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Ishii K, Naito K, Tanaka D, Koto Y, Kurata K, Shimizu H. Molecular Mechanisms of Skatole-Induced Inflammatory Responses in Intestinal Epithelial Caco-2 Cells: Implications for Colorectal Cancer and Inflammatory Bowel Disease. Cells 2024; 13:1730. [PMID: 39451248 PMCID: PMC11505633 DOI: 10.3390/cells13201730] [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: 08/17/2024] [Revised: 10/06/2024] [Accepted: 10/16/2024] [Indexed: 10/26/2024] Open
Abstract
Inflammatory cytokines, such as tumor necrosis factor-α (TNF-α) and interleukin-6 (IL-6), in intestinal epithelial cells significantly contribute to inflammatory bowel disease (IBD) and colorectal cancer (CRC). Given our previous findings that TNF-α is upregulated in intestinal epithelial Caco-2 cells induced by skatole, a tryptophan-derived gut microbiota metabolite, the present study aimed to explore the relationship between skatole and IL-6, alongside TNF-α. Skatole elevated the promoter activity of IL-6 as well as TNF-α, and increased IL-6 mRNA expression and protein secretion. In addition to activating NF-κB, the NF-κB inhibitor BAY 11-7082 reduced skatole-induced cell survival and the mRNA expression of IL-6 and TNF-α. NF-κB activation was attenuated by the extracellular signal-regulated kinase (ERK) pathway inhibitor U0126 and the p38 inhibitor SB203580, but not by the c-Jun N-terminal kinase (JNK) inhibitor SP600125. U126 and SB203580 also decreased the skatole-induced increase in IL-6 expression. When skatole-induced AhR activation was inhibited by CH223191, in addition to promoting NF-κB activation, IL-6 expression was enhanced in a manner similar to that previously reported for TNF-α. Taken together, these results suggest that skatole-elicited NF-κB activation induces IL-6 and TNF-α expression, although AhR activation partially suppresses this process. The ability of skatole to increase the expression of IL-6 and TNF-α may significantly affect the development and progression of these diseases. Moreover, the balance between NF-κB and AhR activation appears to govern the skatole-induced increases in IL-6 and TNF-α expression. Therefore, the present findings provide new insights into the mechanisms linking tryptophan-derived gut microbiota metabolites with colorectal disease.
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Affiliation(s)
- Katsunori Ishii
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Kazuma Naito
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Dai Tanaka
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Yoshihito Koto
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Koichi Kurata
- Graduate School of Life and Environmental Science, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
| | - Hidehisa Shimizu
- Graduate School of Natural Science and Technology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Graduate School of Life and Environmental Science, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Department of Life Science and Biotechnology, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- The United Graduate School of Agricultural Sciences, Tottori University, 4-101 Koyama-Minami, Tottori 680-8553, Tottori, Japan
- Estuary Research Center, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Interdisciplinary Center for Science Research, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
- Institute of Agricultural and Life Sciences, Academic Assembly, Shimane University, 1060 Nishikawatsu-Cho, Matsue 690-8504, Shimane, Japan
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van Baarle L, De Simone V, Schneider L, Santhosh S, Abdurahiman S, Biscu F, Schneider R, Zanoletti L, Siqueira de Mello R, Verbandt S, Hu Z, Stakenborg M, Ke BJ, Stakenborg N, Salvador Laureano R, García-Reyes B, Henn J, Toma M, Vanmechelen M, Boeckxstaens G, De Smet F, Garg AD, Ibiza S, Tejpar S, Wehner S, Matteoli G. IL-1R signaling drives enteric glia-macrophage interactions in colorectal cancer. Nat Commun 2024; 15:6079. [PMID: 39030280 PMCID: PMC11271635 DOI: 10.1038/s41467-024-50438-2] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2023] [Accepted: 07/11/2024] [Indexed: 07/21/2024] Open
Abstract
Enteric glia have been recently recognized as key components of the colonic tumor microenvironment indicating their potential role in colorectal cancer pathogenesis. Although enteric glia modulate immune responses in other intestinal diseases, their interaction with the colorectal cancer immune cell compartment remains unclear. Through a combination of single-cell and bulk RNA-sequencing, both in murine models and patients, here we find that enteric glia acquire an immunomodulatory phenotype by bi-directional communication with tumor-infiltrating monocytes. The latter direct a reactive enteric glial cell phenotypic and functional switch via glial IL-1R signaling. In turn, tumor glia promote monocyte differentiation towards pro-tumorigenic SPP1+ tumor-associated macrophages by IL-6 release. Enteric glia cell abundancy correlates with worse disease outcomes in preclinical models and colorectal cancer patients. Thereby, our study reveals a neuroimmune interaction between enteric glia and tumor-associated macrophages in the colorectal tumor microenvironment, providing insights into colorectal cancer pathogenesis.
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Affiliation(s)
- Lies van Baarle
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Veronica De Simone
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Linda Schneider
- Department of Surgery, University Hospital Bonn, Medical Faculty, Bonn, Germany
| | - Sneha Santhosh
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Anatomy and Physiology, University of Melbourne, Parkville, VIC, Australia
| | - Saeed Abdurahiman
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Francesca Biscu
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Centre for Inflammation Research, University of Edinburgh, Edinburgh, UK
| | - Reiner Schneider
- Department of Surgery, University Hospital Bonn, Medical Faculty, Bonn, Germany
| | - Lisa Zanoletti
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
- Department of Biology and Biotechnology "L. Spallanzani", University of Pavia, Pavia, Italy
| | - Renata Siqueira de Mello
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Sara Verbandt
- Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Zedong Hu
- Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Michelle Stakenborg
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Bo-Jun Ke
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Nathalie Stakenborg
- Laboratory for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Raquel Salvador Laureano
- Cell Stress and Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Balbina García-Reyes
- Department of Surgery, University Hospital Bonn, Medical Faculty, Bonn, Germany
- Mildred Scheel School of Oncology, Aachen Bonn Cologne Düsseldorf (MSSO ABCD), University Hospital Bonn, Medical Faculty, Bonn, Germany
| | - Jonas Henn
- Department of Surgery, University Hospital Bonn, Medical Faculty, Bonn, Germany
| | - Marieta Toma
- Department of Pathology, University Hospital Bonn, Medical Faculty, Bonn, Germany
| | - Maxime Vanmechelen
- Translational Cell and Tissue Research Unit, Department of Imaging & Pathology, Laboratory for Precision Cancer Medicine, KU Leuven, Leuven, Belgium
- Leuven Institute for Single-Cell Omics (LISCO), KU Leuven, Leuven, Belgium
| | - Guy Boeckxstaens
- Laboratory for Intestinal Neuro-Immune Interaction, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium
| | - Frederik De Smet
- Translational Cell and Tissue Research Unit, Department of Imaging & Pathology, Laboratory for Precision Cancer Medicine, KU Leuven, Leuven, Belgium
- Leuven Institute for Single-Cell Omics (LISCO), KU Leuven, Leuven, Belgium
| | - Abhishek D Garg
- Cell Stress and Immunity (CSI) Lab, Department of Cellular and Molecular Medicine, KU Leuven, Leuven, Belgium
| | - Sales Ibiza
- Laboratory of Cell Biology & Histology, Department of Veterinary Sciences, University of Antwerp, Antwerp, Belgium
| | - Sabine Tejpar
- Digestive Oncology, Department of Oncology, KU Leuven, Leuven, Belgium
| | - Sven Wehner
- Department of Surgery, University Hospital Bonn, Medical Faculty, Bonn, Germany.
| | - Gianluca Matteoli
- Laboratory of Mucosal Immunology, Department of Chronic Diseases and Metabolism (CHROMETA), Translational Research Center for Gastrointestinal Disorders (TARGID), KU Leuven, Leuven, Belgium.
- Leuven Institute for Single-Cell Omics (LISCO), KU Leuven, Leuven, Belgium.
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Lin T, Zhang S, Tang Y, Xiao M, Li M, Gong H, Xie H, Wang Y. ART1 knockdown decreases the IL-6-induced proliferation of colorectal cancer cells. BMC Cancer 2024; 24:354. [PMID: 38504172 PMCID: PMC10953198 DOI: 10.1186/s12885-024-12120-0] [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: 11/23/2023] [Accepted: 03/13/2024] [Indexed: 03/21/2024] Open
Abstract
Colorectal cancer (CRC) is a worldwide health concern. Chronic inflammation is a risk factor for CRC, and interleukin-6 (IL-6) plays a pivotal role in this process. Arginine-specific mono-ADP-ribosyltransferase-1 (ART1) positively regulates inflammatory cytokines. ART1 knockdown reduces the level of glycoprotein 130 (gp130), a key transducer in the IL-6 signalling pathway. However, the relationship between ART1 and IL-6 and the resulting effects on IL-6-induced proliferation in CRC cells remain unclear. The aims of this study were to investigate the effects of ART1 knockdown on IL-6-induced cell proliferation in vitro and use an in vivo murine model to observe the growth of transplanted tumours. The results showed that compared with the control, ART1-sh cancer cells induced by IL-6 exhibited reduced viability, a lower rate of colony formation, less DNA synthesis, decreased protein levels of gp130, c-Myc, cyclin D1, Bcl-xL, and a reduced p-STAT3/STAT3 ratio (P < 0.05). Moreover, mice transplanted with ART1-sh CT26 cells that had high levels of IL-6 displayed tumours with smaller volumes (P < 0.05). ART1 and gp130 were colocalized in CT26, LoVo and HCT116 cells, and their expression was positively correlated in human CRC tissues. Overall, ART1 may serve as a promising regulatory factor for IL-6 signalling and a potential therapeutic target for human CRC.
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Affiliation(s)
- Ting Lin
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Shuxian Zhang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yi Tang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ming Xiao
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Ming Li
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Hanjuan Gong
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Hailun Xie
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China
| | - Yalan Wang
- Department of Pathology, Molecular Medicine and Cancer Research Center, Basic Medicine College, Chongqing Medical University, Chongqing, 400016, P.R. China.
- Molecular Medicine Diagnostic and Testing Center, Chongqing Medical University, Chongqing, 400016, P.R. China.
