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Rafaqat S, Khurshid H, Hafeez R, Arif M, Zafar A, Gilani M, Ashraf H, Rafaqat S. Role of Interleukins in Pancreatic Cancer: A Literature Review. J Gastrointest Cancer 2024; 55:1498-1510. [PMID: 39256264 DOI: 10.1007/s12029-024-01111-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2024] [Indexed: 09/12/2024]
Abstract
PURPOSE This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). METHODS Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. RESULTS In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/β-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. CONCLUSION The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.
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Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan.
| | - Huma Khurshid
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Ramsha Hafeez
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Mehnaz Arif
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Ayesha Zafar
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Mahrukh Gilani
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Habiba Ashraf
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Sana Rafaqat
- Department of Biotechnology (Human Genetics), Lahore College for Women University, Lahore, 54000, Pakistan
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Dong C, Ma H, Mi N, Fu W, Yi J, Gao L, Wang H, Ren Y, Lin Y, Han F, Chen Z, Zhou W. Integrated analysis of scRNA-seq and bulk RNA-seq reveals that GPRC5A is an important prognostic gene in pancreatic cancer and is associated with B-cell Infiltration in pancreatic cancer. Front Oncol 2024; 14:1283164. [PMID: 38634049 PMCID: PMC11021786 DOI: 10.3389/fonc.2024.1283164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/25/2023] [Accepted: 02/23/2024] [Indexed: 04/19/2024] Open
Abstract
Introduction Pancreatic cancer (PC) is a malignancy with poor prognosis. This investigation aimed to determine the relevant genes that affect the prognosis of PC and investigate their relationship with immune infiltration. Methods : First, we acquired PC single-cell chip data from the GEO database to scrutinize dissimilarities in immune cell infiltration and differential genes between cancerous and adjacent tissues. Subsequently, we combined clinical data from TCGA to identify genes relevant to PC prognosis. Employing Cox and Lasso regression analyses, we constructed a multifactorial Cox prognostic model, which we subsequently confirmed. The prognostic gene expression in PC was authenticated using RT-PCR. Moreover, we employed the TIMER online database to examine the relationship between the expression of prognostic genes and T and B cell infiltration. Additionally, the expression of GPRC5A and its correlation with B cells infiltration and patient prognosis were ascertained in tissue chips using multiple immune fluorescence staining. Results The single-cell analysis unveiled dissimilarities in B-cell infiltration between cancerous and neighboring tissues. We developed a prognostic model utilizing three genes, indicating that patients with high-risk scores experienced a more unfavorable prognosis. Immune infiltration analysis revealed a significant correlation among YWHAZ, GPRC5A, and B cell immune infiltration. In tissue samples, GPRC5A exhibited substantial overexpression and a robust association with an adverse prognosis, demonstrating a positive correlation with B cell infiltration. Conclusion GPRC5A is an independent risk factor in PC and correlated with B cell immune infiltration in PC. These outcomes indicated that GPRC5A is a viable target for treating PC.
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Affiliation(s)
- Chunlu Dong
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Haidong Ma
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
| | - Ningning Mi
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
| | - Wenkang Fu
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
| | - Jianfeng Yi
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- Department of Surgery, The First School of Clinical Medicine of Gansu University of Chinese Medicine, Lanzhou, Gansu, China
| | - Long Gao
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
| | - Haiping Wang
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanxian Ren
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Yanyan Lin
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Fangfang Han
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Zhou Chen
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- The First Hospital of Lanzhou University, Lanzhou, Gansu, China
| | - Wence Zhou
- The First School of Clinical Medicine of Lanzhou University, Lanzhou, Gansu, China
- Lanzhou University Second Hospital, Lanzhou, Gansu, China
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Testoni SGG, Minici C, Benetti E, Clemente F, Boselli D, Sciorati C, De Monte L, Petrone MC, Enderle M, Linzenbold W, Protti MP, Manfredi A, De Cobelli F, Reni M, Falconi M, Capurso G, Arcidiacono PG, Della-Torre E. Immunomodulatory Effects of Endoscopic Ultrasound-Guided Thermal Ablation in Patients with Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2023; 15:3704. [PMID: 37509365 PMCID: PMC10378428 DOI: 10.3390/cancers15143704] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2023] [Revised: 07/10/2023] [Accepted: 07/17/2023] [Indexed: 07/30/2023] Open
Abstract
Immunological consequences of endoscopic ultrasound (EUS)-local thermal ablation (LTA) for pancreatic ductal adenocarcinoma (PDAC) have not been extensively assessed. We aimed to explore EUS-LTA effects on the systemic immune response in PDAC. Peripheral blood was collected from 10 treatment-naïve patients with borderline resectable and locally advanced PDAC, randomly allocated to Nab-paclitaxel plus Gemcitabine chemotherapy (CT-arm, n = 5) or EUS-LTA with HybridTherm Probe plus CT (HTP + CT-arm, n = 5). Twenty healthy donors were included as controls. Flow-cytometry and multiplex assays were used to profile immune cell subsets and measure serum cytokines/chemokines, respectively. At baseline, PDAC patients showed increased circulating monocytes and lower circulating lymphocytes and CD19+ B cells counts compared to healthy controls. After 4 months, CT induced decrease of B regulatory cells, CD4+ cytotoxic T cells and IL-1β. The addition of EUS-HTP to CT selectively decreased the serum levels of APRIL/TNFSF13 as well as T regulatory cells, total, classic and inflammatory monocytes. Serum levels of APRIL/TNFSF13 and total, classic and inflammatory monocytes counts at baseline were associated with worse overall survival. EUS-HTP has the potential to selectively impact on immune cells and cytokines associated with poor outcomes in PDAC.
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Affiliation(s)
- Sabrina Gloria Giulia Testoni
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Claudia Minici
- IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Elisa Benetti
- Center for Omics Sciences, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
- San Raffaele Telethon Institute for Gene Therapy (SR-Tiget) and Pediatric Immunohematology and Bone Marrow Transplantation Unit, IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Francesca Clemente
- Tumor Immunology Unit, Division of Immunology, Transplantation, and Infectious Disease, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Daniela Boselli
- FRACTAL (Flow Cytometry Resource, Advanced Cytometry Technical Applications Laboratory), IRCCS San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy
| | - Clara Sciorati
- Division of Immunology, Transplantation & Infectious Diseases, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Lucia De Monte
- Tumor Immunology Unit, Division of Immunology, Transplantation, and Infectious Disease, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Maria Chiara Petrone
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Markus Enderle
- Department of Research and Basic Technologies, Erbe Elektromedizin GmbH, Waldhörnlestraße 17, 72072 Tübingen, Germany
| | - Walter Linzenbold
- Department of Research and Basic Technologies, Erbe Elektromedizin GmbH, Waldhörnlestraße 17, 72072 Tübingen, Germany
| | - Maria Pia Protti
- Tumor Immunology Unit, Division of Immunology, Transplantation, and Infectious Disease, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Angelo Manfredi
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy (E.D.-T.)
| | - Francesco De Cobelli
- Department of Radiology, Experimental Imaging Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Michele Reni
- Department of Medical Oncology, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Massimo Falconi
- Division of Pancreatic Surgery, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Gabriele Capurso
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Paolo Giorgio Arcidiacono
- Pancreatico-Biliary Endoscopy and Endosonography Division, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy
| | - Emanuel Della-Torre
- Unit of Immunology, Rheumatology, Allergy and Rare Diseases, Pancreas Translational & Clinical Research Center, IRCCS San Raffaele Scientific Institute, Vita-Salute San Raffaele University, Via Olgettina 60, 20132 Milan, Italy (E.D.-T.)
