastric cancer cells. Therapeutic interventions to disrupt these functions may provide a unique strategy for gastric cancer prevention and treatment. This review aims to provide a summary of the role of IL-33 in GC, state its multiple functions in relation to GC, and show potential avenues for promising therapeutic investigation.
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Affiliation(s)
- Annesha Chatterjee
- University of California San Francisco, Department of Pathology, San Francisco, CA, USA
| | | | - Matthew D Stachler
- University of California San Francisco, Department of Pathology, San Francisco, CA, USA
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8
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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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9
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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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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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11
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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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12
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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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13
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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: 23] [Impact Index Per Article: 7.7] [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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14
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Xu Y, Mu J, Zhou Z, Leng Y, Yu Y, Song X, Liu A, Zhu H, Li J, Wang D. Expansion of mouse castration-resistant intermediate prostate stem cells in vitro. Stem Cell Res Ther 2022; 13:299. [PMID: 35841025 PMCID: PMC9284701 DOI: 10.1186/s13287-022-02978-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/19/2022] [Accepted: 06/06/2022] [Indexed: 11/10/2022] Open
Abstract
Background Most castration-resistant prostate cancers (CRPCs) have a luminal phenotype with high androgen receptor (AR) and prostate-specific antigen (PSA) expression. Currently, it is difficult to culture castration-resistant luminal cells with AR and PSA expression. Methods We formulated a custom-made medium and isolated primary cells from the prostate of adult wild-type (WT) and TRAMP mice. The cells were characterized by immunofluorescence staining, transcriptomic analysis, and qRT-PCR verification. Their self-renewal and differentiation potential in vitro and in vivo were examined. We treated the cells with androgen deprivation and enzalutamide and performed immunofluorescence staining and western blotting to analyze their expression of AR and PSA. Results We isolated a novel type of castration-resistant intermediate prostate stem cells (CRIPSCs) from adult WT and TRAMP mice. The mouse CRIPSCs proliferated rapidly in two-dimensional (2D) culture dishes and can be cultured for more than six months. The mouse CRIPSCs expressed luminal markers (AR, PSA, and Dsg4), basal markers (CK5 and p63), Psca, and the intermediate cell marker (Ivl). Transcriptomic analysis showed that the mouse CRIPSCs had upregulated signaling pathways related to cancer development and drug resistance. In the long-term culture, TRAMP CRIPSCs had higher expression of the genes related to stem cells and cancers than WT mice. Both WT and TRAMP CRIPSCs formed organoids in Matrigel. WT CRIPSCs did not form prostate tissues when transplanted in vivo without urogenital sinus mesenchyme (UGM) cells. In contrast, TRAMP CRIPSCs formed prostate ducts in NOG mice without UGM cells and differentiated into luminal, basal, and neuroendocrine cells. Androgens regulated AR translocation between the nucleus and cytoplasm in the mouse CRIPSCs. Treatment of androgen deprivation (ADT) and enzalutamide reduced AR expression in WT and TRAMP CRIPSCs; however, this treatment promoted PSA expression in TRAMP, while not WT CRIPSCs, similar to the clinical observations of CRPC. Conclusions Our study established a method for isolating and expanding mouse CRIPSCs in 2D culture dishes. Mouse CRIPSCs had markers of basal and luminal cells, including AR and PSA, and can differentiate into prostate organoids and tissues. TRAMP CRIPSCs had elevated PSA expression upon ADT and enzalutamide treatment. Our method can be translated into clinical settings for CRPC precision medicine.
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Affiliation(s)
- Yalan Xu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China.,School of Basic Medicine, Qingdao University, Qingdao, 266021, China
| | - Jie Mu
- College of Life Sciences, and School of Pharmacy, Medical College, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Zhixia Zhou
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China
| | - Yu Leng
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China.,School of Basic Medicine, Qingdao University, Qingdao, 266021, China
| | - Yali Yu
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China.,School of Basic Medicine, Qingdao University, Qingdao, 266021, China
| | - Xiuyue Song
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China.,School of Basic Medicine, Qingdao University, Qingdao, 266021, China
| | - Aihua Liu
- College of Life Sciences, and School of Pharmacy, Medical College, Qingdao University, 308 Ningxia Road, Qingdao, 266071, China
| | - Hai Zhu
- Department of Urology, Qingdao Municipal Hospital Affiliated to Qingdao University, Qingdao, 266011, China.
| | - Jing Li
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China.
| | - Dong Wang
- Institute for Translational Medicine, The Affiliated Hospital of Qingdao University, Medical College, Qingdao University, Qingdao, 266021, China.
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15
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Yeoh WJ, Vu VP, Krebs P. IL-33 biology in cancer: An update and future perspectives. Cytokine 2022; 157:155961. [PMID: 35843125 DOI: 10.1016/j.cyto.2022.155961] [Citation(s) in RCA: 35] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2021] [Revised: 05/03/2022] [Accepted: 07/01/2022] [Indexed: 12/14/2022]
Abstract
Interleukin-33 (IL-33) is a member of the IL-1 family of cytokines that is constitutively expressed in the nucleus of epithelial, endothelial and fibroblast-like cells. Upon cell stress, damage or necrosis, IL-33 is released into the cytoplasm to exert its prime role as an alarmin by binding to its specific receptor moiety, ST2. IL-33 exhibits pleiotropic function in inflammatory diseases and particularly in cancer. IL-33 may play a dual role as both a pro-tumorigenic and anti-tumorigenic cytokine, dependent on tumor and cellular context, expression levels, bioactivity and the nature of the inflammatory environment. In this review, we discuss the differential contribution of IL-33 to malignant or inflammatory conditions, its multifaceted effects on the tumor microenvironment, while providing possible explanations for the discrepant findings described in the literature. Additionally, we examine the emerging and divergent functions of IL-33 in the nucleus, and aspects of IL-33 biology that are currently under-addressed.
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Affiliation(s)
- Wen Jie Yeoh
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland
| | - Vivian P Vu
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Switzerland
| | - Philippe Krebs
- Institute of Pathology, University of Bern, Bern, Switzerland.