- Department of Pathology, the First Affiliated Hospital of Chongqing Medical University, Chongqing, 400016, P.R. China.
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Bhat AA, Nisar S, Singh M, Ashraf B, Masoodi T, Prasad CP, Sharma A, Maacha S, Karedath T, Hashem S, Yasin SB, Bagga P, Reddy R, Frennaux MP, Uddin S, Dhawan P, Haris M, Macha MA. Cytokine- and chemokine-induced inflammatory colorectal tumor microenvironment: Emerging avenue for targeted therapy. Cancer Commun (Lond) 2022; 42:689-715. [PMID: 35791509 PMCID: PMC9395317 DOI: 10.1002/cac2.12295] [Citation(s) in RCA: 92] [Impact Index Per Article: 30.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 02/28/2022] [Accepted: 04/24/2022] [Indexed: 12/16/2022] Open
Abstract
Colorectal cancer (CRC) is a predominant life-threatening cancer, with liver and peritoneal metastases as the primary causes of death. Intestinal inflammation, a known CRC risk factor, nurtures a local inflammatory environment enriched with tumor cells, endothelial cells, immune cells, cancer-associated fibroblasts, immunosuppressive cells, and secretory growth factors. The complex interactions of aberrantly expressed cytokines, chemokines, growth factors, and matrix-remodeling enzymes promote CRC pathogenesis and evoke systemic responses that affect disease outcomes. Mounting evidence suggests that these cytokines and chemokines play a role in the progression of CRC through immunosuppression and modulation of the tumor microenvironment, which is partly achieved by the recruitment of immunosuppressive cells. These cells impart features such as cancer stem cell-like properties, drug resistance, invasion, and formation of the premetastatic niche in distant organs, promoting metastasis and aggressive CRC growth. A deeper understanding of the cytokine- and chemokine-mediated signaling networks that link tumor progression and metastasis will provide insights into the mechanistic details of disease aggressiveness and facilitate the development of novel therapeutics for CRC. Here, we summarized the current knowledge of cytokine- and chemokine-mediated crosstalk in the inflammatory tumor microenvironment, which drives immunosuppression, resistance to therapeutics, and metastasis during CRC progression. We also outlined the potential of this crosstalk as a novel therapeutic target for CRC. The major cytokine/chemokine pathways involved in cancer immunotherapy are also discussed in this review.
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Affiliation(s)
- Ajaz A. Bhat
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Sabah Nisar
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Mayank Singh
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Bazella Ashraf
- Department of BiotechnologySchool of Life SciencesCentral University of KashmirGanderbalJammu & Kashmir191201India
| | - Tariq Masoodi
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Chandra P. Prasad
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Atul Sharma
- Department of Medical OncologyDr. B. R. Ambedkar Institute Rotary Cancer HospitalAll India Institute of Medical Sciences (AIIMS)New Delhi110029India
| | - Selma Maacha
- Division of Translational MedicineResearch BranchSidra MedicineDoha26999Qatar
| | | | - Sheema Hashem
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
| | - Syed Besina Yasin
- Department of PathologySher‐I‐Kashmir Institute of Medical SciencesSrinagarJammu & Kashmir190011India
| | - Puneet Bagga
- Department of Diagnostic ImagingSt. Jude Children's Research HospitalMemphisTN38105USA
| | - Ravinder Reddy
- Center for Advanced Metabolic Imaging in Precision MedicineDepartment of RadiologyPerelman School of Medicine at the University of PennsylvaniaPhiladelphiaPA19104USA
| | | | - Shahab Uddin
- Translational Research InstituteHamad Medical CorporationDoha3050Qatar
| | - Punita Dhawan
- Department of Biochemistry and Molecular BiologyUniversity of Nebraska Medical CenterOmahaNE68198USA
| | - Mohammad Haris
- Laboratory of Molecular and Metabolic ImagingCancer Research DepartmentSidra MedicineDoha26999Qatar
- Laboratory Animal Research CenterQatar UniversityDoha2713Qatar
| | - Muzafar A. Macha
- Watson‐Crick Centre for Molecular MedicineIslamic University of Science and TechnologyAwantiporaJammu & Kashmir192122India
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The role of microRNA-30c in targeting interleukin 6, as an inflammatory cytokine, in the mesenchymal stem cell: a therapeutic approach in colorectal cancer. J Cancer Res Clin Oncol 2022:10.1007/s00432-022-04123-w. [PMID: 35876950 DOI: 10.1007/s00432-022-04123-w] [Citation(s) in RCA: 21] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Accepted: 06/07/2022] [Indexed: 10/16/2022]
Abstract
INTRODUCTION Colorectal cancer (CRC) is the third most prevalent cancer and the second significant cause of cancer-associated death worldwide. The microRNA-30 is a substantial member of the miRNA family and plays a vital role in expanding several cancers. This microRNA potentially targets interleukin 6 as an inflammatory cytokine in CRC. MATERIALS AND METHODS MSCs were isolated and identified from mice bone marrow and then transduced with lentiviruses containing miR-30C. Transfected MSCs were collected to evaluate IL-6 levels, CT-26 cells were also co-cultured with MSCs, and the effect of apoptosis and IL-6 on the supernatant was assessed. RESULTS Our result showed the expression of IL-6 mRNA and the level of protein were decreased in the supernatant of miR-30-transduced MSC cells compared to the control group. In addition, the rate of apoptosis was assessed, and the obtained data revealed the induction of apoptosis in CT-26 cells when they are in the vicinity of miR-30c-transduced MSCs. DISCUSSION AND CONCLUSION We demonstrated that downregulation of miR-30c was significantly correlated with CRC progression and survival. So, the present study elucidated the anticancer effects of miR-30c in CRC and presented a novel target for CRC therapy.
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New insights into IL-6 family cytokines in metabolism, hepatology and gastroenterology. Nat Rev Gastroenterol Hepatol 2021; 18:787-803. [PMID: 34211157 DOI: 10.1038/s41575-021-00473-x] [Citation(s) in RCA: 90] [Impact Index Per Article: 22.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 05/20/2021] [Indexed: 02/06/2023]
Abstract
IL-6 family cytokines are defined by the common use of the signal-transducing receptor chain glycoprotein 130 (gp130). Increasing evidence indicates that these cytokines are essential in the regulation of metabolic homeostasis as well as in the pathophysiology of multiple gastrointestinal and liver disorders, thus making them attractive therapeutic targets. Over the past few years, therapies modulating gp130 signalling have grown exponentially in several clinical settings including obesity, cancer and inflammatory bowel disease. A newly engineered gp130 cytokine, IC7Fc, has shown promising preclinical results for the treatment of type 2 diabetes, obesity and liver steatosis. Moreover, drugs that modulate gp130 signalling have shown promise in refractory inflammatory bowel disease in clinical trials. A deeper understanding of the main roles of the IL-6 family of cytokines during homeostatic and pathological conditions, their signalling pathways, sources of production and target cells will be crucial to the development of improved treatments. Here, we review the current state of the role of these cytokines in hepatology and gastroenterology and discuss the progress achieved in translating therapeutics targeting gp130 signalling into clinical practice.
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Salimifard S, Karoon Kiani F, Sadat Eshaghi F, Izadi S, Shahdadnejad K, Masjedi A, Heydari M, Ahmadi A, Hojjat-Farsangi M, Hassannia H, Mohammadi H, Boroumand-Noughabi S, Keramati MR, Jadidi-Niaragh F. Codelivery of BV6 and anti-IL6 siRNA by hyaluronate-conjugated PEG-chitosan-lactate nanoparticles inhibits tumor progression. Life Sci 2020; 260:118423. [PMID: 32941896 DOI: 10.1016/j.lfs.2020.118423] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/04/2020] [Revised: 09/07/2020] [Accepted: 09/09/2020] [Indexed: 02/07/2023]
Abstract
AIMS Increased expression of inhibitor of apoptosis (IAP) genes has been associated with progressive cancer and chemoresistance. Accordingly, blockade of IAPs by BV6 has resulted in ameliorative outcomes. Interleukin (IL)-6 is another important mediator involved in the growth and survival of tumor cells. Therefore, we hypothesized that simultaneous inhibition of IAPs and IL-6 could be a new promising anti-tumor treatment strategy. MATERIALS AND METHODS In this study, we generated and characterized hyaluronate-PEG-Chitosan-Lactate (H-PCL) nanoparticles (NPs) to simultaneously deliver IL6-specific siRNA and BV6 to 4T1 (breast cancer) and CT26 (colon cancer) cells, and investigate the anti-tumor properties of this combination therapy both in vitro and in vivo. KEY FINDINGS H-PCL NPs exhibited good physicochemical properties leading to efficient transfection of cancer cells and suppression of target molecules. Moreover, combination therapy synergistically increased apoptosis, as well as decreased cell migration, proliferation, colony formation, and angiogenesis in both 4T1 and CT26 cell lines and suppressed cancer progression in tumor-bearing mice that was associated with enhanced survival time. SIGNIFICANCE These findings imply the effectiveness of cancer combination therapy by using H-PCL NPs loaded with anti-IL-6 siRNA and BV6.
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Affiliation(s)
- Sevda Salimifard
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Fariba Karoon Kiani
- Drug Applied Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Farzaneh Sadat Eshaghi
- Department of Genetics, Faculty of Medicine, Shahid Sadoughi University of Medical Sciences, Yazd, Iran
| | - Sepideh Izadi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | | | - Ali Masjedi
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Morteza Heydari
- Institute of Biochemistry and Biophysics, University of Tehran, Tehran, Iran
| | - Armin Ahmadi
- Department of Chemical and Materials Engineering, The University of Alabama in Huntsville, AL 35899, USA
| | | | - Hadi Hassannia
- Immunogenetic Research Center, Mazandaran University of Medical Sciences, Sari, Iran
| | - Hamed Mohammadi
- Non-communicable Diseases Research Center, Alborz University of Medical Sciences, Karaj. Iran
| | - Samaneh Boroumand-Noughabi
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Mohammad Reza Keramati
- Cancer Molecular Pathology Research Center, Mashhad University of Medical Sciences, Mashhad, Iran; Department of Hematology and Blood Banking, Faculty of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran.
| | - Farhad Jadidi-Niaragh
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran; Department of Immunology, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran.