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Schmich SKP, Keck J, Bonaterra GA, Bertoune M, Adam A, Wilhelm B, Slater EP, Schwarzbach H, Fendrich V, Kinscherf R, Hildebrandt W. Effects of Monoamino-Oxidase-A (MAO-A) Inhibition on Skeletal Muscle Inflammation and Wasting through Pancreatic Ductal Adenocarcinoma in Triple Transgenic Mice. Biomedicines 2023; 11:biomedicines11030912. [PMID: 36979889 PMCID: PMC10046345 DOI: 10.3390/biomedicines11030912] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/15/2022] [Revised: 03/08/2023] [Accepted: 03/10/2023] [Indexed: 03/17/2023] Open
Abstract
Cancer cachexia describes a syndrome of muscle wasting and lipolysis that is still largely untreatable and negatively impacts prognosis, mobility, and healthcare costs. Since upregulation of skeletal muscle monoamine-oxidase-A (MAO-A), a source of reactive oxygen species, may contribute to cachexia, we investigated the effects of the MAO-inhibitor harmine-hydrochloride (HH, intraperitoneal, 8 weeks) on muscle wasting in a triple-transgenic mouse model of pancreatic ductal adenocarcinoma (PDAC) and wild type (WT) mice. Gastrocnemius and soleus muscle cryo-cross-sections were analyzed for fiber type-specific cross-sectional area (CSA), fraction and capillarization using ATPase- and lectin-stainings. Transcripts of pro-apoptotic, -atrophic, and -inflammatory signals were determined by RT-qPCR. Furthermore, we evaluated the integrity of neuromuscular junction (NMJ, pre-/post-synaptic co-staining) and mitochondrial ultrastructure (transmission electron microscopy). MAO-A expression in gastrocnemius muscle was increased with PDAC vs. WT (immunohistochemistry: p < 0.05; Western blot: by trend). PDAC expectedly reduced fiber CSA and upregulated IL-1β in both calf muscles, while MuRF1 expression increased in soleus muscle only. Although IL-1β decreased, HH caused an additional 38.65% (p < 0.001) decrease in gastrocnemius muscle (IIBX) fiber CSA. Moreover, soleus muscle CSA remained unchanged despite the downregulation of E3-ligases FBXO32 (p < 0.05) and MuRF1 (p < 0.01) through HH. Notably, HH significantly decreased the post-synaptic NMJ area (quadriceps muscle) and glutathione levels (gastrocnemius muscle), thereby increasing mitochondrial damage and centronucleation in soleus and gastrocnemius type IIBX fibers. Moreover, although pro-atrophic/-inflammatory signals are reversed, HH unfortunately fails to stop and rather promotes PDAC-related muscle wasting, possibly via denervation or mitochondrial damage. These differential adverse vs. therapeutic effects warrant studies regarding dose-dependent benefits and risks with consideration of other targets of HH, such as the dual-specificity tyrosine phosphorylation regulated kinases 1A and B (DYRK1A/B).
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Affiliation(s)
- Simon K. P. Schmich
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Jan Keck
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Gabriel A. Bonaterra
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Mirjam Bertoune
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Anna Adam
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Beate Wilhelm
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Emily P. Slater
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Hans Schwarzbach
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Volker Fendrich
- Department of Visceral-, Thoracic- and Vascular Surgery, Philipps University Marburg, 35043 Marburg, Germany
| | - Ralf Kinscherf
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
| | - Wulf Hildebrandt
- Anatomy and Cell Biology, Department of Medical Cell Biology, University of Marburg, 35032 Marburg, Germany
- Correspondence: ; Tel.: +49-6421-2864042; Fax: +49-6421-2868983
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Marinović S, Cigrovski Berković M, Zjačić-Rotkvić V, Kapitanović S. Analysis of polymorphisms in EGF, EGFR and HER2 genes in pancreatic neuroendocrine tumors (PNETs). Cancer Genet 2022; 266-267:44-50. [PMID: 35777127 DOI: 10.1016/j.cancergen.2022.06.005] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/17/2021] [Revised: 05/31/2022] [Accepted: 06/14/2022] [Indexed: 11/18/2022]
Abstract
OBJECTIVES Pancreatic neuroendocrine tumors (NETs) are rare and account for about 7% of all cancers occurring in the pancreas. The epidermal growth factor family of receptors and their ligands play an important role in the growth and progression of tumors but their role in PNET development remains unknown. We hypothesized that functional single nucleotide polymorphisms (SNPs) in the EGF, EGFR, and HER2 genes might affect individual susceptibility to PNETs development and invasion like it was shown for various other tumors. METHODS We genotyped 68 patients with unresectable PNETs and 300 controls to evaluate the association between EGF, EGFR, and HER2 polymorphisms and susceptibility to PNETs and presence of metastases. RESULTS Genotype analysis of three SNPs EGF +61A/G (rs4444903), EGFR +1562 G/A (rs11543848), and HER2 +1963 A/G (rs1136201) showed that carriers of EGFR +1562 AG genotype and AA/AG EGF +61/HER2 +1963 genotype combination are at risk of developing PNET. Furthermore, EGFR +1562 AA genotype could be associated with the susceptibility to insulinoma development. CONCLUSIONS Our results suggest involvement of EGFR signaling pathway in etiology of PNET development.
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Affiliation(s)
| | - Maja Cigrovski Berković
- Department of Endocrinology, Diabetes, Metabolism and Clinical Pharmacology, University Hospital Dubrava, Zagreb, Croatia; Department of Endocrinology, Diabetes and Metabolism, University Clinical Hospital, Centre "Sestre milosrdnice", Zagreb, Croatia
| | - Vanja Zjačić-Rotkvić
- Department of Endocrinology, Diabetes and Metabolism, University Clinical Hospital, Centre "Sestre milosrdnice", Zagreb, Croatia
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Takahashi R, Macchini M, Sunagawa M, Jiang Z, Tanaka T, Valenti G, Renz BW, White RA, Hayakawa Y, Westphalen CB, Tailor Y, Iuga AC, Gonda TA, Genkinger J, Olive KP, Wang TC. Interleukin-1β-induced pancreatitis promotes pancreatic ductal adenocarcinoma via B lymphocyte-mediated immune suppression. Gut 2021; 70:330-341. [PMID: 32393543 DOI: 10.1136/gutjnl-2019-319912] [Citation(s) in RCA: 28] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 03/25/2020] [Accepted: 04/18/2020] [Indexed: 12/25/2022]
Abstract
OBJECTIVE Long-standing chronic pancreatitis is an established risk factor for pancreatic ductal adenocarcinoma (PDAC). Interleukin-1β (IL-1β) has been associated in PDAC with shorter survival. We employed murine models to investigate the mechanisms by which IL-1β and chronic pancreatitis might contribute to PDAC progression. DESIGN We crossed LSL-Kras+/G12D;Pdx1-Cre (KC) mice with transgenic mice overexpressing IL-1β to generate KC-IL1β mice, and followed them longitudinally. We used pancreatic 3D in vitro culture to assess acinar-to-ductal metaplasia formation. Immune cells were analysed by flow cytometry and immunohistochemical staining. B lymphocytes were adoptively transferred or depleted in Kras-mutant mice. B-cell infiltration was analysed in human PDAC samples. RESULTS KC-IL1β mice developed PDAC with liver metastases. IL-1β treatment increased Kras+/G12D pancreatic spheroid formation. CXCL13 expression and B lymphocyte infiltration were increased in KC-IL1β pancreata. Adoptive transfer of B lymphocytes from KC-IL1β mice promoted tumour formation, while depletion of B cells prevented tumour progression in KC-IL1β mice. B cells isolated from KC-IL1β mice had much higher expression of PD-L1, more regulatory B cells, impaired CD8+ T cell activity and promoted tumorigenesis. IL-35 was increased in the KC-IL1β pancreata, and depletion of IL-35 decreased the number of PD-L1+ B cells. Finally, in human PDAC samples, patients with PDAC with higher B-cell infiltration within tumours showed significantly shorter survival. CONCLUSION We show here that IL-1β promotes tumorigenesis in part by inducing an expansion of immune-suppressive B cells. These findings point to the growing significance of B suppressor cells in pancreatic tumorigenesis.
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Affiliation(s)
- Ryota Takahashi
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Marina Macchini
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
- Department of Oncology, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Masaki Sunagawa
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Zhengyu Jiang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Takayuki Tanaka
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
- Department of Surgery, Nagasaki University Graduate School of Biomedical Sciences, Nagasaki, Japan
| | - Giovanni Valenti
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Bernhard W Renz
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
- Department of General, Visceral and Transplantation Surgery, Hospital of the University of Munich, Munich, Germany
- German Cancer Consortium (DKTK), partner site Munich and German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Ruth A White
- Division of Hematology and Oncology, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Yoku Hayakawa
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
- Department of Gastroenterology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - C Benedikt Westphalen
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
- Department of Internal Medicine III, Hospital of the University of Munich, Munich, Germany
- Comprehensive Cancer Center Munich and German Cancer Consortium (DKTK), partner site Munich, Munich, Germany
| | - Yagnesh Tailor
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Alina C Iuga
- Department of Pathology and Cell Biology, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Tamas A Gonda
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Jeanine Genkinger
- Mailman School of Public Health, Columbia University, New York, New York, USA
| | - Kenneth P Olive
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
| | - Timothy C Wang
- Division of Digestive and Liver Diseases, Department of Medicine, Columbia University College of Physicians and Surgeons, New York, New York, USA
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Gottschlich A, Endres S, Kobold S. Therapeutic Strategies for Targeting IL-1 in Cancer. Cancers (Basel) 2021; 13:477. [PMID: 33530653 PMCID: PMC7865618 DOI: 10.3390/cancers13030477] [Citation(s) in RCA: 34] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2021] [Revised: 01/21/2021] [Accepted: 01/22/2021] [Indexed: 12/19/2022] Open
Abstract
Since its discovery, interleukin-1 has been extensively studied in a wide range of medical fields. Besides carrying out vital physiological functions, it has been implicated with a pivotal role in the progression and spreading of different cancer entities. During the last years, several clinical trials have been conducted, shedding light on the role of IL-1 blocking agents for the treatment of cancer. Additionally, recent developments in the field of immuno-oncology have implicated IL-1-induced signaling cascades as a major driver of severe chimeric antigen receptor T cell-associated toxicities such as cytokine release syndrome and immune effector cell-associated neurotoxicity. In this review, we summarize current clinical trials investigating the role of IL-1 blockade in cancer treatment and elaborate the proposed mechanism of these innovative treatment approaches. Additionally, we highlight cutting-edge developments utilizing IL-1 blocking agents to enhance the safety and efficacy of adoptive T cell therapy.