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16
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Chianca M, Panichella G, Fabiani I, Giannoni A, L'Abbate S, Aimo A, Del Franco A, Vergaro G, Grigoratos C, Castiglione V, Cipolla CM, Fedele A, Passino C, Emdin M, Cardinale DM. Bidirectional Relationship Between Cancer and Heart Failure: Insights on Circulating Biomarkers. Front Cardiovasc Med 2022; 9:936654. [PMID: 35872912 PMCID: PMC9299444 DOI: 10.3389/fcvm.2022.936654] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2022] [Accepted: 06/13/2022] [Indexed: 11/13/2022] Open
Abstract
Cancer and heart failure are the two leading causes of death in developed countries. These two apparently distinct clinical entities share similar risk factors, symptoms, and pathophysiological mechanisms (inflammation, metabolic disturbances, neuro-hormonal and immune system activation, and endothelial dysfunction). Beyond the well-known cardiotoxic effects of oncological therapies, cancer and heart failure are thought to be tied by a bidirectional relationship, where one disease favors the other and vice versa. In this context, biomarkers represent a simple, reproducible, sensitive and cost-effective method to explore such relationship. In this review, we recapitulate the evidence on cardiovascular and oncological biomarkers in the field of cardioncology, focusing on their role in treatment-naïve cancer patients. Cardioncological biomarkers are useful tools in risk stratification, early detection of cardiotoxicity, follow-up, and prognostic assessment. Intriguingly, these biomarkers might contribute to better understand the common pathophysiology of cancer and heart failure, thus allowing the implementation of preventive and treatment strategies in cardioncological patients
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Affiliation(s)
- Michela Chianca
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | | | - Iacopo Fabiani
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
- *Correspondence: Iacopo Fabiani
| | - Alberto Giannoni
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Serena L'Abbate
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
| | - Alberto Aimo
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | | | - Giuseppe Vergaro
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | | | | | - Carlo Maria Cipolla
- Cardioncology Unit, Cardioncology and Second Opinion Division, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), Milan, Italy
| | - Antonella Fedele
- Cardioncology Unit, Cardioncology and Second Opinion Division, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), Milan, Italy
| | - Claudio Passino
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Michele Emdin
- Institute of Life Sciences, Scuola Superiore Sant'Anna, Pisa, Italy
- Cardiology Division, Fondazione Toscana Gabriele Monasterio, Pisa, Italy
| | - Daniela Maria Cardinale
- Cardioncology Unit, Cardioncology and Second Opinion Division, European Institute of Oncology, Istituto di Ricovero e Cura a Carattere Scientifico (I.R.C.C.S.), Milan, Italy
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17
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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: 61] [Impact Index Per Article: 20.3] [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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18
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Ham J, Shin JW, Ko BC, Kim HY. Targeting the Epithelium-Derived Innate Cytokines: From Bench to Bedside. Immune Netw 2022; 22:e11. [PMID: 35291657 PMCID: PMC8901708 DOI: 10.4110/in.2022.22.e11] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/30/2021] [Revised: 02/15/2022] [Accepted: 02/15/2022] [Indexed: 02/05/2023] Open
Abstract
When epithelial cells are exposed to potentially threatening external stimuli such as allergens, bacteria, viruses, and helminths, they instantly produce "alarmin" cytokines, namely, IL-33, IL-25, and TSLP. These alarmins alert the immune system about these threats, thereby mobilizing host immune defense mechanisms. Specifically, the alarmins strongly stimulate type-2 immune cells, including eosinophils, mast cells, dendritic cells, type-2 helper T cells, and type-2 innate lymphoid cells. Given that the alarm-raising role of IL-33, IL-25, and TSLP was first detected in allergic and infectious diseases, most studies on alarmins focus on their role in these diseases. However, recent studies suggest that alarmins also have a broad range of effector functions in other pathological conditions, including psoriasis, multiple sclerosis, and cancer. Therefore, this review provides an update on the epithelium-derived cytokines in both allergic and non-allergic diseases. We also review the progress of clinical trials on biological agents that target the alarmins and discuss the therapeutic potential of these agents in non-allergic diseases.
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Affiliation(s)
- Jongho Ham
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Korea.,CIRNO, Sungkyunkwan University, Suwon 16419, Korea
| | - Jae Woo Shin
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,CIRNO, Sungkyunkwan University, Suwon 16419, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
| | - Byeong Cheol Ko
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Medicine, Seoul National University College of Medicine, Seoul 03080, Korea
| | - Hye Young Kim
- Laboratory of Mucosal Immunology, Department of Biomedical Sciences, Seoul National University College of Medicine, Seoul 03080, Korea.,Department of Biomedical Sciences, BK21 Plus Biomedical Science Project, Seoul National University College of Medicine, Seoul 03080, Korea.,CIRNO, Sungkyunkwan University, Suwon 16419, Korea.,Institute of Allergy and Clinical Immunology, Seoul National University Medical Research Center, Seoul 03080, Korea
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19
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Saliba J, Coutaud B, Makhani K, Epstein Roth N, Jackson J, Park JY, Gagnon N, Costa P, Jeyakumar T, Bury M, Beauchemin N, Mann KK, Blank V. Loss of NFE2L3 protects against inflammation-induced colorectal cancer through modulation of the tumor microenvironment. Oncogene 2022; 41:1563-1575. [PMID: 35091681 PMCID: PMC8913363 DOI: 10.1038/s41388-022-02192-2] [Citation(s) in RCA: 14] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2020] [Revised: 12/16/2021] [Accepted: 01/13/2022] [Indexed: 02/07/2023]
Abstract
We investigated the role of the NFE2L3 transcription factor in inflammation-induced colorectal cancer. Our studies revealed that Nfe2l3−/− mice exhibit significantly less inflammation in the colon, reduced tumor size and numbers, and skewed localization of tumors with a more pronounced decrease of tumors in the distal colon. CIBERSORT analysis of RNA-seq data from normal and tumor tissue predicted a reduction in mast cells in Nfe2l3−/− animals, which was confirmed by toluidine blue staining. Concomitantly, the transcript levels of Il33 and Rab27a, both important regulators of mast cells, were reduced and increased, respectively, in the colorectal tumors of Nfe2l3−/− mice. Furthermore, we validated NFE2L3 binding to the regulatory sequences of the IL33 and RAB27A loci in human colorectal carcinoma cells. Using digital spatial profiling, we found that Nfe2l3−/− mice presented elevated FOXP3 and immune checkpoint markers CTLA4, TIM3, and LAG3, suggesting an increase in Treg counts. Staining for CD3 and FOXP3 confirmed a significant increase in immunosuppressive Tregs in the colon of Nfe2l3−/− animals. Also, Human Microbiome Project (HMP2) data showed that NFE2L3 transcript levels are higher in the rectum of ulcerative colitis patients. The observed changes in the tumor microenvironment provide new insights into the molecular differences regarding colon cancer sidedness. This may be exploited for the treatment of early-onset colorectal cancer as this emerging subtype primarily displays distal/left-sided tumors.
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Affiliation(s)
- James Saliba
- Lady Davis Institute for Medical Research, Montreal, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
| | | | - Kiran Makhani
- Lady Davis Institute for Medical Research, Montreal, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Noam Epstein Roth
- Lady Davis Institute for Medical Research, Montreal, Canada.,Department of Medicine, McGill University, Montreal, Quebec, Canada
| | - Jennie Jackson
- Lady Davis Institute for Medical Research, Montreal, Canada.,Life Sciences Institute and Department of Microbiology and Immunology, University of British Columbia, Vancouver, British Columbia, Canada
| | - Joo Yeoun Park
- Lady Davis Institute for Medical Research, Montreal, Canada
| | | | - Paolo Costa
- Lady Davis Institute for Medical Research, Montreal, Canada
| | - Thiviya Jeyakumar
- Goodman Cancer Institute and Departments of Oncology, Biochemistry and Medicine, McGill University, Montreal, Quebec, Canada
| | - Marina Bury
- Lady Davis Institute for Medical Research, Montreal, Canada.,De Duve Institute, UCLouvain, Brussels, Belgium
| | - Nicole Beauchemin
- Goodman Cancer Institute and Departments of Oncology, Biochemistry and Medicine, McGill University, Montreal, Quebec, Canada
| | - Koren K Mann
- Lady Davis Institute for Medical Research, Montreal, Canada.,Department of Pharmacology and Therapeutics, McGill University, Montreal, Quebec, Canada
| | - Volker Blank
- Lady Davis Institute for Medical Research, Montreal, Canada. .,Department of Medicine, McGill University, Montreal, Quebec, Canada. .,Department of Physiology, McGill University, Montreal, Quebec, Canada.