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Ungaro F, D’Alessio S, Danese S. The Role of Pro-Resolving Lipid Mediators in Colorectal Cancer-Associated Inflammation: Implications for Therapeutic Strategies. Cancers (Basel) 2020; 12:cancers12082060. [PMID: 32722560 PMCID: PMC7463689 DOI: 10.3390/cancers12082060] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2020] [Revised: 07/23/2020] [Accepted: 07/24/2020] [Indexed: 02/06/2023] Open
Abstract
Inflammation is a recognized hallmark of cancer that contributes to the development and progression of colorectal cancer (CRC). Anti-inflammatory drugs currently used for the treatment of CRC show many adverse side effects that prompted researchers to propose the polyunsaturated fatty acids-derived specialized pro-resolving mediators (SPMs) as promoters of resolution of cancer-associated inflammation. SPMs were found to inhibit the CRC-associated pro-inflammatory milieu via specific G-coupled protein receptors, although clinical data are still lacking. This review aims to summarize the state-of-the-art in this field, ultimately providing insights for the development of innovative anti-CRC therapies that promote the endogenous lipid-mediated resolution of CRC-associated inflammation.
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Affiliation(s)
- Federica Ungaro
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy; (S.D.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Rozzano, 20089 Milan, Italy
- Correspondence:
| | - Silvia D’Alessio
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy; (S.D.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Rozzano, 20089 Milan, Italy
| | - Silvio Danese
- IBD Center, Laboratory of Gastrointestinal Immunopathology, Humanitas Clinical and Research Center, Rozzano, 20089 Milan, Italy; (S.D.); (S.D.)
- Department of Biomedical Sciences, Humanitas University, Rozzano, 20089 Milan, Italy
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Circulating Interleukin-6 Level, Dietary Antioxidant Capacity, and Risk of Colorectal Cancer. Antioxidants (Basel) 2019; 8:antiox8120595. [PMID: 31795177 PMCID: PMC6943549 DOI: 10.3390/antiox8120595] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/21/2019] [Revised: 11/25/2019] [Accepted: 11/26/2019] [Indexed: 12/19/2022] Open
Abstract
Chronic inflammation is one of the causes of colorectal cancer (CRC), and circulating levels of inflammatory biomarkers have been linked to tumor promotion and progression. We aimed to evaluate the interleukin-6 (IL-6) level in CRC patients and determine whether a diet rich in antioxidants was associated with CRC. This study included 654 cases and 1312 controls matched for age and sex. We measured the plasma IL-6 concentration and estimated dietary antioxidant capacity based on oxygen radical absorbance capacity (ORAC) combined with a 106-item semiquantitative food frequency questionnaire. The IL-6 concentration was significantly increased in individuals with CRC (OR Q4 vs. Q1, 95% CI = 6.23, 4.10-9.45, p < 0.001). High dietary ORAC showed an inverse association with CRC (total ORAC OR Q4 vs. Q1, 95% CI = 0.26, 0.16-0.40, p < 0.001; total phenolics = 0.32, 0.21-0.50, p < 0.001). We found that low dietary ORAC was associated with a significant increase in CRC in the group with elevated IL-6 levels (total ORAC OR Q4 vs. Q1, 95% CI = 4.34, 3.12-6.02, p < 0.001; total phenolics = 4.61, 3.33-6.39, p < 0.001). This study suggested an inverse association between dietary antioxidant capacity and IL-6 level among patients with CRC.
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Polak KL, Chernosky NM, Smigiel JM, Tamagno I, Jackson MW. Balancing STAT Activity as a Therapeutic Strategy. Cancers (Basel) 2019; 11:cancers11111716. [PMID: 31684144 PMCID: PMC6895889 DOI: 10.3390/cancers11111716] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/17/2019] [Revised: 10/23/2019] [Accepted: 10/31/2019] [Indexed: 12/13/2022] Open
Abstract
Driven by dysregulated IL-6 family member cytokine signaling in the tumor microenvironment (TME), aberrant signal transducer and activator of transcription (STAT3) and (STAT5) activation have been identified as key contributors to tumorigenesis. Following transformation, persistent STAT3 activation drives the emergence of mesenchymal/cancer-stem cell (CSC) properties, important determinants of metastatic potential and therapy failure. Moreover, STAT3 signaling within tumor-associated macrophages and neutrophils drives secretion of factors that facilitate metastasis and suppress immune cell function. Persistent STAT5 activation is responsible for cancer cell maintenance through suppression of apoptosis and tumor suppressor signaling. Furthermore, STAT5-mediated CD4+/CD25+ regulatory T cells (Tregs) have been implicated in suppression of immunosurveillance. We discuss these roles for STAT3 and STAT5, and weigh the attractiveness of different modes of targeting each cancer therapy. Moreover, we discuss how anti-tumorigenic STATs, including STAT1 and STAT2, may be leveraged to suppress the pro-tumorigenic functions of STAT3/STAT5 signaling.
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Affiliation(s)
- Kelsey L Polak
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Noah M Chernosky
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Jacob M Smigiel
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Ilaria Tamagno
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
| | - Mark W Jackson
- Department of Pathology, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
- Case Comprehensive Cancer Center, Case Western Reserve University, School of Medicine, Cleveland, OH 44106, USA.
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Bazzichetto C, Conciatori F, Falcone I, Cognetti F, Milella M, Ciuffreda L. Advances in Tumor-Stroma Interactions: Emerging Role of Cytokine Network in Colorectal and Pancreatic Cancer. JOURNAL OF ONCOLOGY 2019; 2019:5373580. [PMID: 31191652 PMCID: PMC6525927 DOI: 10.1155/2019/5373580] [Citation(s) in RCA: 15] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/27/2019] [Accepted: 04/22/2019] [Indexed: 02/07/2023]
Abstract
Cytokines are a family of soluble factors (Growth Factors (GFs), chemokines, angiogenic factors, and interferons), which regulate a wide range of mechanisms in both physiological and pathological conditions, such as tumor cell growth and progression, angiogenesis, and metastasis. In recent years, the growing interest in developing new cancer targeted therapies has been accompanied by the effort to characterize Tumor Microenvironment (TME) and Tumor-Stroma Interactions (TSI). The connection between tumor and stroma is now well established and, in the last decade, evidence from genetic, pharmacological, and epidemiological data supported the importance of microenvironment in tumor progression. However, several of the mechanisms behind TSI and their implication in tumor progression remain still unclear and it is crucial to establish their potential in determining pharmacological response. Many studies have demonstrated that cytokines network can profoundly affect TME, thus displaying potential therapeutic efficacy in both preclinical and clinical models. The goal of this review is to give an overview of the most relevant cytokines involved in colorectal and pancreatic cancer progression and their implication in drug response.
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Affiliation(s)
- Chiara Bazzichetto
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Fabiana Conciatori
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Italia Falcone
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Francesco Cognetti
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
| | - Michele Milella
- Section of Oncology, Department of Medicine, University of Verona School of Medicine and Verona University Hospital Trust, Verona 37126, Italy
| | - Ludovica Ciuffreda
- Medical Oncology 1, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
- SAFU, Department of Research, Advanced Diagnostics, and Technological Innovation, IRCCS - Regina Elena National Cancer Institute, Rome 00144, Italy
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Taher MY, Davies DM, Maher J. The role of the interleukin (IL)-6/IL-6 receptor axis in cancer. Biochem Soc Trans 2018; 46:1449-1462. [PMID: 30467123 DOI: 10.1042/bst20180136] [Citation(s) in RCA: 88] [Impact Index Per Article: 12.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2018] [Revised: 10/19/2018] [Accepted: 10/22/2018] [Indexed: 12/14/2022]
Abstract
Interleukin-6 (IL-6) is a pleiotropic cytokine that activates a classic signalling pathway upon binding to its membrane-bound receptor (IL-6R). Alternatively, IL-6 may 'trans-signal' in a manner that is facilitated by its binding to a soluble derivative of the IL-6 receptor (sIL-6R). Resultant signal transduction is, respectively, driven by the association of IL-6/IL-6R or IL-6/sIL-6R complex with the membrane-associated signal transducer, gp130 (Glycoprotein 130). Distinct JAK (Janus tyrosine kinase)/STAT (signal transducers and activators of transcription) and other signalling pathways are activated as a consequence. Of translational relevance, overexpression of IL-6 has been documented in several neoplastic disorders, including but not limited to colorectal, ovarian and breast cancer and several haematological malignancies. This review attempts to summarise our current understanding of the role of IL-6 in cancer development. In short, these studies have shown important roles for IL-6 signalling in tumour cell growth and survival, angiogenesis, immunomodulation of the tumour microenvironment, stromal cell activation, and ultimate disease progression. Given this background, we also consider the potential for therapeutic targeting of this system in cancer.
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Affiliation(s)
- Mustafa Yassin Taher
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, U.K
- Department of Laboratory Medicine, Taibah University, Medina 42353, Saudi Arabia
| | - David Marc Davies
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, U.K
| | - John Maher
- King's College London, School of Cancer and Pharmaceutical Studies, Guy's Hospital, Great Maze Pond, London SE1 9RT, U.K.