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Affiliation(s)
- Adrian Gottschlich
- Center for Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany; (A.G.); (S.E.)
| | - Stefan Endres
- Center for Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany; (A.G.); (S.E.)
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, 80337 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
| | - Sebastian Kobold
- Center for Integrated Protein Science Munich (CIPS-M) and Division of Clinical Pharmacology, Department of Medicine IV, University Hospital, Ludwig-Maximilians-Universität München, 80337 Munich, Germany; (A.G.); (S.E.)
- German Center for Translational Cancer Research (DKTK), Partner Site Munich, 80337 Munich, Germany
- Einheit für Klinische Pharmakologie (EKLiP), Helmholtz Zentrum München, German Research Center for Environmental Health (HMGU), 85764 Neuherberg, Germany
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Association study indicates combined effect of interleukin-10 and angiotensin-converting enzyme in basal cell carcinoma development. Arch Dermatol Res 2020; 313:373-380. [PMID: 32772162 DOI: 10.1007/s00403-020-02113-x] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2019] [Revised: 06/18/2020] [Accepted: 07/31/2020] [Indexed: 01/25/2023]
Abstract
Cytokines involved in inflammatory and immune response have been associated with risk for development of basal cell carcinoma (BCC). In this study, three functional DNA polymorphisms affecting gene expression were investigated in 54 BCC patients and 111 healthy controls: interleukin-1b (IL-1b) +3953C/T, interleukin-10 (IL-10) - 1082G/A and angiotensin-converting enzyme (ACE) insertion/deletion (I/D) polymorphisms. Significant increase of the variant alleles was observed in IL-10 - 1082G (P = 0.019) and in ACE D (P = 0.003) in BCC patients in comparison to controls. Multivariate logistic regression models evaluated the contribution of homozygous and heterozygous variant polymorphisms to the risk for BCC development. The studied polymorphisms influencing the expression of IL-10 and ACE genes were recognized as potential predictive factors for BCC. These findings suggest a possible molecular mechanism leading to BCC development that is likely to involve the activation of angiotensin receptors in combination with increased plasma levels of IL-10 in patients.
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9
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Gentiluomo M, Canzian F, Nicolini A, Gemignani F, Landi S, Campa D. Germline genetic variability in pancreatic cancer risk and prognosis. Semin Cancer Biol 2020; 79:105-131. [DOI: 10.1016/j.semcancer.2020.08.003] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/15/2020] [Revised: 08/04/2020] [Accepted: 08/06/2020] [Indexed: 02/07/2023]
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10
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Cardoso AR, de Sá M, Sales MGF. An impedimetric molecularly-imprinted biosensor for Interleukin-1β determination, prepared by in-situ electropolymerization on carbon screen-printed electrodes. Bioelectrochemistry 2019; 130:107287. [DOI: 10.1016/j.bioelechem.2019.04.017] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Revised: 04/20/2019] [Accepted: 04/20/2019] [Indexed: 12/24/2022]
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11
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Pfalzer AC, Crott JW, Koh GY, Smith DE, Garcia PE, Mason JB. Interleukin-1 Signaling Mediates Obesity-Promoted Elevations in Inflammatory Cytokines, Wnt Activation, and Epithelial Proliferation in the Mouse Colon. J Interferon Cytokine Res 2019; 38:445-451. [PMID: 30328795 DOI: 10.1089/jir.2017.0134] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022] Open
Abstract
Obesity is a prominent risk factor for colorectal cancer (CRC). One mechanism by which obesity promotes the development of CRC is by generating a chronic, low-grade state of colonic inflammation. Interleukin-1β (IL-1β), a proinflammatory cytokine often elevated in obesity, is known to activate several procarcinogenic signaling pathways that are implicated in colonic carcinogenesis. We therefore sought to define the role of IL-1β in mediating some of the early biochemical and molecular events leading up to obesity-promoted CRC. Twenty-five wild-type (WT) C57BL/6J mice and 24 lacking a functional IL-1 receptor (IL1R-/-) were each randomized to either low-fat or high-fat diets, resulting in lean and obese mice. Compared to WT lean controls, WT obese mice displayed 30%-80% greater concentrations of IL-1β and tumor necrosis factor-α (TNF-α) in the colonic mucosa (IL-1β: P = 0.04; TNF-α: P < 0.05), activation of the Wnt signaling cascade [evidenced by a 2-fold increase in colonic crypt cells displaying intranuclear β-catenin (P < 0.03)], and a significant expansion of the proliferation zone of the colonic crypt (P < 0.04). These obesity-induced alterations in colonic cytokines, Wnt signaling, and proliferation were absent in the obese IL1R-/- mice. In the absence of IL-1 signaling, obesity-induced elevations of colonic IL-1β, TNF-α, Wnt activation, and enhanced epithelial proliferation no longer occur. These observations underscore the important mechanistic roles that IL-1 signaling appears to play in mediating the procancerous effects of obesity in the colon, thereby identifying a potential target for future strategies aimed at chemoprevention.
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Affiliation(s)
- Anna C Pfalzer
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts
| | - Jimmy W Crott
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts
| | - Gar Yee Koh
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts
| | - Donald E Smith
- 3 Comparative Biology Unit, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University , Boston, Massachusetts
| | - Paloma E Garcia
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts
| | - Joel B Mason
- 1 Vitamins and Carcinogenesis Laboratory , Boston, Massachusetts.,2 Friedman School of Nutritional Science and Policy, Tufts University , Boston, Massachusetts.,4 Department of Gastroenterology, Tufts University School of Medicine , Boston, Massachusetts
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12
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Abstract
Pancreatic cancer is a devastating disease with poor prognosis in the modern era. Inflammatory processes have emerged as key mediators of pancreatic cancer development and progression. Recently, studies have been carried out to investigate the underlying mechanisms that contribute to tumorigenesis induced by inflammation. In this review, the role of inflammation in the initiation and progression of pancreatic cancer is discussed.
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Affiliation(s)
- Kamleshsingh Shadhu
- Pancreas Center of The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
- Pancreas Institute of Nanjing Medical University, Nanjing, P.R. China
- School of International Education of Nanjing Medical University, Nanjing, P.R. China
| | - Chunhua Xi
- Pancreas Center of The First Affiliated Hospital of Nanjing Medical University, Nanjing, P.R. China
- Pancreas Institute of Nanjing Medical University, Nanjing, P.R. China
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13
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Förnvik K, Ahlstedt J, Osther K, Salford LG, Redebrandt HN. Anti-C1-inactivator treatment of glioblastoma. Oncotarget 2018; 9:37421-37428. [PMID: 30647842 PMCID: PMC6324776 DOI: 10.18632/oncotarget.26456] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/13/2018] [Accepted: 11/26/2018] [Indexed: 12/22/2022] Open
Abstract
Purpose Glioblastoma multiforme (GBM) or astrocytoma grade IV is the most common type of primary brain tumor in adults. In the present study, we investigate the role of the complement system in the glioblastoma situation in an experimental model, since we have previously been able to show a blockade of this system in the glioblastoma setting. Technique and results A GFP-positive glioblastoma cell line was used to induce glioblastomas subcutaneously in rats (n=42). Antibodies against C1-Inactivator (C1-IA) were used to try to re-activate the complement system. We were able to demonstrate an increased survival in rats treated with anti-C1-IA with an intratumoral route, and we could establish the same the results in a second series. Serum analyses revealed decreased levels of IL-1b and GM-CSF in animals 24 days after tumor cell inoculation in the anti-C1-IA group when compared to controls. Immunohistochemistry revealed decreased expression of C1-IA following treatment. Interpretation These results are in line with our previous work showing an upregulation of C1-IA, which is able to block the classical complement pathway, in glioblastomas. Treatment with antibodies against C1-IA seems to be beneficial in the glioblastoma situation, and no side effects could be seen in our experiments.