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20
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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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21
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Subtil B, Cambi A, Tauriello DVF, de Vries IJM. The Therapeutic Potential of Tackling Tumor-Induced Dendritic Cell Dysfunction in Colorectal Cancer. Front Immunol 2021; 12:724883. [PMID: 34691029 PMCID: PMC8527179 DOI: 10.3389/fimmu.2021.724883] [Citation(s) in RCA: 22] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2021] [Accepted: 09/14/2021] [Indexed: 12/12/2022] Open
Abstract
Colorectal cancer (CRC) is the third most diagnosed malignancy and the second leading cause of cancer-related deaths worldwide. Locally advanced and metastatic disease exhibit resistance to therapy and are prone to recurrence. Despite significant advances in standard of care and targeted (immuno)therapies, the treatment effects in metastatic CRC patients have been modest. Untreatable cancer metastasis accounts for poor prognosis and most CRC deaths. The generation of a strong immunosuppressive tumor microenvironment (TME) by CRC constitutes a major hurdle for tumor clearance by the immune system. Dendritic cells (DCs), often impaired in the TME, play a critical role in the initiation and amplification of anti-tumor immune responses. Evidence suggests that tumor-mediated DC dysfunction is decisive for tumor growth and metastasis initiation, as well as for the success of immunotherapies. Unravelling and understanding the complex crosstalk between CRC and DCs holds promise for identifying key mechanisms involved in tumor progression and spread that can be exploited for therapy. The main goal of this review is to provide an overview of the current knowledge on the impact of CRC-driven immunosuppression on DCs phenotype and functionality, and its significance for disease progression, patient prognosis, and treatment response. Moreover, present knowledge gaps will be highlighted as promising opportunities to further understand and therapeutically target DC dysfunction in CRC. Given the complexity and heterogeneity of CRC, future research will benefit from the use of patient-derived material and the development of in vitro organoid-based co-culture systems to model and study DCs within the CRC TME.
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Affiliation(s)
- Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Alessandra Cambi
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
| | - I. Jolanda M. de Vries
- Department of Tumor Immunology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, Nijmegen, Netherlands
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22
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Allavena P, Digifico E, Belgiovine C. Macrophages and cancer stem cells: a malevolent alliance. Mol Med 2021; 27:121. [PMID: 34583655 PMCID: PMC8480058 DOI: 10.1186/s10020-021-00383-3] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/16/2021] [Accepted: 09/17/2021] [Indexed: 12/11/2022] Open
Abstract
Myeloid cells infiltrating tumors are gaining ever growing attention in the last years because their pro-tumor and immunosuppressive functions are relevant for disease progression and therapeutic responses. The functional ambiguity of tumor-associated macrophages (TAMs), mostly promoting tumor evolution, is a challenging hurdle. This is even more evident in the case of cancer stem cells (CSCs); as active participants in the specialized environment of the cancer stem cell niche, TAMs initiate a reciprocal conversation with CSCs. TAMs contribute to protect CSCs from the hostile environment (exogenous insults, toxic compounds, attacks from the immune cells), and produce several biologically active mediators that modulate crucial developmental pathways that sustain cancer cell stemness. In this review, we have focused our attention on the interaction between TAMs and CSCs; we describe how TAMs impact on CSC biology and, in turn, how CSCs exploit the tissue trophic activity of macrophages to survive and progress. Since CSCs are responsible for therapy resistance and tumor recurrence, they are important therapeutic targets. In view of the recent success in oncology obtained by stimulating the immune system, we discuss some macrophage-targeted therapeutic strategies that may also affect the CSCs and interrupt their malevolent alliance.
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Affiliation(s)
- Paola Allavena
- Humanitas Clinical and Research Center -IRCCS, via Manzoni 56, 20089, Rozzano, MI, Italy.
| | - Elisabeth Digifico
- Humanitas Clinical and Research Center -IRCCS, via Manzoni 56, 20089, Rozzano, MI, Italy
| | - Cristina Belgiovine
- Humanitas Clinical and Research Center -IRCCS, via Manzoni 56, 20089, Rozzano, MI, Italy
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23
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Inhibition of NF- κB/IL-33/ST2 Axis Ameliorates Acute Bronchiolitis Induced by Respiratory Syncytial Virus. J Immunol Res 2021; 2021:6625551. [PMID: 34395633 PMCID: PMC8357524 DOI: 10.1155/2021/6625551] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2020] [Revised: 06/04/2021] [Accepted: 07/16/2021] [Indexed: 12/16/2022] Open
Abstract
Background/Aim Bronchiolitis is a common acute lower respiratory tract infectious disease in infants. Respiratory syncytial virus (RSV) infection is one of the main causes. Bronchiolitis can lead to a significant increase in the incidence of asthma in young children, but the mechanism of bronchiolitis transforming into asthma is still unclear. The study was aimed at investigating the role of NF-κB/IL-33/ST2 axis on RSV-induced acute bronchiolitis. Methods A total of 40 infants diagnosed with acute bronchiolitis infected by RSV, and 20 normal infants were included in this study. BALB/c mice (6-8 weeks old, 20 ± 1.1 g) were used as study models. Enzyme-linked immunosorbent assay (ELISA), quantitative real time PCR, western blot analysis, immunohistochemical staining, and flow cytometry analysis were performed to examine relevant indicators. Results IL-33 level was significantly elevated, and Th1/Th2 ratio is imbalance after in infants with acute bronchiolitis. In vivo study, we found that NF-κB/IL-33/ST2 axis is mediated the Th2 cytokine levels and BAL cell number induced by RSV. Acute bronchiolitis induced by RSV in a mouse model is attenuated after inhibition of NF-κB/IL-33/ST2 pathway. Moreover, we also confirmed that macrophages are important sources of IL-33 and are regulated by NF-κB pathway in RSV-induced mice. Conclusion We confirmed that inhibition of NF-κB/IL-33/ST2 axis could attenuate acute bronchiolitis by RSV infected. Our findings not only demonstrate the potential role of IL-33 antibody in attenuating RSV-induced lung damage but also provide a new insight into better prevention of RSV-induced asthma by mediating NF-κB/IL-33/ST2 axis.