- Department of Clinical Immunology and Allergy, King's College Hospital NHS Foundation Trust, London, U.K
- Department of Immunology, Eastbourne Hospital, East Sussex BN21 2UD, U.K
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Ubiquitination and SUMOylation in the chronic inflammatory tumor microenvironment. Biochim Biophys Acta Rev Cancer 2018; 1870:165-175. [DOI: 10.1016/j.bbcan.2018.08.002] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/07/2018] [Revised: 08/10/2018] [Accepted: 08/15/2018] [Indexed: 12/28/2022]
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Park JH, Kim JK. Pristimerin, a naturally occurring triterpenoid, attenuates tumorigenesis in experimental colitis-associated colon cancer. PHYTOMEDICINE : INTERNATIONAL JOURNAL OF PHYTOTHERAPY AND PHYTOPHARMACOLOGY 2018; 42:164-171. [PMID: 29655682 DOI: 10.1016/j.phymed.2018.03.033] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/22/2017] [Revised: 01/24/2018] [Accepted: 03/17/2018] [Indexed: 06/08/2023]
Abstract
BACKGROUND Pristimerin is a quinonemethide triterpenoid with anti-cancer, anti-angiogenic, anti-inflammatory and anti-protozoal activity. However, the therapeutic role of pristimerin in colitis-associated colorectal carcinogenesis is unknown. PURPOSE We sought to examine the therapeutic effects of pristimerin on colitis-associated colon cancer induced in mice using azoxymethane (AOM)/dextran sulfate sodium (DSS). The goal was to identify the potential mechanism of action underlying the pharmacological activity of pristimerin. METHODS BALB/c mice were injected with AOM and administered 2% DSS in drinking water. The mice were fed with a diet supplemented with pristimerin (1 to 5 ppm), and colonic tissue was collected at 64 days. The inflammatory status of the colon was assessed by determining the levels of cyclooxygenase-2, inducible nitric oxide synthase and pro-inflammatory cytokines using Western blotting, immunohistochemistry and real-time RT-PCR analyses. Markers of proliferation (proliferating cell nuclear antigen) and apoptosis (TUNEL) were identified in the colon tissues immunohistochemically. The levels of cell cycle-, apoptosis-, and signaling-related proteins were detected by Western blot in colon tissues. RESULTS Administration of pristimerin significantly reduced the formation of colonic tumors. Western blot and immunohistological analyses revealed that dietary pristimerin markedly reduced NF-κB-positive cells and levels of inflammation-related proteins in colon tissue. Pristimerin also reduced cell proliferation, induced apoptosis, and decreased the phosphorylation of AKT and FOXO3a in colon tissue. CONCLUSION Pristimerin administration decreased inflammation and proliferation induced by AOM/DSS in colon tissue. It also induced apoptosis and regulated the AKT/FOXO3a signaling pathway. Overall, this study indicates the potential value of pristimerin in suppressing colon tumorigenesis.
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Affiliation(s)
- Ju-Hyung Park
- Department of Biomedical Science, Catholic University of Daegu, Gyeongsan-Si 38430, Republic of Korea
| | - Jin-Kyung Kim
- Department of Biomedical Science, Catholic University of Daegu, Gyeongsan-Si 38430, Republic of Korea.
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Mucin 2 silencing promotes colon cancer metastasis through interleukin-6 signaling. Sci Rep 2017; 7:5823. [PMID: 28725043 PMCID: PMC5517441 DOI: 10.1038/s41598-017-04952-7] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2017] [Accepted: 05/23/2017] [Indexed: 12/19/2022] Open
Abstract
Downregulation of Mucin 2 (MUC2) expression is associated with early carcinogenesis events in colon cancer. MUC2 plays a role in the progression of colon cancer, and reduced MUC2 protein expression correlates with increased interleukin-6 (IL-6) expression. However, the interaction between MUC2 and IL-6 in colorectal cancer metastasis remains unclear. We systematically analyzed MUC2 and IL-6 expression and determined the survival of cancer patients with high or low MUC2 and IL-6 expression using the Oncomine and PrognoScan databases, respectively. This analysis identified downregulation of MUC2 and overexpression of IL-6 in colon cancer but not in normal colon tissue, and this expression pattern was correlated with poor survival of colon cancer patients. We examined the effects of MUC2 on colon cancer metastasis and used vector-mediated application of short hairpin RNA (shRNA) to suppress MUC2 expression. MUC2 suppressed the migration of colon cancer cells in vitro and dramatically diminished liver metastases in vivo. Treatment with IL-6 increased signal transducer and activator of transcription 3 (STAT3) phosphorylation, promoted checkpoint kinase 2 (Chk2) activation, attenuated cAMP response element-binding protein (CREB) phosphorylation, and suppressed E-cadherin protein expression in MUC2-silenced HT-29 cancer cells. Most importantly, MUC2 is a potential prognostic indicator for colon cancer.
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The MUTYH base excision repair gene protects against inflammation-associated colorectal carcinogenesis. Oncotarget 2016; 6:19671-84. [PMID: 26109431 PMCID: PMC4637313 DOI: 10.18632/oncotarget.4284] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2015] [Accepted: 06/05/2015] [Indexed: 12/19/2022] Open
Abstract
MUTYH DNA glycosylase removes mismatched adenine opposite 7, 8-dihydro-8-oxoguanine (8-oxoG), which is the major mutagenic lesion induced by oxidative stress. Biallelic mutations in MUTYH are associated with MUTYH-Associated polyposis (MAP) and increased risk in colorectal cancer (CRC). We investigated cancer susceptibility associated with MUTYH inactivation in a mouse model of inflammation-dependent carcinogenesis induced by azoxymethane (AOM) and dextran sulphate (DSS). Mutyh−/− mice were more sensitive than wild-type (WT) animals to AOM/DSS toxicity and accumulated DNA 8-oxoG in their gastrointestinal tract. AOM/DSS-induced colonic adenomas were significantly more numerous in Mutyh−/− than in WT animals, and frequently showed a tubulo-villous feature along with high-grade dysplasia and larger size lesions. This condition resulted in a greater propensity to develop adenocarcinomas. The colon of untreated Mutyh−/− mice expressed higher basal levels of pro-inflammatory cytokines GM-CSF and IFNγ, and treatment with AOM/DSS induced an early decrease in circulating CD4+ and CD8+ T lymphocytes and an increase in myeloid-derived suppressor cells (MDSCs). Adenomas from Mutyh−/− mice had a greater infiltrate of Foxp3+ T regulatory cells, granulocytes, macrophages, MDSCs and strong expression of TGF-β-latency-associated peptide and IL6. Our findings indicate that MUTYH loss is associated with an increase in CRC risk, which involves immunosuppression and altered inflammatory response. We propose that the AOM/DSS initiation/promotion protocol in Mutyh−/− mice provides a good model for MAP.
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Mager LF, Wasmer MH, Rau TT, Krebs P. Cytokine-Induced Modulation of Colorectal Cancer. Front Oncol 2016; 6:96. [PMID: 27148488 DOI: 10.3389/fonc.2016.00096] [Citation(s) in RCA: 166] [Impact Index Per Article: 18.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/28/2016] [Accepted: 04/02/2016] [Indexed: 12/12/2022] Open
Abstract
The emergence of novel immunomodulatory cancer therapies over the last decade, above all immune checkpoint blockade, has significantly advanced tumor treatment. For colorectal cancer (CRC), a novel scoring system based on the immune cell infiltration in tumors has greatly improved disease prognostic evaluation and guidance to more specific therapy. These findings underline the relevance of tumor immunology in the future handling and therapeutic approach of malignant disease. Inflammation can either promote or suppress CRC pathogenesis and inflammatory mediators, mainly cytokines, critically determine the pro- or anti-tumorigenic signals within the tumor environment. Here, we review the current knowledge on the cytokines known to be critically involved in CRC development and illustrate their mechanisms of action. We also highlight similarities and differences between CRC patients and murine models of CRC and point out cytokines with an ambivalent role for intestinal cancer. We also identify some of the future challenges in the field that should be addressed for the development of more effective immunomodulatory therapies.
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Affiliation(s)
- Lukas F Mager
- Institute of Pathology, University of Bern , Bern , Switzerland
| | - Marie-Hélène Wasmer
- Institute of Pathology, University of Bern, Bern, Switzerland; Graduate School for Cellular and Biomedical Sciences, University of Bern, Bern, Switzerland
| | - Tilman T Rau
- Institute of Pathology, University of Bern , Bern , Switzerland
| | - Philippe Krebs
- Institute of Pathology, University of Bern , Bern , Switzerland
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Ren W, Sun Z, Zeng Q, Han S, Zhang Q, Jiang L. Aberrant Expression of CUL4A Is Associated with IL-6/ STAT3 Activation in Colorectal Cancer Progression. Arch Med Res 2016; 47:214-222. [PMID: 27418574 DOI: 10.1016/j.arcmed.2016.07.001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/26/2015] [Accepted: 06/28/2016] [Indexed: 11/15/2022]
Abstract
BACKGROUND AND AIMS Although it has been indicated that the cytokine interleukin-6 (IL-6) promotes colorectal cancer (CRC) tumorigenesis in tumor microenvironment, the mechanisms related to IL-6-induced tumor progression are still not well understood. METHODS First, the correlation between pSTAT3, CUL4A and ZEB1 was analyzed using immunocytochemistry. Logistic regression analysis was then used to observe the relationship between levels of pSTAT3, CUL4A and ZEB1 and clinicopathological characteristics. Finally, the mechanism of the effect of the expression level of pSTAT3, CUL4A and ZEB1 on cell invasion ability was verified by cell experiment. RESULTS We discovered that the increased expression levels of pSTAT3, CUL4A and ZEB1 had significant relationships in CRC patients. These up-regulated expression levels were also closely associated with CRC aggressiveness. Furthermore, in vitro, we discovered that expression levels of CUL4A and ZEB1 were significantly up-regulated when IL-6 stimulated. However, the CUL4A-knockdown, IL-6, could not induce expression of ZEB1. CHIP assay authenticated that pSTAT3 could bind to CUL4A promoter and worked as their transcription factors. We also demonstrated that IL-6 markedly increased the reporter activity using a luciferase reporter gene containing CUL4A promoter. Finally, silencing CUL4A blocked IL-6-driven invasion in matrigel invasion assay. CONCLUSION This study proposed that CUL4A played an oncogene role through ZEB1 in IL-6-induced colorectal carcinoma progression.