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Affiliation(s)
- Karolina Förnvik
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Clinical Chemistry, Skåne University Hospital, Lund, Sweden
| | - Jonatan Ahlstedt
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Kurt Osther
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Leif G Salford
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden
| | - Henrietta Nittby Redebrandt
- The Rausing Laboratory, Division of Neurosurgery, Department of Clinical Sciences, Lund University, Lund, Sweden.,Department of Neurosurgery, Skåne University Hospital, Lund, Sweden
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14
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Wang W, Marinis JM, Beal AM, Savadkar S, Wu Y, Khan M, Taunk PS, Wu N, Su W, Wu J, Ahsan A, Kurz E, Chen T, Yaboh I, Li F, Gutierrez J, Diskin B, Hundeyin M, Reilly M, Lich JD, Harris PA, Mahajan MK, Thorpe JH, Nassau P, Mosley JE, Leinwand J, Kochen Rossi JA, Mishra A, Aykut B, Glacken M, Ochi A, Verma N, Kim JI, Vasudevaraja V, Adeegbe D, Almonte C, Bagdatlioglu E, Cohen DJ, Wong KK, Bertin J, Miller G. RIP1 Kinase Drives Macrophage-Mediated Adaptive Immune Tolerance in Pancreatic Cancer. Cancer Cell 2018; 34:757-774.e7. [PMID: 30423296 PMCID: PMC6836726 DOI: 10.1016/j.ccell.2018.10.006] [Citation(s) in RCA: 171] [Impact Index Per Article: 24.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/12/2018] [Revised: 07/23/2018] [Accepted: 10/12/2018] [Indexed: 12/18/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDA) is characterized by immune tolerance and immunotherapeutic resistance. We discovered upregulation of receptor-interacting serine/threonine protein kinase 1 (RIP1) in tumor-associated macrophages (TAMs) in PDA. To study its role in oncogenic progression, we developed a selective small-molecule RIP1 inhibitor with high in vivo exposure. Targeting RIP1 reprogrammed TAMs toward an MHCIIhiTNFα+IFNγ+ immunogenic phenotype in a STAT1-dependent manner. RIP1 inhibition in TAMs resulted in cytotoxic T cell activation and T helper cell differentiation toward a mixed Th1/Th17 phenotype, leading to tumor immunity in mice and in organotypic models of human PDA. Targeting RIP1 synergized with PD1-and inducible co-stimulator-based immunotherapies. Tumor-promoting effects of RIP1 were independent of its co-association with RIP3. Collectively, our work describes RIP1 as a checkpoint kinase governing tumor immunity.
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Affiliation(s)
- Wei Wang
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Jill M Marinis
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Allison M Beal
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Shivraj Savadkar
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Yue Wu
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Mohammed Khan
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Pardeep S Taunk
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Nan Wu
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Wenyu Su
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Jingjing Wu
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Aarif Ahsan
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Emma Kurz
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Ting Chen
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Inedouye Yaboh
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Fei Li
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Johana Gutierrez
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Brian Diskin
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Mautin Hundeyin
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Michael Reilly
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - John D Lich
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Philip A Harris
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Mukesh K Mahajan
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - James H Thorpe
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Pamela Nassau
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Julie E Mosley
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA
| | - Joshua Leinwand
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Juan A Kochen Rossi
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Ankita Mishra
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Berk Aykut
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Michael Glacken
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Atsuo Ochi
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Narendra Verma
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Jacqueline I Kim
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA
| | - Varshini Vasudevaraja
- Department of Pathology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Dennis Adeegbe
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Christina Almonte
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Ece Bagdatlioglu
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Deirdre J Cohen
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - Kwok-Kin Wong
- Department of Medicine, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA
| | - John Bertin
- Pattern Recognition Receptor Discovery Performance Unit, Immuno-Inflammation Therapeutic Area, GlaxoSmithKline, 1250 South Collegeville Road, Collegeville, PA 19426, USA.
| | - George Miller
- S. Arthur Localio Laboratory, Department of Surgery, New York University School of Medicine, 435 East 30th Street, 4th Floor, New York, NY 10016, USA; Department of Cell Biology, New York University School of Medicine, 550 First Avenue, New York, NY 10016, USA.
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15
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Maeda H, Okada KI, Fujii T, Oba MS, Kawai M, Hirono S, Kodera Y, Sho M, Akahori T, Shimizu Y, Ambo Y, Kondo N, Murakami Y, Ohuchida J, Eguchi H, Nagano H, Sakamoto J, Yamaue H. Transition of serum cytokines following pancreaticoduodenectomy: A subsidiary study of JAPAN-PD. Oncol Lett 2018; 16:6847-6853. [PMID: 30333892 DOI: 10.3892/ol.2018.9422] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2018] [Accepted: 08/22/2018] [Indexed: 02/04/2023] Open
Abstract
Our previous study aimed to examine the effect of TJ-100, a widely used herbal medicine, on intestinal function following pancreaticoduodenectomy (PD) in a multicenter, randomized, double-blinded, placebo-controlled manner (JAPAN-PD study). This concomitant study investigated the effect of TJ-100 on serum cytokine levels in patients who underwent PD. Due to the fact that several clinical variables can affect the absolute values of baseline serum cytokine levels, the ratios of the cytokine levels on postoperative day (POD)3 to those on POD1 were also used for analysis. The present study enrolled 180/224 randomized patients, of whom 91 received TJ-100 and 89 received placebo. As the main findings of the analysis, Wilcoxon signed-rank test revealed no significant difference in the levels of serum cytokines between the groups; however, patients in the TJ-100 group without severe inflammatory complications exhibited significantly higher ratios of interleukin (IL)-4 (n=123), IL-9 (n=72), IL-10 (n=97), PDGF-BB (n=143) and tumor necrosis factor-α (n=135), compared with patients in the Placebo Group (P<0.05). According to the results of the present study, TJ-100 has an effect on the change in serum cytokine levels from POD1 to POD3 following PD. However, the role of different transition pattern of cytokines in postoperative recovery following PD has to be investigated by further mechanical studies focusing on these extracted cytokines (ClinicalTrials.gov; no. NCT01607307; May 30, 2012).
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Affiliation(s)
- Hiromichi Maeda
- Cancer Treatment Center, Kochi Medical School, Nankoku, Kochi 783-8505, Japan
| | - Ken-Ichi Okada
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
| | - Tsutomu Fujii
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8560, Japan
| | - Mari S Oba
- Department of Medical Statistics Faculty of Medicine, Toho University, Tokyo 143-8540, Japan
| | - Manabu Kawai
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
| | - Seiko Hirono
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
| | - Yasuhiro Kodera
- Department of Gastroenterological Surgery (Surgery II), Nagoya University Graduate School of Medicine, Nagoya, Aichi 466-8560, Japan
| | - Masayuki Sho
- Department of Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Takahiro Akahori
- Department of Surgery, Nara Medical University, Kashihara, Nara 634-8521, Japan
| | - Yasuhiro Shimizu
- Department of Gastroenterological Surgery, Aichi Cancer Center Hospital, Nagoya, Aichi 464-8681, Japan
| | - Yoshiyasu Ambo
- Department of Surgery, Teine-Keijinkai Hospital, Sapporo, Hokkaido 006-8555, Japan
| | - Naru Kondo
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553, Japan
| | - Yoshiaki Murakami
- Department of Surgery, Institute of Biomedical and Health Sciences, Hiroshima University, Hiroshima, Hiroshima 734-8553, Japan
| | - Jiro Ohuchida
- Department of Surgery, Miyazaki Prefectural Miyazaki Hospital, Miyazaki, Miyazaki 880-8510, Japan
| | - Hidetoshi Eguchi
- Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | - Hiroaki Nagano
- Department of Surgery, Graduate School of Medicine, Osaka University, Suita, Osaka 565-0871, Japan
| | | | - Hiroki Yamaue
- Second Department of Surgery, Wakayama Medical University, Wakayama, Wakayama 641-8510, Japan
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16
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Abstract
Preterm infants (i.e., born before <37 wk of gestation) are at increased risk of morbidity and mortality and long-term disabilities. Global prevalence of preterm birth (PTB) varies from 5 to 18 per cent. There are multiple aetiological causes and factors associated with PTB. Intrapartum infections are conventionally associated with PTB. However, maternal genotype modulates response to these infections. This review highlights the association of cytokine gene polymorphisms and their levels with PTB. Varying PTB rates across the different ethnic groups may be as a result of genetically mediated varying cytokines response to infections. Studies on genetic variations in tumour necrosis factor-alpha, interleukin-1 alpha (IL-1α), IL-1β, IL-6, IL-10 and toll-like receptor-4 genes and their association with PTB, have been reviewed. No single polymorphism of the studied genes was found to be associated with PTB. However, increased maternal levels of IL-1β and IL-6 and low levels of IL-10 have been found to be associated with PTB.