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24
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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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25
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The Janus Face of IL-33 Signaling in Tumor Development and Immune Escape. Cancers (Basel) 2021; 13:cancers13133281. [PMID: 34209038 PMCID: PMC8268428 DOI: 10.3390/cancers13133281] [Citation(s) in RCA: 24] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2021] [Revised: 06/06/2021] [Accepted: 06/25/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Interleukin-33 (IL-33) is often released from damaged cells, acting as a danger signal. IL-33 exerts its function by interacting with its receptor suppression of tumorigenicity 2 (ST2) that is constitutively expressed on most immune cells. Therefore, IL-33/ST2 signaling can modulate immune responses to participate actively in a variety of pathological conditions, such as cancer. Like a two-faced Janus, which faces opposite directions, IL-33/ST2 signaling may play contradictory roles on its impact on cancer progression through both immune and nonimmune cellular components. Accumulating evidence demonstrates both pro- and anti-tumorigenic properties of IL-33, depending on the complex nature of different tumor immune microenvironments. We summarize and discuss the most recent studies on the contradictory effects of IL-33 on cancer progression and treatment, with a goal to better understanding the various ways for IL-33 as a therapeutic target. Abstract Interleukin-33 (IL-33), a member of the IL-1 cytokine family, plays a critical role in maintaining tissue homeostasis as well as pathological conditions, such as allergy, infectious disease, and cancer, by promoting type 1 and 2 immune responses. Through its specific receptor ST2, IL-33 exerts multifaceted functions through the activation of diverse intracellular signaling pathways. ST2 is expressed in different types of immune cells, including Th2 cells, Th1 cells, CD8+ T cells, regulatory T cells (Treg), cytotoxic NK cells, group 2 innate lymphoid cells (ILC2s), and myeloid cells. During cancer initiation and progression, the aberrant regulation of the IL-33/ST2 axis in the tumor microenvironment (TME) extrinsically and intrinsically mediates immune editing via modulation of both innate and adaptive immune cell components. The summarized results in this review suggest that IL-33 exerts dual-functioning, pro- as well as anti-tumorigenic effects depending on the tumor type, expression levels, cellular context, and cytokine milieu. A better understanding of the distinct roles of IL-33 in epithelial, stromal, and immune cell compartments will benefit the development of a targeting strategy for this IL-33/ST2 axis for cancer immunotherapy.
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26
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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: 61] [Impact Index Per Article: 15.3] [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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27
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Zefferino R, Piccoli C, Di Gioia S, Capitanio N, Conese M. How Cells Communicate with Each Other in the Tumor Microenvironment: Suggestions to Design Novel Therapeutic Strategies in Cancer Disease. Int J Mol Sci 2021; 22:ijms22052550. [PMID: 33806300 PMCID: PMC7961918 DOI: 10.3390/ijms22052550] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/25/2021] [Accepted: 02/26/2021] [Indexed: 02/06/2023] Open
Abstract
Connexin- and pannexin (Panx)-formed hemichannels (HCs) and gap junctions (GJs) operate an interaction with the extracellular matrix and GJ intercellular communication (GJIC), and on account of this they are involved in cancer onset and progression towards invasiveness and metastatization. When we deal with cancer, it is not correct to omit the immune system, as well as neglecting its role in resisting or succumbing to formation and progression of incipient neoplasia until the formation of micrometastasis, nevertheless what really occurs in the tumor microenvironment (TME), which are the main players and which are the tumor or body allies, is still unclear. The goal of this article is to discuss how the pivotal players act, which can enhance or contrast cancer progression during two important process: "Activating Invasion and Metastasis" and the "Avoiding Immune Destruction", with a particular emphasis on the interplay among GJIC, Panx-HCs, and the purinergic system in the TME without disregarding the inflammasome and cytokines thereof derived. In particular, the complex and contrasting roles of Panx1/P2X7R signalosome in tumor facilitation and/or inhibition is discussed in regard to the early/late phases of the carcinogenesis. Finally, considering this complex interplay in the TME between cancer cells, stromal cells, immune cells, and focusing on their means of communication, we should be capable of revealing harmful messages that help the cancer growth and transform them in body allies, thus designing novel therapeutic strategies to fight cancer in a personalized manner.
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Affiliation(s)
- Roberto Zefferino
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
- Correspondence: ; Tel.: +39-0881-884673
| | - Claudia Piccoli
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Sante Di Gioia
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
| | - Nazzareno Capitanio
- Department of Clinical and Experimental Medicine, University of Foggia, 71122 Foggia, Italy; (C.P.); (N.C.)
| | - Massimo Conese
- Department of Medical and Surgical Sciences, University of Foggia, 71122 Foggia, Italy; (S.D.G.); (M.C.)
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28
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Nagaoka S, Yamada D, Eguchi H, Yokota Y, Iwagami Y, Asaoka T, Noda T, Kawamoto K, Gotoh K, Kobayashi S, Miyoshi E, Doki Y, Mori M. The blockade of interleukin-33 released by hepatectomy would be a promising treatment option for cholangiocarcinoma. Cancer Sci 2021; 112:347-358. [PMID: 33098728 PMCID: PMC7780022 DOI: 10.1111/cas.14709] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2020] [Revised: 09/30/2020] [Accepted: 10/17/2020] [Indexed: 02/06/2023] Open
Abstract
Interleukin-33 (IL-33), an alarmin released during tissue injury, facilitates the development of cholangiocarcinoma (CCA) in a murine model. However, it is unclear whether IL-33 is associated with human CCA. The aim of this study was to support the following hypothesis: IL-33 is released during hepatectomy for CCA, subsequently facilitating the development of subclinical CCA and eventually leading to recurrent disease. IL-33 expression was assessed in various samples from both humans and mice including resected liver and paired plasma samples collected at hepatectomy and after surgery, and its influences on recurrent disease and patient prognosis were determined. Homogenized human liver samples with high or low IL-33 expression were added to the culture medium of human CCA cells, and the changes in proliferation and migration were evaluated. To examine the effects of inhibiting the IL-33 release induced by hepatectomy, syngraft transplantation of murine CCA cells was performed in C57BL/6J mice with or without IL-33 blockade. The amount of IL-33 released into the plasma during hepatectomy correlated with the background liver expression. High expression of IL-33 in the liver was an independent risk factor for recurrence. Homogenized liver tissue strongly expressing IL-33 increased both the proliferation and migration of tumor cells. Mice who underwent hepatectomy exhibited CCA progression in the remnant liver, whereas blockade of IL-33 during hepatectomy inhibited tumor progression. Thus, we concluded that surgery for CCA with curative intent paradoxically induced IL-33 release, which facilitated CCA recurrence, and anti-IL-33 therapy during hepatectomy might reduce the risk of CCA recurrence.
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Affiliation(s)
- Satoshi Nagaoka
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Daisaku Yamada
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Hidetoshi Eguchi
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Yuki Yokota
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Yoshifumi Iwagami
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Tadafumi Asaoka
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Takehiro Noda
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Koichi Kawamoto
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Kunihito Gotoh
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Shogo Kobayashi
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Eiji Miyoshi
- Department of Molecular Biochemistry and Clinical InvestigationGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Yuichiro Doki
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
| | - Masaki Mori
- Department of Gastroenterological SurgeryGraduate School of MedicineOsaka UniversityOsakaJapan
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29
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Yang J, Bahcecioglu G, Zorlutuna P. The Extracellular Matrix and Vesicles Modulate the Breast Tumor Microenvironment. Bioengineering (Basel) 2020; 7:E124. [PMID: 33050609 PMCID: PMC7712041 DOI: 10.3390/bioengineering7040124] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2020] [Revised: 10/06/2020] [Accepted: 10/08/2020] [Indexed: 12/18/2022] Open
Abstract
Emerging evidence has shown multiple roles of the tumor microenvironment (TME) components, specifically the extracellular matrix (ECM), in breast cancer development, progression, and metastasis. Aside from the biophysical properties and biochemical composition of the breast ECM, the signaling molecules are extremely important in maintaining homeostasis, and in the breast TME, they serve as the key components that facilitate tumor progression and immune evasion. Extracellular vesicles (EVs), the mediators that convey messages between the cells and their microenvironment through signaling molecules, have just started to capture attention in breast cancer research. In this comprehensive review, we first provide an overview of the impact of ECM in breast cancer progression as well as the alterations occurring in the TME during this process. The critical importance of EVs and their biomolecular contents in breast cancer progression and metastasis are also discussed. Finally, we discuss the potential biomedical or clinical applications of these extracellular components, as well as how they impact treatment outcomes.