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Affiliation(s)
- Weiguo Ren
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China.
| | - Zhenqiang Sun
- Surgical Gastroenterology, Xinjiang Medical University Cancer Hospital, Urumqi, Xinjiang, China
| | - Qinglei Zeng
- Department of Infectious Diseases, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Shuang Han
- Department of Oncology, Yantai Affiliated Hospital of Binzhou Medical University, Yantai, Shandong, China
| | - Qinglin Zhang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
| | - Libin Jiang
- Department of Gastroenterology, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
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Ren W, Shen S, Sun Z, Shu P, Shen X, Bu C, Ai F, Zhang X, Tang A, Tian L, Li G, Li X, Ma J. Jak-STAT3 pathway triggers DICER1 for proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) to promote colon cancer development. Cancer Lett 2016; 375:209-220. [PMID: 26965998 DOI: 10.1016/j.canlet.2016.02.055] [Citation(s) in RCA: 30] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/24/2015] [Revised: 02/06/2016] [Accepted: 02/29/2016] [Indexed: 12/13/2022]
Abstract
Chronic intestinal inflammation is closely associated with colon cancer development and STAT3 seems to take center stage in bridging chronic inflammation to colon cancer progress. Here, we discovered that DICER1 was significantly downregulated in response to IL-6 or LPS stimulation and identified a novel mechanism for DICER1 downregulation via proteasomal degradation by ubiquitin ligase complex of CUL4A(DCAF1) in colon cancer cells. Meanwhile, PI3K-AKT signaling pathway phosphorylated DICER1 and contributed to its proteasomal degradation. The regulation of DICER1 by CUL4A(DCAF1) affected cell growth and apoptosis which is controlled by IL-6 activated Jak-STAT3 pathway. Intervention of CUL4A(DCAF1) ubiquitin ligase complex led to fluctuation in expression levels of DICER1 and microRNAs, and thus affected tumor growth in a mouse xenograft model. A panel of microRNAs that were downregulated by IL-6 stimulation was rescued by siRNA-CUL4A, and their predicated functions are involved in regulation of cell proliferation, apoptosis and motility. Furthermore, clinical specimen analysis revealed that decreased DICER1 expression was negatively correlated with STAT3 activation and cancer progression in human colon cancers. DICER1 and p-STAT3 expression levels correlated with 5-year overall survival of colon cancer patients. Consequently, this study proposes that inflammation-induced Jak-STAT3 signaling leads to colon cancer development through proteasomal degradation of DICER1 by ubiquitin ligase complex of CUL4A(DCAF1), which suggests a novel therapeutic opportunity for colon cancer.
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Affiliation(s)
- Weiguo Ren
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Shourong Shen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Zhenqiang Sun
- Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Peng Shu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Xiaohua Shen
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Chibin Bu
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China
| | - Feiyan Ai
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Xuemei Zhang
- Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Anliu Tang
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Li Tian
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China
| | - Guiyuan Li
- Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China
| | - Xiayu Li
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China.
| | - Jian Ma
- Department of Gastroenterology, The Third Xiangya Hospital of Central South University, Changsha, Hunan, China; Hunan Key Laboratory of Nonresolving Inflammation and Cancer, Changsha, Hunan, China; Cancer Research Institute, Central South University, Key Laboratory of Carcinogenesis, Ministry of Health, Key Laboratory of Carcinogenesis and Cancer Invasion, Ministry of Education, Changsha, Hunan, China.
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Liu H, Ren G, Wang T, Chen Y, Gong C, Bai Y, Wang B, Qi H, Shen J, Zhu L, Qian C, Lai M, Shao J. Aberrantly expressed Fra-1 by IL-6/STAT3 transactivation promotes colorectal cancer aggressiveness through epithelial-mesenchymal transition. Carcinogenesis 2015; 36:459-68. [PMID: 25750173 PMCID: PMC4392608 DOI: 10.1093/carcin/bgv017] [Citation(s) in RCA: 112] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2014] [Accepted: 02/24/2015] [Indexed: 12/12/2022] Open
Abstract
The pro-inflammatory cytokine interleukin-6 (IL-6) in tumor microenvironment has been suggested to promote development and progression of colorectal cancer (CRC). However, the underlying molecular mechanisms remain elusive. In this study, we demonstrate that fos-related antigen-1 (Fra-1) plays a critical role in IL-6 induced CRC aggressiveness and epithelial-mesenchymal transition (EMT). In CRC cell lines, the expression of Fra-1 gene was found significantly upregulated during IL-6-driven EMT process. The Fra-1 induction occurred at transcriptional level in a manner dependent on signal transducer and activator of transcription 3 (STAT3), during which both phosphorylated and acetylated post-translational modifications were required for STAT3 activation to directly bind to the Fra-1 promoter. Importantly, RNA interference-based attenuation of either STAT3 or Fra-1 prevented IL-6-induced EMT, cell migration and invasion, whereas ectopic expression of Fra-1 markedly reversed the STAT3-knockdown effect and enhanced CRC cell aggressiveness by regulating the expression of EMT-promoting factors (ZEB1, Snail, Slug, MMP-2 and MMP-9). Furthermore, Fra-1 levels were positively correlated with the local invasion depth as well as lymph node and liver metastasis in a total of 229 CRC patients. Intense immunohistochemical staining of Fra-1 was observed at the tumor marginal area adjacent to inflammatory cells and in parallel with IL-6 secretion and STAT3 activation in CRC tissues. Together, this study proposes the existence of an aberrant IL-6/STAT3/Fra-1 signaling axis leading to CRC aggressiveness through EMT induction, which suggests novel therapeutic opportunities for the malignant disease.
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Affiliation(s)
- Hong Liu
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Guoping Ren
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Tingyang Wang
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yuexia Chen
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Chaoju Gong
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Yanfeng Bai
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Bo Wang
- Department of Pathology, First Affiliated Hospital, Zhejiang University School of Medicine, Hangzhou 310003, China
| | - Hongyan Qi
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jing Shen
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Lijun Zhu
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Cheng Qian
- Institute of Pathology and Southwest Cancer Center, Southwest Hospital, Third Military Medical University, Chongqing 400038, China
| | - Maode Lai
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China
| | - Jimin Shao
- Department of Pathology and Pathophysiology, Zhejiang Key Laboratory for Disease Proteomics, Zhejiang University School of Medicine, Hangzhou 310058, China,
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Functions and regulation of MUC13 mucin in colon cancer cells. J Gastroenterol 2014; 49:1378-91. [PMID: 24097071 PMCID: PMC3979492 DOI: 10.1007/s00535-013-0885-z] [Citation(s) in RCA: 40] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/10/2013] [Accepted: 09/09/2013] [Indexed: 02/04/2023]
Abstract
BACKGROUND MUC13 is overexpressed and aberrantly localized in colon cancer tissue; however, the specific functions and regulation of MUC13 expression are unknown. METHODS Stable cell lines with either overexpressed or suppressed MUC13 levels were analyzed to determine cell growth, colony formation, cell migration, and cell invasion assays. The molecular mechanisms involved in MUC13 regulation were elucidated via chromatin immunoprecipitation (ChIP) and analysis of interleukin 6 (IL6) treatments. Colon cancer tissues were analyzed by immunohistochemistry (IHC) for the protein levels of MUC13 and P-STAT5 in colon cancer cells. RESULTS Overexpression of MUC13 increased cell growth, colony formation, cell migration, and invasion. In concordance, MUC13 silencing decreased these tumorigenic features. Overexpression of MUC13 also modulated various cancer-associated proteins, including telomerase reverse transcriptase, sonic hedgehog, B cell lymphoma murine like site 1, and GATA like transcription factor 1. Additionally, MUC13-overexpressing cells showed increased HER2 and P-ERK expression. ChIP analysis revealed binding of STAT5 to the predicted MUC13 promoter. IL6 treatment of colon cancer cells increased the expression of MUC13 via activation of the JAK2/STAT5 signaling pathway. Suppression of JAK2 and STAT5 signaling by chemical inhibitors abolished IL6-induced MUC13 expression. IHC analysis showed increased expression of both P-STAT5 and MUC13 in colon cancer as compared to adjacent normal tissue. CONCLUSIONS The results of this study, for the first time, suggest functional roles of MUC13 in colon cancer progression and provide information regarding the regulation of MUC13 expression via JAK2/STAT5 which may reveal promising therapeutic approaches for colon cancer treatment.
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Mathonnet M, Perraud A, Christou N, Akil H, Melin C, Battu S, Jauberteau MO, Denizot Y. Hallmarks in colorectal cancer: Angiogenesis and cancer stem-like cells. World J Gastroenterol 2014; 20:4189-4196. [PMID: 24764657 PMCID: PMC3989955 DOI: 10.3748/wjg.v20.i15.4189] [Citation(s) in RCA: 64] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/13/2013] [Revised: 01/26/2014] [Accepted: 03/19/2014] [Indexed: 02/06/2023] Open
Abstract
Carcinogenesis is a multistep process that requires the accumulation of various genetic and epigenetic aberrations to drive the progressive malignant transformation of normal human cells. Two major hallmarks of carcinogenesis that have been described are angiogenesis and the stem cell characteristic of limitless replicative potential. These properties have been targeted over the past decade in the development of therapeutic treatments for colorectal cancer (CRC), one of the most commonly diagnosed and lethal cancers worldwide. The treatment of solid tumor cancers such as CRC has been challenging due to the heterogeneity of the tumor itself and the chemoresistance of the malignant cells. Furthermore, the same microenvironment that maintains the pool of intestinal stem cells that contribute to the continuous renewal of the intestinal epithelia also provides the necessary conditions for proliferative growth of cancer stem-like cells. These cancer stem-like cells are responsible for the resistance to therapy and cancer recurrence, though they represent less than 2.5% of the tumor mass. The stromal environment surrounding the tumor cells, referred to as the tumor niche, also supports angiogenesis, which supplies the oxygen and nutrients needed for tumor development. Anti-angiogenic therapy, such as with bevacizumab, a monoclonal antibody against vascular-endothelial growth factor, significantly prolongs the survival of metastatic CRC patients. However, such treatments are not completely curative, and a large proportion of patient tumors retain chemoresistance or show recurrence. This article reviews the current knowledge regarding the molecular phenotype of CRC cancer cells, as well as discusses the mechanisms contributing to their maintenance. Future personalized therapeutic approaches that are based on the interaction of the carcinogenic hallmarks, namely angiogenic and proliferative attributes, could improve survival and decrease adverse effects induced by unnecessary chemotherapy.