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Affiliation(s)
- Monika Pandey
- Department of Pediatrics, Translational Medicine Unit, King George's Medical University, Lucknow, India
| | - Mradula Chauhan
- Department of Pediatrics, Translational Medicine Unit, King George's Medical University, Lucknow, India
| | - Shally Awasthi
- Department of Pediatrics, Translational Medicine Unit, King George's Medical University, Lucknow, India
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17
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LOX-1 is a poor prognostic indicator and induces epithelial-mesenchymal transition and metastasis in pancreatic cancer patients. Cell Oncol (Dordr) 2017; 41:73-84. [DOI: 10.1007/s13402-017-0360-6] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 10/24/2017] [Indexed: 10/18/2022] Open
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18
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Nomura A, Gupta VK, Dauer P, Sharma NS, Dudeja V, Merchant N, Saluja AK, Banerjee S. NFκB-Mediated Invasiveness in CD133 + Pancreatic TICs Is Regulated by Autocrine and Paracrine Activation of IL1 Signaling. Mol Cancer Res 2017; 16:162-172. [PMID: 28970361 DOI: 10.1158/1541-7786.mcr-17-0221] [Citation(s) in RCA: 37] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/24/2017] [Revised: 08/14/2017] [Accepted: 09/22/2017] [Indexed: 12/21/2022]
Abstract
Tumor-initiating cells (TIC) have been implicated in pancreatic tumor initiation, progression, and metastasis. Among different markers that define this cell population within the tumor, the CD133+ cancer stem cell (CSC) population has reliably been described in these processes. CD133 expression has also been shown to functionally promote metastasis through NF-κB activation in this population, but the mechanism is unclear. In the current study, overexpression of CD133 increased expression and secretion of IL1β (IL1B), which activates an autocrine signaling loop that upregulates NF-κB signaling, epithelial-mesenchymal transition (EMT), and cellular invasion. This signaling pathway also induces CXCR4 expression, which in turn is instrumental in imparting an invasive phenotype to these cells. In addition to the autocrine signaling of the CD133 secreted IL1β, the tumor-associated macrophages (TAM) also produced IL1β, which further activated this pathway in TICs. The functional significance of the TIC marker CD133 has remained elusive for a very long time; the current study takes us one step closer to understanding how the downstream signaling pathways in these cells regulate the functional properties of TICs.Implications: This study demonstrates the important role of tumor- and macrophage-derived IL1β stimulation in pancreatic cancer. IL1 signaling is increased in cells with CD133 expression, leading to increased NF-kB activity, EMT induction, and invasion. Increased invasiveness via IL1β stimulation is mediated by the upregulation of CXCR4 expression. The study highlights the importance of IL1-mediated signaling in TICs. Mol Cancer Res; 16(1); 162-72. ©2017 AACR.
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Affiliation(s)
- Alice Nomura
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.,II. Medizinische Klinik, Klinikum rechts der Isar, Technische Universität München, München, Germany
| | - Vineet K Gupta
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Patricia Dauer
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.,Department of Pharmacology, University of Minnesota, Minneapolis, Minnesota
| | - Nikita S Sharma
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.,Sheila and David Fuente Graduate Program in Cancer Biology, University of Miami Miller School of Medicine, Miami, Florida
| | - Vikas Dudeja
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Nipun Merchant
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Ashok K Saluja
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida
| | - Sulagna Banerjee
- Division of Surgical Oncology, Department of Surgery Sylvester Comprehensive Cancer Center, University of Miami, Miami, Florida.
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19
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Lin C, Zhang J. Inflammasomes in Inflammation-Induced Cancer. Front Immunol 2017; 8:271. [PMID: 28360909 PMCID: PMC5350111 DOI: 10.3389/fimmu.2017.00271] [Citation(s) in RCA: 74] [Impact Index Per Article: 9.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2016] [Accepted: 02/24/2017] [Indexed: 12/19/2022] Open
Abstract
The inflammasome is an important multiprotein complex that functions during inflammatory immune responses. The activation of inflammasome will lead to the autoactivation of caspase-1 and subsequent cleavage of proIL-1β and proIL-18, which are key sources of inflammatory manifestations. Recently, the roles of inflammasomes in cancers have been extensively explored, especially in inflammation-induced cancers. In different and specific contexts, inflammasomes exhibit distinct and even contrasting effects in cancer development. In some cases, inflammasomes initiate carcinogenesis through the extrinsic pathway and maintain the malignant cancer microenvironment through the intrinsic pathway. On the contrary, inflammasomes also exert anticancer effects by specialized programmed cell death called pyroptosis and immune regulatory functions. The phases and compartments in which inflammasomes are activated strongly influence the final immune effects. We systemically summarize the functions of inflammasomes in inflammation-induced cancers, especially in gastrointestinal and skin cancers. Besides, information about the current therapeutic use of inflammasome-related products and potential future developing directions are also introduced.
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Affiliation(s)
- Chu Lin
- Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, National Health and Family Planning Commission of the People's Republic of China, Peking University Health Science Center , Beijing , China
| | - Jun Zhang
- Department of Immunology, School of Basic Medical Sciences, Key Laboratory of Medical Immunology, National Health and Family Planning Commission of the People's Republic of China, Peking University Health Science Center , Beijing , China
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Leal AS, Sporn MB, Pioli PA, Liby KT. The triterpenoid CDDO-imidazolide reduces immune cell infiltration and cytokine secretion in the KrasG12D;Pdx1-Cre (KC) mouse model of pancreatic cancer. Carcinogenesis 2016; 37:1170-1179. [PMID: 27659181 DOI: 10.1093/carcin/bgw099] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/13/2016] [Revised: 07/11/2016] [Accepted: 09/21/2016] [Indexed: 02/07/2023] Open
Abstract
Because the 5-year survival rate for pancreatic cancer remains under 10%, new drugs are needed for the prevention and treatment of this devastating disease. Patients with chronic pancreatitis have a 12-fold higher risk of developing pancreatic cancer. LSL-KrasG12D/+;Pdx-1-Cre (KC) mice replicate the genetics, symptoms and histopathology found in human pancreatic cancer. Immune cells infiltrate into the pancreas of these mice and produce inflammatory cytokines that promote tumor growth. KC mice are particularly sensitive to the effects of lipopolysaccharide (LPS), as only 48% of KC mice survived an LPS challenge while 100% of wildtype (WT) mice survived. LPS also increased the percentage of CD45+ immune cells in the pancreas and immunosuppressive Gr1+ myeloid-derived suppressor cell in the spleen of these mice. The triterpenoid CDDO-imidazolide (CDDO-Im) not only reduced the lethal effects of LPS (71% survival) but also decreased the infiltration of CD45+ cells into the pancreas and the percentage of Gr1+ myeloid-derived suppressor cell in the spleen of KC mice 4-8 weeks after the initial LPS challenge. While the levels of inflammatory cytokine levels were markedly higher in KC mice versus WT mice challenged with LPS, CDDO-Im significantly decreased the production of IL-6, CCL-2, vascular endothelial growth factor and G-CSF in the KC mice. All of these cytokines are prognostic markers in pancreatic cancer or play important roles in the progression of this disease. Disrupting the inflammatory process with drugs such as CDDO-Im might be useful for preventing pancreatic cancer, especially in high-risk populations.
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Affiliation(s)
- Ana S Leal
- Department of Pharmacology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA.,Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA and
| | - Michael B Sporn
- Department of Pharmacology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA
| | - Patricia A Pioli
- Department of Microbiology and Immunology, Geisel School of Medicine at Dartmouth, Lebanon, NH 03756, USA
| | - Karen T Liby
- Department of Pharmacology, Geisel School of Medicine at Dartmouth, Hanover, NH 03756, USA, .,Department of Pharmacology and Toxicology, Michigan State University, East Lansing, MI 48824, USA and
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Hefler LA, Ludwig E, Lebrecht A, Zeillinger R, Tong-Cacsire D, Koelbl H, Leodolter S, Tempfer CB. Polymorphisms of the Interleukin-1 Gene Cluster and Ovarian Cancer. ACTA ACUST UNITED AC 2016. [DOI: 10.1177/107155760200900610] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/16/2022]
Affiliation(s)
- Lukas A. Hefler
- Department of Obstetrics and Gynecology, University of Vienna Medical School, Vienna, Austria; Department of Obstetrics and Gynecology, Martin-Luther-University Halle-Wittenberg, Halle, Germany; Department of Obstetrics and Gynecology, University of Vienna Medical School, Waehringer Guertel 18-20, A-1090 Viennia, Austria
| | | | | | | | | | | | | | - Clemens B. Tempfer
- Department of Obstetrics and Gynecology, University of Vienna Medical School, Vienna, Austria; Department of Obstetrics and Gynecology, Martin-Luther-University Halle-Wittenberg, Halle, Germany
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Elevated IL-1β expression induces invasiveness of triple negative breast cancer cells and is suppressed by zerumbone. Chem Biol Interact 2016; 258:126-33. [PMID: 27567548 DOI: 10.1016/j.cbi.2016.08.021] [Citation(s) in RCA: 38] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2016] [Revised: 07/29/2016] [Accepted: 08/24/2016] [Indexed: 12/23/2022]
Abstract
Aberrant interleukin-1 beta (IL-1β) expression is associated with cancer development, metastasis, and poor prognosis. Here, we have investigated the regulatory mechanism of IL-1β expression, and the inhibitory effect of zerumbone (ZER) on IL-1β expression and IL-1β-induced signatures, including cell invasion and signaling activation in triple negative breast cancer (TNBC) cells. The basal IL-1β and cell invasiveness levels were significantly higher in TNBC cells, compared with non-TNBC cells. The invasiveness of TNBC cells was also increased following IL-1β treatment. In contrast, the invasiveness of TNBC cells was decreased following IL-1 receptor antagonist (IL-1RA) treatment. Additionally, the basal IL-1β level and the invasiveness of TNBC cells were decreased by Bay11-7085. In contrast, overexpression of NF-κB (p65) caused an increase in IL-1β expression in TNBC cells. Our results showed that treatment with ZER decreased the basal IL-1β expression level, and the phosphorylation level of NF-κB, in TNBC cells. Furthermore, we found that ZER completely suppressed IL-1β-induced NF-κB phosphorylation, but did not suppress IL-1β-induced Akt phosphorylation, in TNBC cells. Our results also demonstrate that IL-1β-induced cell invasion is suppressed by ZER in TNBC cells. Taken together, we demonstrated that IL-1β expression is regulated by the NF-κB-dependent pathway, and that elevated IL-1β is directly influencing the invasiveness of TNBC cells. ZER down-regulates IL-1β expression through the inhibition of NF-κB activity, and then suppresses cell invasiveness of TNBC.