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Affiliation(s)
- Jun Yang
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA;
| | - Gokhan Bahcecioglu
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA;
| | - Pinar Zorlutuna
- Department of Chemical and Biomolecular Engineering, University of Notre Dame, Notre Dame, IN 46556, USA;
- Department of Aerospace and Mechanical Engineering, University of Notre Dame, Notre Dame, IN 46556, USA;
- Bioengineering Graduate Program, University of Notre Dame, Notre Dame, IN 46556, USA
- Harper Cancer Research Institute, University of Notre Dame, Notre Dame, IN 46556, USA
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30
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De Boeck A, Ahn BY, D'Mello C, Lun X, Menon SV, Alshehri MM, Szulzewsky F, Shen Y, Khan L, Dang NH, Reichardt E, Goring KA, King J, Grisdale CJ, Grinshtein N, Hambardzumyan D, Reilly KM, Blough MD, Cairncross JG, Yong VW, Marra MA, Jones SJM, Kaplan DR, McCoy KD, Holland EC, Bose P, Chan JA, Robbins SM, Senger DL. Glioma-derived IL-33 orchestrates an inflammatory brain tumor microenvironment that accelerates glioma progression. Nat Commun 2020; 11:4997. [PMID: 33020472 PMCID: PMC7536425 DOI: 10.1038/s41467-020-18569-4] [Citation(s) in RCA: 124] [Impact Index Per Article: 24.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/25/2018] [Accepted: 08/31/2020] [Indexed: 02/06/2023] Open
Abstract
Despite a deeper molecular understanding, human glioblastoma remains one of the most treatment refractory and fatal cancers. It is known that the presence of macrophages and microglia impact glioblastoma tumorigenesis and prevent durable response. Herein we identify the dual function cytokine IL-33 as an orchestrator of the glioblastoma microenvironment that contributes to tumorigenesis. We find that IL-33 expression in a large subset of human glioma specimens and murine models correlates with increased tumor-associated macrophages/monocytes/microglia. In addition, nuclear and secreted functions of IL-33 regulate chemokines that collectively recruit and activate circulating and resident innate immune cells creating a pro-tumorigenic environment. Conversely, loss of nuclear IL-33 cripples recruitment, dramatically suppresses glioma growth, and increases survival. Our data supports the paradigm that recruitment and activation of immune cells, when instructed appropriately, offer a therapeutic strategy that switches the focus from the cancer cell alone to one that includes the normal host environment.
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Affiliation(s)
- Astrid De Boeck
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Bo Young Ahn
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Charlotte D'Mello
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Xueqing Lun
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Shyam V Menon
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Mana M Alshehri
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- King Abdullah International Medical Research Center, King Saud Bin Abdulaziz University for Health Sciences, King Abdulaziz Medical City, Ministry of National Guard Health Affairs, Riyadh, Saudi Arabia
| | - Frank Szulzewsky
- Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Yaoqing Shen
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Lubaba Khan
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Ngoc Ha Dang
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Elliott Reichardt
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Kimberly-Ann Goring
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jennifer King
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Cameron J Grisdale
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Natalie Grinshtein
- Department of Molecular Genetics, University of Toronto and Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada
| | - Dolores Hambardzumyan
- Department of Oncological Sciences, The Tisch Cancer Institute and the Department of Neurosurgery, Icahn School of Medicine at Mount Sinai, New York, New York, United States
| | - Karlyne M Reilly
- Center for Cancer Research, National Cancer Institute, Bethesda, MD, United States
| | - Michael D Blough
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - J Gregory Cairncross
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - V Wee Yong
- Department of Clinical Neurosciences, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Marco A Marra
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - Steven J M Jones
- Canada's Michael Smith Genome Sciences Centre, British Columbia Cancer Agency, Vancouver, BC, Canada
| | - David R Kaplan
- Department of Molecular Genetics, University of Toronto and Program in Neurosciences and Mental Health, Hospital for Sick Children, Toronto, ON, Canada
| | - Kathy D McCoy
- Department of Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Eric C Holland
- Divison of Human Biology, Fred Hutchinson Cancer Research Center, Seattle, WA, United States
| | - Pinaki Bose
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Jennifer A Chan
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
- Department of Pathology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Stephen M Robbins
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
| | - Donna L Senger
- Clark Smith Brain Tumour Centre, Arnie Charbonneau Cancer Institute, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
- Department of Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada.
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CD44, IL-33, and ST2 Gene Polymorphisms on Hepatocellular Carcinoma Susceptibility in the Chinese Population. BIOMED RESEARCH INTERNATIONAL 2020; 2020:2918517. [PMID: 33062675 PMCID: PMC7538256 DOI: 10.1155/2020/2918517] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Subscribe] [Scholar Register] [Received: 05/19/2020] [Revised: 08/24/2020] [Accepted: 09/17/2020] [Indexed: 01/27/2023]
Abstract
The interleukin- (IL-) 33/ST2 axis plays a pivotal role in tumorigenesis through influencing cancer stemness and other mechanisms. CD44 is one of the critical markers of hepatocellular carcinoma (HCC) among the cancer stem cells (CSCs). There is still a lack of CD44 gene single-nucleotide polymorphisms (SNPs) combined with IL-33/ST2 pathway single-nucleotide polymorphisms in HCC susceptibility analysis literature, although CD44 and IL-33/ST2 have been reported separately in human cancers. This study is aimed at investigating the relationship between CD44, IL-33, and ST2 SNPs and HCC susceptibility and clinicopathological features. We analyzed 565 HCC patients and 561 healthy controls in the Chinese population. The genes for CD44rs187115A>G, IL-33 rs1929992A>G, and ST2 rs3821204G>C were typed using the SNaPshot method. We found that the distribution frequencies of CD44 and ST2 alleles and genotypes in both the HCC case group and the control group were statistically significant (p < 0.05). The results showed that individuals carrying at least one G allele of the CD44 rs187115 gene were at a higher risk than the AA genotype carriers (p = 0.007, odds ratio (OR) = 1.429, 95% confidence interval (CI): 1.102-1.854). Similarly, individuals with at least one C allele of ST2 rs3821204 had a higher risk of HCC than those with GG genes (p ≤ 0.001, OR = 1.647, 95% CI: 1.296-2.093). Combining the haplotype analysis of the 3 loci suggested that CD44 rs187115, IL-33 rs1929992, and ST2 rs3821204 are associated with the risk of HCC and could potentially serve as useful genetic markers for HCC in some populations of China.