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Waldner MJ, Neurath MF. Master regulator of intestinal disease: IL-6 in chronic inflammation and cancer development. Semin Immunol 2014; 26:75-9. [DOI: 10.1016/j.smim.2013.12.003] [Citation(s) in RCA: 169] [Impact Index Per Article: 15.4] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/15/2013] [Accepted: 12/16/2013] [Indexed: 10/25/2022]
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Middleton K, Jones J, Lwin Z, Coward JIG. Interleukin-6: an angiogenic target in solid tumours. Crit Rev Oncol Hematol 2013; 89:129-39. [PMID: 24029605 DOI: 10.1016/j.critrevonc.2013.08.004] [Citation(s) in RCA: 106] [Impact Index Per Article: 8.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2013] [Revised: 07/29/2013] [Accepted: 08/13/2013] [Indexed: 12/18/2022] Open
Abstract
During the past decade, incorporating anti-angiogenic agents into the therapeutic management of a myriad of malignancies has in certain cases made a significant impact on survival. However, the development of resistance to these drugs is inevitable and swift disease progression on their cessation often ensues. Hence, there is a drive to devise strategies that aim to enhance response to anti-angiogenic therapies by combining them with other targeted agents that facilitate evasion from resistance. The pleiotropic cytokine, interleukin-6 (IL-6), exerts pro-angiogenic effects in the tumour microenvironment of several solid malignancies and there is emerging evidence that reveals significant relationships between IL-6 signalling and treatment failure with antibodies directed against vascular endothelial growth factor (VEGF). This review summarises the role of IL-6 in pivotal angiogenic processes and preclinical/clinical research to support the future introduction of anti-IL-6 therapies to be utilised either in combination with other anti-angiogenic drugs or as a salvage therapy for patients with diseases that become refractory to these approaches.
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Affiliation(s)
- Kathryn Middleton
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia
| | - Joanna Jones
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia
| | - Zarnie Lwin
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia
| | - Jermaine I G Coward
- Mater Adult Hospital, Department of Medical Oncology, Raymond Terrace, Brisbane, QLD 4101, Australia; Inflammation & Cancer Therapeutics Group, Mater Research, Level 4, Translational Research Institute, 37 Kent Street, Woolloongabba, Brisbane, QLD 4102, Australia; School of Medicine, University of Queensland, St Lucia, Brisbane, QLD 4072, Australia.
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Gordziel C, Bratsch J, Moriggl R, Knösel T, Friedrich K. Both STAT1 and STAT3 are favourable prognostic determinants in colorectal carcinoma. Br J Cancer 2013; 109:138-46. [PMID: 23756862 PMCID: PMC3708576 DOI: 10.1038/bjc.2013.274] [Citation(s) in RCA: 85] [Impact Index Per Article: 7.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2013] [Revised: 04/30/2013] [Accepted: 05/14/2013] [Indexed: 01/03/2023] Open
Abstract
BACKGROUND Aberrant activities of Janus kinase (JAK)/signal transducer and activator of transcription (STAT) signalling pathways have been implicated in the development and spread of various cancer entities, among them colorectal carcinoma (CRC). Transcription factors STAT3 and STAT1, both downstream effectors of interleukin (IL)-6 and its receptor, are involved in growth and developmental control of CRC cells. Constituents of the signalling network around IL-6 and STAT activation are discussed as potential biomarkers and therapeutic targets in CRC. METHODS By immunohistochemical analysis of a tissue microarray covering >400 CRC biopsies, the expression and activity status of STAT1, STAT3 as well as of IL-6 and the IL-6 receptor α-chain was determined. The outcome was correlated with clinical information and patients' survival data. Colorectal carcinoma biopsies were also analysed for specific DNA-binding activity of STATs. RESULTS Statistical analysis showed tendential associations between individual STATs, IL-6/IL-6 receptor-α and clinicopathological parameters. The study revealed a significant correlation of high STAT1 activity with longer patient overall survival. Surprisingly, strong STAT3 expression in surgical specimens was correlated with an increase in median overall survival by about 30 months. Statistical analysis revealed that high expression levels of STAT1 and STAT3 were associated. This finding was backed up by biochemical data that showed simultaneous STAT1 and STAT3 DNA-binding activity in randomly selected CRC biopsies. CONCLUSION By multivariate data analysis, we could show that STAT3 expression and activity constitutes an independent favourable prognostic marker for CRC.
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Affiliation(s)
- C Gordziel
- Institute of Biochemistry II, University Hospital Jena, Jena, Germany
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Shen A, Chen Y, Hong F, Lin J, Wei L, Hong Z, Sferra TJ, Peng J. Pien Tze Huang suppresses IL-6-inducible STAT3 activation in human colon carcinoma cells through induction of SOCS3. Oncol Rep 2012; 28:2125-2130. [PMID: 23027374 DOI: 10.3892/or.2012.2067] [Citation(s) in RCA: 34] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/20/2012] [Accepted: 09/13/2012] [Indexed: 11/06/2022] Open
Abstract
IL-6/STAT3 is one of the most critical cellular signal transduction pathways known to malfunction in colorectal cancer (CRC). As a target gene of signal transducer and activator of transcription 3 (STAT3) signaling, suppressor of cytokine signaling 3 (SOCS3) can be quickly induced by interleukin-6 (IL-6) stimulation but it then strongly inhibits IL-6-mediated STAT3 activation, functioning as a negative feedback regulator of the IL-6/STAT3 pathway. Aberrant activation of STAT3 and/or reduced expression of SOCS are strongly correlated with carcinogenesis, which therefore becomes a promising target for the development of novel anticancer chemotherapies. Pien Tze Huang (PZH) is a well-known traditional Chinese formula that was first prescribed by a royal physician 450 years ago in the Ming Dynasty. It has been used in China and Southeast Asia for centuries as a folk remedy for various types of cancer including CRC. However, the precise mechanism of its antitumor activity remains largely unclear. In the present study, we found that PZH could significantly and dose-dependently inhibit IL-6-mediated increase of STAT3 phosphorylation levels and transcriptional activity in the human colon carcinoma HT-29 cells, resulting in the suppression of cell proliferation and the induction of apoptosis. In addition, PZH treatment profoundly inhibited IL-6-induced upregulation of cyclin D1 and Bcl-2, two key target genes of the STAT3 pathway. Moreover, PZH treatment increased the expression of SOCS3. These results suggest that PZH could effectively inhibit proliferation and promote apoptosis of human colon carcinoma cells via modulation of the IL-6/STAT3 signaling pathway and its target genes.
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Affiliation(s)
- Aling Shen
- Academy of Integrative Medicine Biomedical Research Center, Fujian University of Traditional Chinese Medicine, Fuzhou, Fujian 350122, PR China
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Waldner MJ, Foersch S, Neurath MF. Interleukin-6--a key regulator of colorectal cancer development. Int J Biol Sci 2012; 8:1248-53. [PMID: 23136553 PMCID: PMC3491448 DOI: 10.7150/ijbs.4614] [Citation(s) in RCA: 294] [Impact Index Per Article: 22.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/18/2012] [Accepted: 07/26/2012] [Indexed: 12/31/2022] Open
Abstract
Growing evidence proposes an important role for pro-inflammatory cytokines during tumor development. Several experimental and clinical studies have linked the pleiotropic cytokine interleukin-6 (IL-6) to the pathogenesis of sporadic and inflammation-associated colorectal cancer (CRC). Increased IL-6 expression has been related to advanced stage of disease and decreased survival in CRC patients. According to experimental studies, these effects are mediated through IL-6 trans-signaling promoting tumor cell proliferation and inhibiting apoptosis through gp130 activation on tumor cells with subsequent signaling through Janus kinases (JAKs) and signal transducer and activator of transcription 3 (STAT3). During recent years, several therapeutics targeting the IL-6/STAT3 pathway have been developed and pose a promising strategy for the treatment of CRC. This review discusses the molecular mechanisms and possible therapeutic targets involved in IL-6 signaling in CRC.
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Lee WS, Baek JH, You DH, Nam MJ. Prognostic value of circulating cytokines for stage III colon cancer. J Surg Res 2012; 182:49-54. [PMID: 23010514 DOI: 10.1016/j.jss.2012.08.051] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2012] [Revised: 08/13/2012] [Accepted: 08/24/2012] [Indexed: 12/31/2022]
Abstract
BACKGROUND This study was to determine preoperative serum levels of epidermal growth factor (EGF), interleukin-6 (IL-6), and C-reactive protein (CRP) in stage III colon cancer and correlate them with disease status and prognosis. The circulating EGF in correlation with primary site epidermal growth factor receptor (EGFR) was also evaluated. METHODS Seventy-seven patients with curatively resected stage III colon cancer were selected for analysis. Enzyme-linked immunosorbent assay was used to determine EGF and IL-6 serum levels, and serum CRP levels were measured via immunoturbidimetry. EGFR expression was observed with immunohistochemical studies. RESULTS The median levels of EGFR, IL-6, and CRP were 189.4 pg/mL, 9.09 pg/mL, and 1.4 mg/mL, respectively. The factors related to recurrence with statistical significance included positive node status (P = 0.041), lymphovascular invasion (P = 0.001), and preoperative IL-6 level ≥9 pg/mL (P = 0.020). CRP and EGF levels were not significantly associated with disease-free survival rates (P = 0.438 and P = 0.309, respectively). Multivariate analysis using Cox's proportion model revealed that lymph node status was the single independent prognostic factor for predicting time until recurrence (odds ratio, 4.99; 95% confidence interval, 1.09-22.91; P = 0.038). CONCLUSION IL-6 expression in stage III colon cancer patients appears to be a prognostic marker of tumor behavior. No correlations between serum EGF concentrations and tumor EGFR positivity were found in this study.