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Abstract
The human body combats infection and promotes wound healing through the remarkable process of inflammation. Inflammation is characterized by the recruitment of stromal cell activity including recruitment of immune cells and induction of angiogenesis. These cellular processes are regulated by a class of soluble molecules called cytokines. Based on function, cell target, and structure, cytokines are subdivided into several classes including: interleukins, chemokines, and lymphokines. While cytokines regulate normal physiological processes, chronic deregulation of cytokine expression and activity contributes to cancer in many ways. Gene polymorphisms of all types of cytokines are associated with risk of disease development. Deregulation RNA and protein expression of interleukins, chemokines, and lymphokines have been detected in many solid tumors and hematopoetic malignancies, correlating with poor patient prognosis. The current body of literature suggests that in some tumor types, interleukins and chemokines work against the human body by signaling to cancer cells and remodeling the local microenvironment to support the growth, survival, and invasion of primary tumors and enhance metastatic colonization. Some lymphokines are downregulated to suppress tumor progression by enhancing cytotoxic T cell activity and inhibiting tumor cell survival. In this review, we will describe the structure/function of several cytokine families and review our current understanding on the roles and mechanisms of cytokines in tumor progression. In addition, we will also discuss strategies for exploiting the expression and activity of cytokines in therapeutic intervention.
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Affiliation(s)
- M Yao
- University of Kansas Medical Center, Kansas City, KS, United States
| | - G Brummer
- University of Kansas Medical Center, Kansas City, KS, United States
| | - D Acevedo
- University of Kansas Medical Center, Kansas City, KS, United States
| | - N Cheng
- University of Kansas Medical Center, Kansas City, KS, United States.
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Karakaxas D, Sioziou A, Aravantinos G, Coker A, Papanikolaou IS, Liakakos T, Dervenis C, Gazouli M. Genetic polymorphisms of interleukin 1β gene and sporadic pancreatic neuroendocrine tumors susceptibility. World J Gastrointest Oncol 2016; 8:520-525. [PMID: 27326321 PMCID: PMC4909453 DOI: 10.4251/wjgo.v8.i6.520] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/01/2016] [Accepted: 03/17/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the association between the interleukin 1β (IL-1β) polymorphisms and the pancreatic neuroendocrine tumor (pNET) development. METHODS A case-control study was conducted analyzing IL-1β polymorphisms using germline DNA collected in a population-based case-control study of pancreatic cancer (51 pNET cases, 85 pancreatic ductal adenocarcinoma cases, 19 intraductal papillary mucinous neoplasm and 98 healthy controls). RESULTS The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients. CONCLUSION The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only.
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Yako YY, Kruger D, Smith M, Brand M. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review. PLoS One 2016; 11:e0154016. [PMID: 27170998 PMCID: PMC4865360 DOI: 10.1371/journal.pone.0154016] [Citation(s) in RCA: 59] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 04/07/2016] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. MATERIALS AND METHODS A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. RESULTS Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19-9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. CONCLUSION Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals.
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Affiliation(s)
- Yandiswa Yolanda Yako
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Deirdré Kruger
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Martin Smith
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Martin Brand
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
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Zaaber I, Mestiri S, Hammedi H, Marmouch H, Mahjoub S, Tensaout BBHJ, Said K. Association of Interleukin-1B and Interleukin-4 Gene Variants with Autoimmune Thyroid Diseases in Tunisian Population. Immunol Invest 2016; 45:284-97. [PMID: 27100882 DOI: 10.3109/08820139.2016.1153650] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/13/2022]
Abstract
Autoimmune thyroid diseases (AITD) including Graves' disease (GD) and Hashimoto's thyroiditis (HT) are complex genetic diseases. Cytokines IL-1B and IL-4 play a role in the pathogenesis of AITD. This study was conducted on Tunisian patients with GD or HT to investigate the association of IL-1B and IL-4 gene polymorphisms with the risk and the prognosis of AITD. A total of 358 healthy controls and 341 patients with AITDs (249 HT and 92 GD) were genotyped for IL-1B+3953C/T and IL-4 intron 3 VNTR polymorphisms. A significant association was found between IL-1B+3953C/T polymorphism and GD or HT, both in the dominant and additive models. The IL-1B+3953T allele was associated with GD (p = 0.0003, OR = 1.93, CI = 1.34-2.78) and HT (p = 0.009, OR = 1.43, CI = 1.09-1.88). The IL-4 VNTR polymorphism was associated only with HT risk both in additive (p = 0.03, OR = 0.31, CI = 0.11-0.86) and recessive (p = 0.03, OR = 3.04, CI = 1.13-8.17) models. No significant association was found between IL-1B+3953C/T polymorphism and change in the serum concentrations of TSH and FT4 in GD and HT patients. In HT patients, the IL-1B+3953T allele (p = 0.009, OR = 0.42, CI = 0.22-0.83) and the IL-1B+3953T/T genotype (p = 0.03, OR = 0.21, CI = 0.04-1.07) were more frequent in the absence than in the presence of an anti-TPO antibody. The proportion of HT patients with the P1P2 genotype of the IL-4 gene was significantly higher in the absence than in the presence of the anti-TPO antibody (p = 0.04, OR = 0.39, CI = 0.17-0.89). These preliminary results suggest that IL-1B and IL-4 gene polymorphisms may be associated with GD and HT susceptibility and may represent prognostic factors for predicting the severity of HT.
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Affiliation(s)
- Ines Zaaber
- a Laboratory of Genetics, Biodiversity and Bioresource Valorization , Superior Institute of Biotechnology of Monastir, University of Monastir , Monastir , Tunisia
| | - Souhir Mestiri
- a Laboratory of Genetics, Biodiversity and Bioresource Valorization , Superior Institute of Biotechnology of Monastir, University of Monastir , Monastir , Tunisia
| | - Hounayda Hammedi
- a Laboratory of Genetics, Biodiversity and Bioresource Valorization , Superior Institute of Biotechnology of Monastir, University of Monastir , Monastir , Tunisia
| | - Hela Marmouch
- b Department of Internal Medicine-Endocrinology , Hospital Fattouma Bourguiba in Monastir , Monastir , Tunisia
| | - Silvia Mahjoub
- b Department of Internal Medicine-Endocrinology , Hospital Fattouma Bourguiba in Monastir , Monastir , Tunisia
| | - Besma Bel Hadj Jrad Tensaout
- a Laboratory of Genetics, Biodiversity and Bioresource Valorization , Superior Institute of Biotechnology of Monastir, University of Monastir , Monastir , Tunisia
| | - Khaled Said
- a Laboratory of Genetics, Biodiversity and Bioresource Valorization , Superior Institute of Biotechnology of Monastir, University of Monastir , Monastir , Tunisia
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Johns N, Tan BH, MacMillan M, Solheim TS, Ross JA, Baracos VE, Damaraju S, Fearon KCH. Genetic basis of interindividual susceptibility to cancer cachexia: selection of potential candidate gene polymorphisms for association studies. J Genet 2015; 93:893-916. [PMID: 25572253 DOI: 10.1007/s12041-014-0405-9] [Citation(s) in RCA: 18] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/06/2023]
Abstract
Cancer cachexia is a complex and multifactorial disease. Evolving definitions highlight the fact that a diverse range of biological processes contribute to cancer cachexia. Part of the variation in who will and who will not develop cancer cachexia may be genetically determined. As new definitions, classifications and biological targets continue to evolve, there is a need for reappraisal of the literature for future candidate association studies. This review summarizes genes identified or implicated as well as putative candidate genes contributing to cachexia, identified through diverse technology platforms and model systems to further guide association studies. A systematic search covering 1986-2012 was performed for potential candidate genes / genetic polymorphisms relating to cancer cachexia. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Pathway analysis software was used to reveal possible network associations between genes. Functionality of SNPs/genes was explored based on published literature, algorithms for detecting putative deleterious SNPs and interrogating the database for expression of quantitative trait loci (eQTLs). A total of 154 genes associated with cancer cachexia were identified and explored for functional polymorphisms. Of these 154 genes, 119 had a combined total of 281 polymorphisms with functional and/or clinical significance in terms of cachexia associated with them. Of these, 80 polymorphisms (in 51 genes) were replicated in more than one study with 24 polymorphisms found to influence two or more hallmarks of cachexia (i.e., inflammation, loss of fat mass and/or lean mass and reduced survival). Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides a contemporary basis to select genes and/or polymorphisms for further association studies in cancer cachexia, and to develop their potential as susceptibility biomarkers of cachexia.