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Yangngam S, Thongchot S, Pongpaibul A, Vaeteewoottacharn K, Pinlaor S, Thuwajit P, Okada S, Hermoso MA, Thuwajit C. High level of interleukin-33 in cancer cells and cancer-associated fibroblasts correlates with good prognosis and suppressed migration in cholangiocarcinoma. J Cancer 2020; 11:6571-6581. [PMID: 33046978 PMCID: PMC7545672 DOI: 10.7150/jca.48327] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2020] [Accepted: 09/06/2020] [Indexed: 12/19/2022] Open
Abstract
Interleukin 33 (IL-33) promotes cholangiocarcinoma (CCA) genesis in a mouse model, however, its function in human CCA has not been clearly understood. This study was aimed to investigate IL-33 level in CCA tissues and its clinicopathological correlations. The results revealed that IL-33 was found in both cancer cells and stromal cancer-associated fibroblast (CAFs) staining patterns which were divided into high (CH) and low level (CL) in cancer cells; and presence (FP) and absence (FA) in CAFs. Kaplan-Meier analysis showed that patients in the CL group were significantly correlated with a short 2-year survival time (P = 0.027). The CL/FP group had a shorter survival time compared to the other groups with statistical significance for 2-year (P = 0.030) and 5-year (P = 0.023) survivals. In contrast, CH/FP patients had significantly greater 2-year (P = 0.003) and 5-year (P = 0.003) survivals. Univariate and multivariate analysis confirmed that CL/FP was a significantly independent risk factor whereas CH/FP was a significant protective factor in CCA patients. High IL-33 expressing CCA cells had low migration, but they showed increased migration when IL-33 expression was knocked down. The low level of recombinant human IL-33 (rhIL-33) (0.002 - 2 ng/ml) could promote CCA cell migration, in contrast to the suppressive effect at a high dose (20 - 200 ng/ml). In conclusion, the combination of high IL-33 level in cancer cells and CAFs is a potentially good prognosis marker in CCA patients. The in vitro migration suppressive effect of IL-33 may be the potential mechanism supporting its role as a good prognostic marker in CCA patients. The obtained results strengthen IL-33 as a promising predictor and therapeutic target for CCA.
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Affiliation(s)
- Supaporn Yangngam
- Graduate Program in Immunology, Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Suyanee Thongchot
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
- Siriraj Center of Research Excellence for Cancer Immunotherapy (SiCORE-CIT), Faculty of Medicine Siriraj Hospital, Mahidol University 10700, Thailand
| | - Ananya Pongpaibul
- Department of Pathology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | | | - Somchai Pinlaor
- Department of Parasitology, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
| | - Peti Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
| | - Seiji Okada
- Division of Hematopoiesis, Joint Research Center for Human Retrovirus Infection, Kumamoto University, Kumamoto 860-0811, Japan
| | - Marcela A. Hermoso
- Programa Disciplinario de Inmunología, Instituto de Ciencias Biomédicas, Facultad de Medicina, Universidad de Chile, Santiago, CL 8380453 Chile
| | - Chanitra Thuwajit
- Department of Immunology, Faculty of Medicine Siriraj Hospital, Mahidol University, Bangkok 10700, Thailand
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33
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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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34
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Janssen E, Subtil B, de la Jara Ortiz F, Verheul HMW, Tauriello DVF. Combinatorial Immunotherapies for Metastatic Colorectal Cancer. Cancers (Basel) 2020; 12:cancers12071875. [PMID: 32664619 PMCID: PMC7408881 DOI: 10.3390/cancers12071875] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Revised: 07/06/2020] [Accepted: 07/09/2020] [Indexed: 12/11/2022] Open
Abstract
Colorectal cancer (CRC) is one of the most frequent and deadly forms of cancer. About half of patients are affected by metastasis, with the cancer spreading to e.g., liver, lungs or the peritoneum. The majority of these patients cannot be cured despite steady advances in treatment options. Immunotherapies are currently not widely applicable for this disease, yet show potential in preclinical models and clinical translation. The tumour microenvironment (TME) has emerged as a key factor in CRC metastasis, including by means of immune evasion-forming a major barrier to effective immuno-oncology. Several approaches are in development that aim to overcome the immunosuppressive environment and boost anti-tumour immunity. Among them are vaccination strategies, cellular transplantation therapies, and targeted treatments. Given the complexity of the system, we argue for rational design of combinatorial therapies and consider the implications of precision medicine in this context.
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Affiliation(s)
- Eline Janssen
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
| | - Beatriz Subtil
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
| | - Fàtima de la Jara Ortiz
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
| | - Henk M. W. Verheul
- Department of Medical Oncology, Radboud University Medical Center, PO Box 9101, 6500 HBNijmegen, The Netherlands;
| | - Daniele V. F. Tauriello
- Department of Cell Biology, Radboud Institute for Molecular Life Sciences, Radboud University Medical Center, PO Box 9101, 6500 HB Nijmegen, The Netherlands; (E.J.); (B.S.); (F.d.l.J.O.)
- Correspondence:
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35
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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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36
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Kienzl M, Hasenoehrl C, Valadez-Cosmes P, Maitz K, Sarsembayeva A, Sturm E, Heinemann A, Kargl J, Schicho R. IL-33 reduces tumor growth in models of colorectal cancer with the help of eosinophils. Oncoimmunology 2020; 9:1776059. [PMID: 32923137 PMCID: PMC7458617 DOI: 10.1080/2162402x.2020.1776059] [Citation(s) in RCA: 46] [Impact Index Per Article: 9.2] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022] Open
Abstract
In many types of cancer, presence of eosinophils in tumors correlate with an improved disease outcome. In line with this, activated eosinophils have been shown to reduce tumor growth in colorectal cancer (CRC). Interleukin (IL)-33 has recently emerged as a cytokine that is able to inhibit the development of tumors through eosinophils and other cells of the tumor microenvironment thereby positively influencing disease progress. Here, we asked whether eosinophils are involved in the effects of IL-33 on tumor growth in CRC. In models of CT26 cell engraftment and colitis-associated CRC, tumor growth was reduced after IL-33 treatment. The growth reduction was absent in eosinophil-deficient ΔdblGATA-1 mice but was restored by adoptive transfer of ex vivo-activated eosinophils indicating that the antitumor effect of IL-33 depends on the presence of eosinophils. In vitro, IL-33 increased the expression of markers of activation and homing in eosinophils, such as CD11b and Siglec-F, and the degranulation markers CD63 and CD107a. Increased expression of Siglec-F, CD11b and CD107a was also seen in vivo in eosinophils after IL-33 treatment. Viability and cytotoxic potential of eosinophils and their migration properties toward CCL24 were enhanced indicating direct effects of IL-33 on eosinophils. IL-33 treatment led to increased levels of IL-5 and CCL24 in tumors. Our data show that the presence of eosinophils is mandatory for IL-33-induced tumor reduction in models of CRC and that the mechanisms include eosinophil recruitment, activation and degranulation. Our findings also emphasize the potential use of IL-33 as an adjuvants in CRC immunotherapy. Abbreviations AOM: azoxymethane; bmRPMI: bone marrow RPMI; CRC: colorectal cancer; CFSE: carboxyfluorescein succinimidyl ester; DSS: dextran sulfate sodium; EPX: eosinophil peroxidase; INF-γ: interferon gamma; ILC: innate lymphoid cell; IL-33: interleukin-33; IL-5: interleukin-5; MDSC: myeloid derived suppressor cells; NK cells: natural killer cells; P/S: penicillin/streptomycin; rm: recombinant mouse; T regs: regulatory T cells; TATE: tumor associated tissue eosinophilia; TNF-α: tumor necrosis factor alpha
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Affiliation(s)
- Melanie Kienzl
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed, Graz, Austria
| | - Carina Hasenoehrl
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Paulina Valadez-Cosmes
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Kathrin Maitz
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Arailym Sarsembayeva
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Eva Sturm
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Akos Heinemann
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed, Graz, Austria
| | - Julia Kargl
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria
| | - Rudolf Schicho
- Otto Loewi Research Center, Division of Pharmacology, Medical University of Graz, Graz, Austria.,BioTechMed, Graz, Austria
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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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38
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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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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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40
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Deb B, George IA, Sharma J, Kumar P. Phosphoproteomics Profiling to Identify Altered Signaling Pathways and Kinase-Targeted Cancer Therapies. Methods Mol Biol 2020; 2051:241-264. [PMID: 31552632 DOI: 10.1007/978-1-4939-9744-2_10] [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: 12/26/2022]
Abstract
Phosphorylation is one of the most extensively studied posttranslational modifications (PTM), which regulates cellular functions like cell growth, differentiation, apoptosis, and cell signaling. Kinase families cover a wide number of oncoproteins and are strongly associated with cancer. Identification of driver kinases is an intense area of cancer research. Thus, kinases serve as the potential target to improve the efficacy of targeted therapies. Mass spectrometry-based phosphoproteomic approach has paved the way to the identification of a large number of altered phosphorylation events in proteins and signaling cascades that may lead to oncogenic processes in a cell. Alterations in signaling pathways result in the activation of oncogenic processes predominantly regulated by kinases and phosphatases. Therefore, drugs such as kinase inhibitors, which target dysregulated pathways, represent a promising area for cancer therapy.