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Affiliation(s)
- Won-Suk Lee
- Department of Surgery, Gil Medical Center, Gachon University, School of medicine, Incheon, Korea
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Eiró N, Vizoso FJ. Inflammation and cancer. World J Gastrointest Surg 2012; 4:62-72. [PMID: 22530080 PMCID: PMC3332223 DOI: 10.4240/wjgs.v4.i3.62] [Citation(s) in RCA: 104] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/20/2010] [Revised: 11/17/2011] [Accepted: 11/25/2011] [Indexed: 02/06/2023] Open
Abstract
There is evidence supporting the hypothesis that inflammation participates in providing conditions that lead to cancer. An unresolved inflammation due to any failure in the precise control of the immune response can continue to perturb the cellular microenvironment, thereby leading to alterations in cancer-related genes and posttranslational modification in crucial cellular proteins involved in the cell cycle, DNA repair and apoptosis. In addition, there are data indicating that inflammatory cells and immunomodulatory mediators present in the tumor microenvironment influence tumor progression and metastasis. Historically, tumor-infiltrating leukocytes have been considered to be manifestations of an intrinsic defence mechanism against developing tumors. However, increasing evidence indicates that leukocyte infiltration can promote tumor phenotypes, such as angiogenesis, growth and invasion. This may be due to inflammatory cells that probably can influence cancer promotion by secreting cytokines, growth factors, chemokines and proteases, which stimulate proliferation and invasiveness of cancer cells. Consequently, events and molecules implicated in this cross talk between the tumor microenvironment and inflammatory process may emerge as attractive targets in anticancer therapeutic interventions with significant clinical impact.
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Affiliation(s)
- Noemí Eiró
- Noemí Eiró, Francisco J Vizoso, Research Unit, Fundación Hospital de Jove, 33290 Gijón, Asturias, Spain
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Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 2009; 9:351-69. [PMID: 19665429 PMCID: PMC2730981 DOI: 10.1016/j.coph.2009.06.020] [Citation(s) in RCA: 277] [Impact Index Per Article: 17.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2009] [Revised: 06/22/2009] [Accepted: 06/23/2009] [Indexed: 02/03/2023]
Abstract
Evidence has emerged in the last two decades that at the molecular level most chronic diseases, including cancer, are caused by a dysregulated inflammatory response. The identification of transcription factors such as NF-kappaB, AP-1 and STAT3 and their gene products such as tumor necrosis factor, interleukin-1, interleukin-6, chemokines, cyclooxygenase-2, 5 lipooxygenase, matrix metalloproteases, and vascular endothelial growth factor, adhesion molecules and others have provided the molecular basis for the role of inflammation in cancer. These inflammatory pathways are activated by tobacco, stress, dietary agents, obesity, alcohol, infectious agents, irradiation, and environmental stimuli, which together account for as much as 95% of all cancers. These pathways have been implicated in transformation, survival, proliferation, invasion, angiogenesis, metastasis, chemoresistance, and radioresistance of cancer, so much so that survival and proliferation of most types of cancer stem cells themselves appear to be dependent on the activation of these inflammatory pathways. Most of this evidence, however, is from preclinical studies. Whether these pathways have any role in prevention, progression, diagnosis, prognosis, recurrence or treatment of cancer in patients, is the topic of discussion of this review. We present evidence that inhibitors of inflammatory biomarkers may have a role in both prevention and treatment of cancer.
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Michael M, Goldstein D, Clarke SJ, Milner AD, Beale P, Friedlander M, Mitchell P. Prognostic factors predictive of response and survival to a modified FOLFOX regimen: importance of an increased neutrophil count. Clin Colorectal Cancer 2007; 6:297-304. [PMID: 17241514 DOI: 10.3816/ccc.2006.n.048] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
PURPOSE The aim of this study was to identify prognostic indicators of survival and response in a homogeneous population of chemotherapy-naive patients treated with oxaliplatin as part of 3 successive trials. PATIENTS AND METHODS Patient data were derived from 3 successive phase II trials evaluating modifications of the FOLFOX4 (oxaliplatin/5-fluorouracil/leucovorin) regimen. Clinical and laboratory prognostic factors were identified from the literature. Multifactor analyses stratified by treatment cohort were performed to identify independent prognostic factors for progression-free survival (PFS), overall survival (OS), and response rate. RESULTS One hundred thirty-four patients were enrolled across all 3 studies. Reduced PFS (n = 128) was associated with patients with the following characteristics: no previous surgery (P = 0.003); previous adjuvant chemotherapy (P = 0.015); > 1 organ involvement (P = 0.001); baseline absolute neutrophil count (ANC) > or = upper limit of normal (P = 0.001); and time from diagnosis to metastases < 9 months (P = 0.043). Poor OS (n = 128) was associated with patients with the following characteristics: performance status > 1 (P < 0.001); > 1 organ involvement (P = 0.018); and baseline ANC > or = upper limit of normal (P < 0.001). Response rate was related to previous surgery (P = 0.017) and performance status (P = 0.02). CONCLUSION This analysis has identified the additional prognostic importance of an increased ANC for PFS and OS. Further consideration needs to be given to include markers of systemic inflammation such as ANC as well as relevant cytokine levels in a larger cohort of identically treated patients.
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Affiliation(s)
- Michael Michael
- Division of Haematology and Medical Oncology, Peter MacCallum Cancer Centre, Victoria, 8006, Australia.
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Jin LQ, Zheng ZJ, Peng Y, Li WX, Chen XM, Lu JX. Opposite effects on tumor growth depending on dose of Achyranthes bidentata polysaccharides in C57BL/6 mice. Int Immunopharmacol 2007; 7:568-77. [PMID: 17386404 DOI: 10.1016/j.intimp.2006.12.009] [Citation(s) in RCA: 32] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2006] [Revised: 12/18/2006] [Accepted: 12/18/2006] [Indexed: 01/24/2023]
Abstract
We report here the investigation on the effects of Achyranthes bidentata polysaccharides (ABPS) against Lewis lung cancer (LLC) in C57BL/6 mice. Depending on its doses administered in vivo, ABPS was shown to have inhibitory as well as stimulative effects on tumor growth in LLC-bearing C57BL/6 mice. ABPS at low dose could significantly inhibit LLC growth, while high dose treatment of ABPS stimulated, rather than inhibited, LLC growth in C57BL/6 mice. Tumor cell cycle analysis revealed that more tumor cells arrested at G2/M phase after daily low dose intraperitoneal injection of ABPS for consecutive 15 days. The spleen weight increased markedly in LLC-bearing C57BL/6 mice treated with high dose of ABPS. However, the spleen cytotoxicity activity was significantly despaired in mice of high dose treatment of ABPS. Furthermore, we demonstrated that the expressions of IL-6 mRNA and TNF-alpha mRNA were markedly up-regulated in spleens from mice treated with a high dose of ABPS by RT-PCR reactions, suggesting that the low dose of ABPS inhibits tumor growth via its effect on tumor cell cycle distribution, rather than activation of NK activity as previously suggested. We postulate that the stimulation of tumor growth by high dose of ABPS is associated with dysfunction of NK cell and up-regulation of IL-6 mRNA and TNF-alpha mRNA expression in murine spleen.
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Affiliation(s)
- Li-Qin Jin
- Institute of Cellular and Molecular Medicine, Wenzhou Medical College, Wenzhou, Zhejiang 325035, China
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Brozek W, Bises G, Girsch T, Cross HS, Kaiser HE, Peterlik M. Differentiation-dependent expression and mitogenic action of interleukin-6 in human colon carcinoma cells: relevance for tumour progression. Eur J Cancer 2005; 41:2347-54. [PMID: 16176872 DOI: 10.1016/j.ejca.2005.07.014] [Citation(s) in RCA: 35] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/28/2005] [Revised: 06/27/2005] [Accepted: 07/05/2005] [Indexed: 10/25/2022]
Abstract
Interleukin (IL)-6 mRNA expression in general is low in normal, adenomatous and cancerous human colon mucosa, except in rather undifferentiated lesions, in which IL-6 is overexpressed. Cytokeratin (CK) 8-positive carcinoma cells were identified by double immunostaining as almost exclusive source of IL-6. Likewise, in five (sub)clones of primary culture COGA-1 and COGA-13 human colon carcinoma cells, and in three established cell lines (Caco-2/AQ, Caco-2/15 and HT-29), efficient translation of IL-6 mRNA into protein was observed only in the least differentiated COGA-13 cells. Notably, IL-1beta (5 ng/ml) enhanced IL-6 release in COGA-13 cultures by three orders of magnitude. Although all cell clones studied expressed the IL-6 receptor (IL-6R), rhIL-6 (1-100 ng/ml) had a significant effect on cellular proliferation only in highly differentiated Caco-2 cells. Our data imply that IL-6, when released from rather undifferentiated carcinoma cells, particularly in response to IL-1beta, can advance tumour progression through paracrine growth stimulation of normal or highly differentiated colon tumour cells with intact STAT-3-mediated IL-6 signalling.
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Affiliation(s)
- Wolfgang Brozek
- Department of Pathophysiology, Medical University of Vienna, Waehringer Guertel 18-20, A-1090 Vienna, Austria
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Meng F, Yamagiwa Y, Taffetani S, Han J, Patel T. IL-6 activates serum and glucocorticoid kinase via p38alpha mitogen-activated protein kinase pathway. Am J Physiol Cell Physiol 2005; 289:C971-81. [PMID: 15917303 PMCID: PMC1513290 DOI: 10.1152/ajpcell.00081.2005] [Citation(s) in RCA: 52] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/22/2022]
Abstract
Interleukin-6 (IL-6) has been implicated as an autocrine factor involved in growth of several human cancers, such as tumors arising from the biliary tract or cholangiocarcinoma. In malignant biliary tract epithelia, IL-6 activates the p38 MAPK pathway, which mediates a dominant survival signaling pathway. Serum and glucocorticoid-stimulated kinase (SGK) has been implicated as a survival kinase, but its role in survival signaling by IL-6 is unknown. After IL-6 stimulation, p38 MAPK activation preceded phosphorylation of SGK at Ser78. Pretreatment with the pharmacological inhibitors of p38 MAPK SB-203580 or SB-202190 blocked IL-6-induced SGK phosphorylation at Ser78 and SGK activation. Overexpression of p38alpha increased constitutive SGK phosphorylation at Ser78, whereas dominant negative p38alpha MAPK blocked IL-6-induced SGK phosphorylation and nuclear translocation. Interestingly, in addition to stimulating SGK phosphorylation, both IL-6 stimulation and p38alpha MAPK overexpression increased SGK mRNA and protein expression. An increase in p38 MAPK and SGK occurred following enforced expression of IL-6 in vivo. Furthermore, inhibition of SGK expression by siRNA increased toxicity due to chemotherapeutic drugs. Taken together, these data identify SGK as both a downstream kinase substrate as well as a transcriptionally regulated gene target of p38 MAPK in response to IL-6 and support a role of SGK during survival signaling by IL-6 in human cancers, such as cholangiocarcinoma.