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Affiliation(s)
- N Johns
- Department of Clinical and Surgical Sciences, University of Edinburgh, Edinburgh, EH16 4SB, UK.
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Sun Y, Zhu D, Wang G, Wang D, Zhou H, Liu X, Jiang M, Liao L, Zhou Z, Hu J. Pro-Inflammatory Cytokine IL-1β Up-Regulates CXC Chemokine Receptor 4 via Notch and ERK Signaling Pathways in Tongue Squamous Cell Carcinoma. PLoS One 2015; 10:e0132677. [PMID: 26176534 PMCID: PMC4503771 DOI: 10.1371/journal.pone.0132677] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/29/2015] [Accepted: 06/18/2015] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation contributes to tumor development through the induction of oncogenic mutations, genomic instability, early tumor promotion, and enhanced angiogenesis. Here, we report that IL-1 receptor 1 (IL-1R1) was expressed in 40 of 41 human tongue squamous cell carcinomas (TSCC). IL-1β up-regulated the expression of CXCR4, a CXC chemokine receptor that mediates cancer growth and metastasis, at both mRNA and protein levels in Tca8113 TSCC cells. IL-1β treatment of Tca8113 cells promoted migration in response to CXCR4 ligand stromal-derived factor α (SDF-1α). The inhibition of IL-1R1 by its antagonist IL-1Ra or RNA interference significantly reversed the up-regulation of CXCR4 induced by IL-1β. IL-1R1 activation also up-regulated the expression of IL-1β itself, suggesting a positive feedback regulation of CXCR4 expression. Furthermore, IL-1β induced the activation of Notch, which was originally considered a stem cell regulator. Pharmacological inhibition of Notch signaling reversed the up-regulation of CXCR4 induced by IL-1β, suggesting that Notch signaling may be involved in the growth and metastasis of cancers via up-regulation of CXCR4. In addition, IL-1β induced the activation of extracellular signal regulated kinase (ERK) and ERK inhibition decreased the up-regulation of CXCR4 induced by IL-1β, suggesting the involvement of ERK signaling in cancer metastasis. Taken together these data suggest that IL-1β and IL-1R1 promote cancer growth and metastasis by up-regulating CXCR4 expression and that CXCR4 may be a link between inflammation and cancer.
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Affiliation(s)
- Yi Sun
- Department of Pathology, The Second Xiangya Hospital, Central South University, Changsha, China
- Medical Research Center, Changsha Central Hospital, Changsha, China
| | - Demao Zhu
- Department of Pathology, Changsha Central Hospital, Changsha, China
| | - Guihua Wang
- Department of Oncology, Changsha Central Hospital, Changsha, China
| | - Di Wang
- Department of Oncology, Changsha Central Hospital, Changsha, China
| | - Huashan Zhou
- Department of Pathology, Changsha Central Hospital, Changsha, China
| | - Xueting Liu
- Medical Research Center, Changsha Central Hospital, Changsha, China
| | - Manli Jiang
- Medical Research Center, Changsha Central Hospital, Changsha, China
| | - Lingjuan Liao
- Medical Research Center, Changsha Central Hospital, Changsha, China
| | - Zhiguang Zhou
- Institute of Metabolism and Endocrinology, The Second Xiangya Hospital, Central South University, Changsha, China
- * E-mail: (ZZ); (JH)
| | - Jinyue Hu
- Medical Research Center, Changsha Central Hospital, Changsha, China
- * E-mail: (ZZ); (JH)
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Changes of immunocytic phenotypes and functions from human colorectal adenomatous stage to cancerous stage: Update. Immunobiology 2015; 220:1186-96. [PMID: 26153874 DOI: 10.1016/j.imbio.2015.06.003] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/06/2015] [Revised: 05/27/2015] [Accepted: 06/01/2015] [Indexed: 02/07/2023]
Abstract
It is believed that chronic inflammation as seen in patients with ulcerative colitis significantly increases the colorectal cancer (CRC) risk and functions as the main driving force for the development of colitis associated CRC. Recently, increasing evidences suggest that inflammation is also involved in the processing of sporadic CRCs that mostly develop from the preformed adenomas through a long-term progression. Within the adenoma/CRC tumor microenvironment, high dense immunocytes with significant phenotypic and functional changes have been observed. These cells might produce high level of inflammatory mediators and then affect the adenoma-cancer transition. In this review, we summarize the update on altered phenotypes and inflammatory mediators within the tumor microenvironment from the adenomatous stage to the cancerous stage, and discuss the significance of inflammatory mediators as biomarkers in predicating the progression from the premalignant adenoma lesion to the sporadic CRC lesion and the potential as therapeutic targets.
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Rasch S, Algül H. A clinical perspective on the role of chronic inflammation in gastrointestinal cancer. Clin Exp Gastroenterol 2014; 7:261-72. [PMID: 25143751 PMCID: PMC4134025 DOI: 10.2147/ceg.s43457] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
Chronic inflammation has been identified as an important risk factor for the development of malignancy, and knowledge about its molecular and cellular mechanisms is increasing. Several chronic inflammatory diseases of the gastrointestinal tract are important as risk factors for malignancy and have been studied in detail. In this review, we summarize important molecular mechanisms in chronic inflammation and highlight established and potential links between chronic inflammation and gastrointestinal cancer. In addition, we present the role of chronic inflammation in numerous tumors within the gastrointestinal tract as well as the relevant pathways or epidemiologic observations linking the pathogenesis of these tumors to inflammation.
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Affiliation(s)
- Sebastian Rasch
- II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
| | - Hana Algül
- II Medizinische Klinik und Poliklinik, Klinikum rechts der Isar, Technische Universität München, Munich, Germany
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Mueller TC, Burmeister MA, Bachmann J, Martignoni ME. Cachexia and pancreatic cancer: Are there treatment options? World J Gastroenterol 2014; 20:9361-9373. [PMID: 25071331 PMCID: PMC4110568 DOI: 10.3748/wjg.v20.i28.9361] [Citation(s) in RCA: 48] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2013] [Revised: 01/14/2014] [Accepted: 02/17/2014] [Indexed: 02/06/2023] Open
Abstract
Cachexia is frequently described in patients with pancreatic ductal adenocarcinoma (PDAC) and is associated with reduced survival and quality of life. Unfortunately, the therapeutic options of this multi-factorial and complex syndrome are limited. This is due to the fact that, despite extensive preclinical and clinical research, the underlying pathological mechanisms leading to PDAC-associated cachexia are still not fully understood. Furthermore, there is still a lack of consensus on the definition of cachexia, which complicates the standardization of diagnosis and treatment as well as the analysis of the current literature. In order to provide an efficient therapy for cachexia, an early and reliable diagnosis and consistent monitoring is required, which can be challenging especially in obese patients. Although many substances have been tested in clinical and preclinical settings, so far none of them have been proven to have a long-term effect in ameliorating cancer-associated cachexia. However, recent studies have demonstrated that multidimensional therapeutic modalities are able to alleviate pancreatic cancer-associated cachexia and ultimately improve patients’ outcome. In this current review, we propose a stepwise and pragmatic approach to facilitate and standardize the treatment of cachexia in pancreatic cancer patients. This strategy consists of nutritional, dietary, pharmacological, physical and psychological methods.