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Affiliation(s)
- Barnali Deb
- Institute of Bioinformatics, International Technology Park, Bangalore, India.,Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Irene A George
- Institute of Bioinformatics, International Technology Park, Bangalore, India
| | - Jyoti Sharma
- Institute of Bioinformatics, International Technology Park, Bangalore, India.,Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India
| | - Prashant Kumar
- Institute of Bioinformatics, International Technology Park, Bangalore, India. .,Manipal Academy of Higher Education (MAHE), Manipal, Karnataka, India.
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41
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Feng X, Liu H, Chu X, Sun P, Huang W, Liu C, Yang X, Sun W, Bai H, Ma Y. Recombinant virus-like particles presenting IL-33 successfully modify the tumor microenvironment and facilitate antitumor immunity in a model of breast cancer. Acta Biomater 2019; 100:316-325. [PMID: 31542504 DOI: 10.1016/j.actbio.2019.09.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/23/2019] [Revised: 09/04/2019] [Accepted: 09/16/2019] [Indexed: 12/11/2022]
Abstract
Recently, interleukin (IL)-33 has been closely associated with a variety of clinical cancers. IL-33 presents both protumorigenic, and less frequently, antitumorigenic functions depending on disease conditions. IL-33 signaling appears to be a possible target for the treatment of applicable tumor diseases. This study aimed to develop an effective approach to intervene in IL-33 functioning in tumors and reveal the immunotherapeutic potential of anti-IL-33 active immunization. Recombinant truncated hepatitis B virus core antigen (HBcAg), presenting mature IL-33 molecules on the surface of virus-like particles (VLPs), was prepared and used to immunize BALB/c mice in a model of murine 4T1 breast cancer. The immunization was performed through either a preventive or therapeutic strategy in two separate studies. Anti-IL-33 immunization with VLPs elicited a persistent and highly titrated specific antibody response and significantly suppressed orthotopic tumor growth in the preventive study and lung metastasis in both studies. The underlying mechanisms might include promoting tumor-specific Th1 and CTL-mediated cellular responses and the expression of the effector molecule interferon-γ (IFN-γ), suppressing T-helper type 2 (Th2) responses, and significantly reducing the infiltration of immunosuppressive Treg (regulatory T) cells and myeloid-derived suppressor cells (MDSCs) into tumor tissues in the immunized mice. In conclusion, anti-IL-33 active immunization employing recombinant VLPs as an antigen delivery platform effectively modified the tumor microenvironment and promoted antitumor immunity, indicating the potential of this approach as a new and promising immunotherapeutic strategy for the treatment of cancers where IL-33 plays a definite protumorigenic role. STATEMENT OF SIGNIFICANCE: Interleukin (IL)-33 is closely associated with a variety of clinical cancers. IL-33 signaling appears to be a possible target for the treatment of applicable tumor diseases. Recombinant truncated hepatitis B virus core antigen (HBcAg), presenting mature IL-33 molecules on the surface of virus-like particles (VLPs), was prepared and used to immunize BALB/c mice in a model of murine 4T1 breast cancer. The immunization was performed through either a preventive or therapeutic strategy in two separate studies. Anti-IL-33 immunization with VLPs elicited a persistent and highly titrated specific antibody response and significantly suppressed orthotopic tumor growth and lung metastasis in both studies. Furthermore, anti-IL-33 active immunization employing recombinant VLPs as an antigen delivery platform effectively modified the tumor microenvironment and promoted antitumor immunity, indicating its potential as a new and promising immunotherapeutic strategy for the treatment of cancers where IL-33 plays a definite protumorigenic role.
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Affiliation(s)
- Xuejun Feng
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Department of Experimental Center, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei, China
| | - Hongxian Liu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Xiaojie Chu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Pengyan Sun
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Weiwei Huang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Cunbao Liu
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Xu Yang
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Wenjia Sun
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Hongmei Bai
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China
| | - Yanbing Ma
- Laboratory of Molecular Immunology, Institute of Medical Biology, Chinese Academy of Medical Science & Peking Union Medical College, China; Yunnan Key Laboratory of Vaccine Research & Development on Severe Infectious Disease, China.
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42
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Xia Y, Ohno T, Nishii N, Bhingare A, Tachinami H, Kashima Y, Nagai S, Saito H, Nakae S, Azuma M. Endogenous IL-33 exerts CD8+ T cell antitumor responses overcoming pro-tumor effects by regulatory T cells in a colon carcinoma model. Biochem Biophys Res Commun 2019; 518:331-336. [DOI: 10.1016/j.bbrc.2019.08.058] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 08/09/2019] [Indexed: 12/11/2022]
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43
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B cells with aberrant activation of Notch1 signaling promote Treg and Th2 cell-dominant T-cell responses via IL-33. Blood Adv 2019; 2:2282-2295. [PMID: 30213787 DOI: 10.1182/bloodadvances.2018019919] [Citation(s) in RCA: 17] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/18/2018] [Accepted: 08/19/2018] [Indexed: 01/14/2023] Open
Abstract
The Notch-signaling pathway in a variety of mature B-cell neoplasms is often activated by gene alterations, but its role remains unclear. Here, we show that B cells harboring dysregulated activation of Notch1 signaling have an immunomodulatory effect on T cells by amplifying regulatory T (Treg) and T helper 2 (Th2) cell responses in an interleukin-33 (IL-33)-dependent manner. A conditional mouse model, in which constitutive expression of an active form of Notch1 is induced in B cells by Aicda gene promoter-driven Cre recombinase, revealed no obvious phenotypic changes in B cells; however, mice demonstrated an expansion of Treg and Th2 cell subsets and a decrease in cytokine production by Th1 and CD8+ T cells. The mice were susceptible to soft tissue sarcoma and defective production of CD8+ T cells specific for inoculated tumor cells, suggesting impaired antitumor T-cell activity. Gene-expression microarray revealed that altered T-cell responses were due to increased IL-33 production by Notch1-activated B cells. Knockout of IL33 or blockade of IL-33 by a receptor-blocking antibody abrogated the Treg and Th2 cell-dominant T-cell response triggered by B cells. Gene-expression data derived from human diffuse large B-cell lymphoma (DLBCL) samples showed that an activated Notch-signaling signature correlates positively with IL33 expression and Treg cell-rich gene-expression signatures. These findings indicate that B cells harboring dysregulated Notch signaling alter T-cell responses via IL-33, and suggest that aberrant activation of Notch signaling plays a role in fostering immune privilege in mature B-cell neoplasms.