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Affiliation(s)
- Fanyin Meng
- Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas; and
| | - Yoko Yamagiwa
- Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas; and
| | - Silvia Taffetani
- Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas; and
| | - Jiahuai Han
- Department of Immunology, The Scripps Research Institute, La Jolla, California
| | - Tushar Patel
- Department of Internal Medicine, Scott and White Clinic, Texas A&M University System Health Science Center College of Medicine, Temple, Texas; and
- Address for reprint requests and other correspondence: T. Patel, Scott and White Clinic, Texas A&M Univ. Health Science Center, 2401 South 31st St., Temple, TX 76508 (e-mail: )
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Nikiteas NI, Tzanakis N, Gazouli M, Rallis G, Daniilidis K, Theodoropoulos G, Kostakis A, Peros G. Serum IL-6, TNFalpha and CRP levels in Greek colorectal cancer patients: prognostic implications. World J Gastroenterol 2005; 11:1639-1643. [PMID: 15786541 PMCID: PMC4305945 DOI: 10.3748/wjg.v11.i11.1639] [Citation(s) in RCA: 114] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/13/2004] [Revised: 09/01/2004] [Accepted: 09/30/2004] [Indexed: 02/06/2023] Open
Abstract
AIM The significance of preoperative serum IL-6, TNFalpha and CRP levels in the progression of colorectal cancer (CRC) has not been fully elucidated. Our intention was to investigate their role and identify their prognostic significance. METHODS The IL-6, TNFalpha and CRP levels were measured in 74 CRC patients and the relationships between their elevations and both the clinicopathological factors and prognosis of patients were investigated. Serum concentrations of human IL-6 and TNFalpha were determined by enzyme-linked immunosorbent assay (ELISA). CRP was measured by an immunoturbinometric method. RESULTS Median IL-6, TNFalpha and CRP levels were significantly higher in CRC patients than in normal controls. High levels of serum IL-6, TNFalpha and CRP were correlated with larger tumor size. Furthermore, high IL-6 and high CRP levels were associated with reduced overall survival. CONCLUSION Serum IL-6, TNFalpha and CRP levels definitely increase in CRC patients. Pre-operative serum elevation of IL-6 and CRP was thus found to be predictor of the prognosis of CRC patients. The clinical value of TNFalpha in CRC needs to be further investigated.
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Affiliation(s)
- Nikolaos I Nikiteas
- 2nd Propedeutic Department of Surgery, School of Medicine, University of Athens, Athens 11527, Greece.
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Rich T, Innominato PF, Boerner J, Mormont MC, Iacobelli S, Baron B, Jasmin C, Lévi F. Elevated serum cytokines correlated with altered behavior, serum cortisol rhythm, and dampened 24-hour rest-activity patterns in patients with metastatic colorectal cancer. Clin Cancer Res 2005; 11:1757-64. [PMID: 15755997 DOI: 10.1158/1078-0432.ccr-04-2000] [Citation(s) in RCA: 192] [Impact Index Per Article: 9.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Abstract
PURPOSE Incapacitating symptom burden in cancer patients contributes to poor quality of life (QOL) and can influence treatment outcomes because of poor tolerance to therapy. In this study, the role of circulating cytokines in the production symptoms in cancer patients is evaluated. EXPERIMENTAL DESIGN Eighty patients with metastatic colorectal cancer with either normal (group I, n = 40) or dampened (group II, n = 40) 24-hour rest/activity patterns measured by actigraphy were identified. Actigraphy patterns were correlated with QOL indices, serum cortisol obtained at 8:00 a.m. and 4:00 p.m. and with serum levels of transforming growth factor-alpha, tumor necrosis factor-alpha, and interleukin 6 (IL-6) obtained at 8:00 a.m. and analyzed in duplicate by ELISA. Cytokine levels and survival were also correlated. RESULTS Group II patients had significantly higher pre treatment levels of all three cytokines, displayed significantly poorer emotional and social functioning, had higher fatigue, more appetite loss, and poorer performance status compared with group I patients. Transforming growth factor-alpha (TGF-alpha) and IL-6 were significantly increased in the patients with WHO performance status >1 and in those with appetite loss. Fatigue was significantly associated with elevated TGF-alpha only. IL-6 was increased in those patients with extensive liver involvement and multiple organ replacement, and it was significantly correlated with dampened cortisol rhythm. In a multivariate analysis, IL-6 was correlated with poor treatment outcome. CONCLUSIONS Significant correlations were found between serum levels of TGF-alpha and IL-6, circadian patterns in wrist activity and serum cortisol and tumor-related symptoms in patients with metastatic colorectal cancer. These data support the hypothesis that some cancer patient's symptoms of fatigue, poor QOL, and treatment outcome are related to tumor or host generated cytokines and could reflect cytokine effects on the circadian timing system. This interplay between cytokine signaling pathways, the hypothalamic-pituitary-adrenal axis, the autonomic nervous system, and efferent pathways of the suprachiasmatic nucleus that control circadian physiology, opens the way to new rational interventions for symptom management in cancer patients.
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Affiliation(s)
- Tyvin Rich
- Department of Radiation Oncology, University of Virginia Health System, Charlottesville, VA, USA.
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Chung YC, Chang YF. Serum interleukin-6 levels reflect the disease status of colorectal cancer. J Surg Oncol 2003; 83:222-6. [PMID: 12884234 DOI: 10.1002/jso.10269] [Citation(s) in RCA: 262] [Impact Index Per Article: 11.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
BACKGROUND AND OBJECTIVES Interleukin-6 (IL-6) has been shown to be associated with cancer development. However, its role in the progression of colorectal cancer has never been elucidated. Our intention was to investigate this role and identify its prognostic significance. METHODS One hundred and sixty-four consecutive colorectal cancer patients, whose local lesions were resected, were selected. The preoperative serum IL-6 levels were measured and the relationships between the elevation of IL-6 and both the clinicopathological factors and prognosis of patients were investigated. RESULTS Median IL-6 level was significantly higher in patients with colorectal cancer than in normal controls. High levels of serum IL-6 (>12 pg/ml) were correlated with larger tumor size, elevated serum CRP levels, and liver metastases (P < 0.05). IL-6 levels also increased in a stage-related manner (P < 0.01). Although serum IL-6 correlated with survival, it is not an independent prognostic indicator. CONCLUSIONS Serum IL-6 levels correlated with disease status of colorectal cancer but could not be regarded as an independent predictor for prognosis.
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Affiliation(s)
- Yuan-Chang Chung
- Department of Surgery, Hsin-Chu Hospital, Department of Health, Taiwan, Republic of China.
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Chan MM, Fong D, Soprano KJ, Holmes WF, Heverling H. Inhibition of growth and sensitization to cisplatin-mediated killing of ovarian cancer cells by polyphenolic chemopreventive agents. J Cell Physiol 2003; 194:63-70. [PMID: 12447990 DOI: 10.1002/jcp.10186] [Citation(s) in RCA: 94] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/30/2023]
Abstract
The polyphenolic compounds curcumin and quercetin increased sensitivity of ovarian cancer cells (CAOV3 and SKOV3) to cisplatin. The effect was obtained when the compounds were added simultaneously with cisplatin, as well as when they were added 24 h before. High serum levels of certain cytokines, for example interleukin-6 (IL-6), have been associated with poor prognosis and cisplatin resistance in various forms of cancer. Furthermore, it has been hypothesized that cytokines may increase proliferation, metastasis, and stimulate production of detoxification enzymes and multi-drug resistant proteins. Curcumin inhibits the production of many cytokines. The two ovarian cell lines differ significantly in IL-6 production, and correspondingly the high producer, CAOV3, was less susceptible to cisplatin. Curcumin inhibited the production of IL-6 in this cell suggesting that one of the mechanisms for synergy between cisplatin and curcumin was by reducing the autologous production of IL-6. However, the synergy was also observed in the low IL-6 producer, SKOV3, indicating that the action was most probably a result of multiple targeting. In sum, this study suggests that the compounds, curcumin and quercetin, potentially may be useful for enhancing drug sensitivity in certain cancer.
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Affiliation(s)
- Marion M Chan
- Department of Microbiology and Immunology, Temple University School of Medicine, North Broad Street, Philadelphia, Pennsylvania 19140, USA.
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Syk I, Mangell P, Bjartell A, Jeppsson B. Systemic interleukin-6 response to colorectal surgery originates from the bowel. Dig Surg 2002; 19:210-5. [PMID: 12119524 DOI: 10.1159/000064215] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/10/2022]
Abstract
BACKGROUND Surgical trauma evokes a systemic cytokine response which is enhanced in patients with colorectal cancer. The aim of this study was to locate the origin of the systemic cytokine response to colorectal surgery. METHODS The concentrations of interleukin-6 (IL-6) and tumour necrosis factor-alpha (TNF-alpha) were analysed in systemic and mesenteric venous blood in 12 patients operated on with colorectal resections due to cancer or benign lesions. Immunohistochemical staining and analysis of tissue concentrations of IL-6 and TNF-alpha in homogenates from tumours and benign specimens were performed. RESULTS Mesenteric venous blood contained higher concentrations of IL-6 compared to systemic venous blood after resection, but not before. Tissue concentration of IL-6 was higher in the tumours compared to the benign specimens and immunohistochemistry revealed an abundance of IL-6 and TNF-alpha in malignant epithelium compared to benign mucosa. CONCLUSION The higher concentration of IL-6 in venous blood from the mesenterium of the resected colonic segment compared to systemic levels, indicates that the bowel is the source of the IL-6 response to surgical trauma in colorectal surgery.
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Affiliation(s)
- I Syk
- Department of Surgery, Malmö University Hospital, Lund University, Sweden.
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