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Pleural Effusion IL-33/sST2 Levels and Effects of Low and High IL-33/sST2 Levels on Human Mesothelial Cell Adhesion and Migration. Inflammation 2019; 42:2072-2085. [DOI: 10.1007/s10753-019-01070-6] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
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45
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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: 20] [Impact Index Per Article: 3.3] [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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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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48
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Cui G, Yuan A, Pang Z, Zheng W, Li Z, Goll R. Contribution of IL-33 to the Pathogenesis of Colorectal Cancer. Front Oncol 2018; 8:561. [PMID: 30547011 PMCID: PMC6279916 DOI: 10.3389/fonc.2018.00561] [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] [Received: 06/29/2018] [Accepted: 11/12/2018] [Indexed: 12/13/2022] Open
Abstract
The development of colorectal cancer (CRC) is not only determined by transformed cells per se, but also by factors existing in their immune microenvironment. Accumulating scientific evidence has revealed that interleukin (IL)-33, an IL-1 family member, plays an essential role in the regulation of immune response and is relevant in CRC pathogenesis. Data from both human and experimental studies demonstrated that IL-33 inhibits host anti-tumor immunity, remodels tumor stroma and enhances angiogenesis, thereby promoting the development of CRC. These pro-tumor effects of IL-33 are mainly mediated by IL-33 receptor ST2 (also known as IL-1RL1). Based on those findings, it is currently hypothesized that the IL-33/ST2 pathway is a potential biomarker and therapeutic target for colorectal tumorigenesis. Herein, we summarize the recent discoveries in understanding the critical role of the IL-33/ST2 pathway in contributing to the pathogenesis of colorectal tumorigenesis and discuss its potential implications for the future development of effective anti-tumor strategies.
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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, Levanger, Norway
| | - Aping Yuan
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhigang Pang
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Wei Zheng
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Zhenfeng Li
- Research Group of Gastrointestinal Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, China
| | - Rasmus Goll
- Department of Gastroenterology, University Hospital of North Norway, Tromsø, Norway
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49
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Afferni C, Buccione C, Andreone S, Galdiero MR, Varricchi G, Marone G, Mattei F, Schiavoni G. The Pleiotropic Immunomodulatory Functions of IL-33 and Its Implications in Tumor Immunity. Front Immunol 2018; 9:2601. [PMID: 30483263 PMCID: PMC6242976 DOI: 10.3389/fimmu.2018.02601] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022] Open
Abstract
Interleukin-33 (IL-33) is a IL-1 family member of cytokines exerting pleiotropic activities. In the steady-state, IL-33 is expressed in the nucleus of epithelial, endothelial, and fibroblast-like cells acting as a nuclear protein. In response to tissue damage, infections or necrosis IL-33 is released in the extracellular space, where it functions as an alarmin for the immune system. Its specific receptor ST2 is expressed by a variety of immune cell types, resulting in the stimulation of a wide range of immune reactions. Recent evidences suggest that different IL-33 isoforms exist, in virtue of proteolytic cleavage or alternative mRNA splicing, with potentially different biological activity and functions. Although initially studied in the context of allergy, infection, and inflammation, over the past decade IL-33 has gained much attention in cancer immunology. Increasing evidences indicate that IL-33 may have opposing functions, promoting, or dampening tumor immunity, depending on the tumor type, site of expression, and local concentration. In this review we will cover the biological functions of IL-33 on various immune cell subsets (e.g., T cells, NK, Treg cells, ILC2, eosinophils, neutrophils, basophils, mast cells, DCs, and macrophages) that affect anti-tumor immune responses in experimental and clinical cancers. We will also discuss the possible implications of diverse IL-33 mutations and isoforms in the anti-tumor activity of the cytokine and as possible clinical biomarkers.
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Affiliation(s)
- Claudia Afferni
- National Center for Drug Research and Evaluation, Istituto Superiore di Sanità, Rome, Italy
| | - Carla Buccione
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Sara Andreone
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Maria Rosaria Galdiero
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy
| | - Gilda Varricchi
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy
| | - Gianni Marone
- Department of Translational Medical Sciences and Center for Basic and Clinical Immunology Research (CISI), University of Naples Federico II, Naples, Italy.,WAO Center of Excellence, Naples, Italy.,Institute of Experimental Endocrinology and Oncology "Gaetano Salvatore", National Research Council, Naples, Italy
| | - Fabrizio Mattei
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
| | - Giovanna Schiavoni
- Department of Oncology and Molecular Medicine, Istituto Superiore di Sanità, Rome, Italy
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Kieler M, Unseld M, Wojta J, Kaider A, Bianconi D, Demyanets S, Prager GW. Plasma levels of interleukin-33 and soluble suppression of tumorigenicity 2 in patients with advanced pancreatic ductal adenocarcinoma undergoing systemic chemotherapy. Med Oncol 2018; 36:1. [PMID: 30426271 PMCID: PMC6244890 DOI: 10.1007/s12032-018-1223-3] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/12/2018] [Accepted: 10/26/2018] [Indexed: 02/07/2023]
Abstract
Interleukin-33 (IL-33) and its "decoy" receptor soluble ST2 (sST2) are involved in the development of chronic inflammation and cancer. We explored IL-33 and sST2 as a potential prognostic marker in patients with metastatic and locally advanced pancreatic ductal adenocarcinoma (PDAC). IL-33 and sST2 plasma levels were assessed in 20 patients with advanced PDAC before start of systemic chemotherapy and were analyzed in relation to clinical outcome. Kaplan Meier and multivariable Cox proportional hazards model analysis revealed a significant association between sST2 plasma levels and survival (HR 2.10, 95% CI 1.33-3.41, p = 0.002) and link high sST2 plasma levels to inferior survival in patients with advanced PDAC undergoing chemotherapy.
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Affiliation(s)
- Markus Kieler
- Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Matthias Unseld
- Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Johann Wojta
- Division of Cardiology, Department of Internal Medicine II, Medical University Vienna, Waehringer Guertel 18-20, Vienna, Austria
| | - Alexandra Kaider
- Center for Medical Statistics, Informatics and Intelligent Systems, Medical University of Vienna, Spitalgasse 23, Vienna, Austria
| | - Daniela Bianconi
- Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria
| | - Svitlana Demyanets
- Department of Laboratory Medicine, Medical University of Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
| | - Gerald W Prager
- Division of Oncology, Department of Medicine I, Comprehensive Cancer Center, Medical University Vienna, Waehringer Guertel 18-20, 1090, Vienna, Austria.
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