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Genetic polymorphisms of interleukin-1 beta and osteosarcoma risk. INTERNATIONAL ORTHOPAEDICS 2014; 38:1671-6. [PMID: 24878968 DOI: 10.1007/s00264-014-2374-2] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 04/28/2014] [Accepted: 05/02/2014] [Indexed: 10/25/2022]
Abstract
PURPOSE Osteosarcoma is the most common childhood bone cancer. Interleukin-1 beta (IL-1B) is crucially involved in osteosarcoma carcinogenesis. Whether genetic polymorphisms of IL-1B also influence osteosarcoma risk is unknown. The aim of this study was to investigate the association between IL-1B gene polymorphisms and osteosarcoma risk in Chinese Han patients. METHODS A hospital-based case-control study involving 120 osteosarcoma patients and 120 controls was conducted. Polymerase chain reaction restriction fragment length polymorphism (PCR-RFLP) analysis was performed to detect three IL-1B gene polymorphisms (-31 T/C, -511 C/T and +3954 C/T) in these patients. RESULTS Patients with osteosarcoma had a significantly lower frequency of -31 CC genotype [odds ratio (OR) = 0.40, 95% confidence interval (CI) = 0.17-0.92; P = 0.03] and -31 C allele (OR = 0.67, 95% CI = 0.46-0.99; P = 0.04) than controls. Patients with osteosarcoma had a significantly lower frequency of -511 TT genotype (OR = 0.40, 95% CI = 0.17-0.95; P = 0.04) than controls. The +3954 C/T gene polymorphisms were not associated with a risk of osteosarcoma. When stratified by Enneking stage, tumour location, histological type, tumour metastasis of osteosarcoma and family history of cancer, no statistically significant results were found. CONCLUSIONS This is the first study to provide evidence for an association of IL-1B gene polymorphisms with osteosarcoma risk.
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Tsimikas S, Duff GW, Berger PB, Rogus J, Huttner K, Clopton P, Brilakis E, Kornman KS, Witztum JL. Pro-inflammatory interleukin-1 genotypes potentiate the risk of coronary artery disease and cardiovascular events mediated by oxidized phospholipids and lipoprotein(a). J Am Coll Cardiol 2014; 63:1724-34. [PMID: 24530664 PMCID: PMC4008715 DOI: 10.1016/j.jacc.2013.12.030] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/15/2013] [Revised: 12/03/2013] [Accepted: 12/04/2013] [Indexed: 12/13/2022]
Abstract
OBJECTIVES The aim of this study was to assess the influence of pro-inflammatory interleukin (IL)-1 genotype status on the risk for coronary artery disease (CAD), defined as >50% diameter stenosis, and cardiovascular events mediated by oxidized phospholipids (OxPLs) and lipoprotein (Lp) (a). BACKGROUND OxPLs are pro-inflammatory, circulate on Lp(a), and mediate CAD. Genetic variations in the IL-1 region are associated with increased inflammatory mediators. METHODS IL-1 genotypes, OxPL on apolipoprotein B-100 (OxPL/apoB), and Lp(a) levels were measured in 499 patients undergoing coronary angiography. The composite genotype termed IL-1(+) was defined by 3 single-nucleotide polymorphisms in the IL-1 gene cluster associated with higher levels of pro-inflammatory cytokines. All other IL-1 genotypes were termed IL-1(-). RESULTS Among IL-1(+) patients, the highest quartile of OxPL/apoB was significantly associated with a higher risk for CAD compared with the lowest quartile (odds ratio [OR]: 2.84; p = 0.001). This effect was accentuated in patients age ≤60 years (OR: 7.03; p < 0.001). In IL-1(-) patients, OxPL/apoB levels showed no association with CAD. The interaction was significant for OxPL/apoB (OR: 1.99; p = 0.004) and Lp(a) (OR: 1.96; p < 0.001) in the IL-1(+) group versus the IL-1(-) group in patients age ≤60 years but not in those age >60 years. In IL-1(+) patients age ≤60 years, after adjustment for established risk factors, high-sensitivity C-reactive protein, and Lp(a), OxPL/apoB remained an independent predictor of CAD. IL-1(+) patients above the median OxPL/apoB presented to the cardiac catheterization laboratory a mean of 3.9 years earlier (p = 0.002) and had worse 4-year event-free survival (death, myocardial infarction, stroke, and need for revascularization) compared with other groups (p = 0.006). CONCLUSIONS Our study suggests that IL-1 genotype status can stratify population risk for CAD and cardiovascular events mediated by OxPL. These data suggest a clinically relevant biological link between pro-inflammatory IL-1 genotype, oxidation of phospholipids, Lp(a), and genetic predisposition to CAD and cardiovascular events.
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Affiliation(s)
- Sotirios Tsimikas
- Division of Cardiovascular Diseases, University of California San Diego, La Jolla, California.
| | - Gordon W Duff
- Division of Genomic Medicine, University of Sheffield, Sheffield, United Kingdom
| | - Peter B Berger
- Department of Cardiology, Geisinger Health System, Danville, Pennsylvania
| | - John Rogus
- Interleukin Genetics, Inc., Waltham, Massachusetts
| | | | - Paul Clopton
- Veterans Affairs Medical Center, San Diego, California
| | | | | | - Joseph L Witztum
- Division of Endocrinology and Metabolism, University of California San Diego, La Jolla, California
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Burada F, Dumitrescu T, Nicoli R, Ciurea ME, Angelescu C, Mixich F, Ioana M. IL-1RN +2018T>C polymorphism is correlated with colorectal cancer. Mol Biol Rep 2013; 40:2851-2857. [PMID: 23192617 DOI: 10.1007/s11033-012-2300-x] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2012] [Accepted: 11/19/2012] [Indexed: 01/29/2023]
Abstract
Epidemiological and experimental evidence indicates chronic inflammation as a risk factor for colorectal cancer. We investigated whether IL-1B -511C>T (rs16944), IL-1B +3954C>T (rs1143634) and IL1-RN +2018T>C (rs419598) cytokine polymorphisms are correlated with colorectal cancer. Blood samples were obtained from 377 Romanian subjects: 144 patients with sporadic colorectal cancer and 233 healthy controls. Polymorphisms were analyzed by allelic discrimination TaqMan PCR assays with specific probes. The results of our study showed that IL-1RN +2018T>C polymorphism is associated with colorectal cancer. We found that there was a significant difference in the frequency of CC genotype between patients with colorectal cancer and the control group (OR 2.42, 95 % CI: 1.06-5.53, p = 0,034) when TT genotype was used as reference. Furthermore, in a stratified analysis, a positive association was found only for IL-1RN +2018CC genotype, that was limited to early I and II stages (OR 2.72, 95 % CI: 1.05-7.03, p = 0,033). We did not find any association between any of the IL-1B polymorphisms and colorectal cancer. In conclusion this study found that IL-1RN +2018T>C polymorphism is associated with colorectal cancer, mainly for localized disease.
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Affiliation(s)
- Florin Burada
- Research Center of Gastroenterology and Hepatology and Human Genomic Laboratory, University of Medicine and Pharmacy of Craiova, 1 May Street No 66, Craiova, Romania.
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Saxena R, Chawla YK, Verma I, Kaur J. Interleukin-1 polymorphism and expression in hepatitis B virus-mediated disease outcome in India. J Interferon Cytokine Res 2013; 33:80-89. [PMID: 23210983 DOI: 10.1089/jir.2012.0093] [Citation(s) in RCA: 19] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
The present study evaluated any possible association among Interleukin-1-beta (IL-1B)-511 and IL-1 receptor antagonist (IL-1RN) variable number tandem-repeat (VNTR) genotypes, haplotypes, and IL-1B expression with risk for hepatitis B virus-related hepatocellular carcinoma (HBV-HCC) development in India. For this, 406 subjects (153 controls, 67 inactive HBV-carriers, 65 patients with chronic-active HBV, 62 HBV-cirrhotics, and 59 subjects with HBV-HCC) were enrolled in the study. Polymerase chain reaction (PCR)-restriction fragment length polymorphism, reverse transcriptase-PCR, and enzyme-linked immunosorbent assay methods were used for assessing polymorphism, mRNA, and protein levels, respectively, of IL-1. The study revealed no significant association of IL-1B(-511) CT and TT genotypes, while a significant positive association of the IL-1RN (VNTR) 1/2 genotype with HCC development, among controls and carriers. Besides, 2/2 genotypes acted as a potential risk factor for hepatitis and subsequent cirrhosis development, among the same groups. Furthermore, the IL-1 haplotypes 2 and 3 were found to be significant protective factors for hepatitis and subsequent HCC development, among controls. However, haplotype 4 shared a significant negative association with hepatitis only. Moreover, proinflammatory IL-1B levels significantly and steadily elevated with the disease progression to HCC, as compared to controls. These preliminary findings indicate a key role of IL-1 in the HBV-mediated disease chronicity, in the Indian population.
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Affiliation(s)
- Roli Saxena
- Department of Biochemistry, Postgraduate Institute of Medical Education and Research, Chandigarh, India
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Cigrovski Berković M, Catela Ivković T, Marout J, Zjačić-Rotkvić V, Kapitanović S. Interleukin 1β gene single-nucleotide polymorphisms and susceptibility to pancreatic neuroendocrine tumors. DNA Cell Biol 2012; 31:531-536. [PMID: 21988351 PMCID: PMC3322397 DOI: 10.1089/dna.2011.1317] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2011] [Revised: 08/16/2011] [Accepted: 08/16/2011] [Indexed: 12/17/2022] Open
Abstract
Pancreatic neuroendocrine tumors (pNETs) are rare neoplasms with not fully understood etiology. Interleukin 1β (IL1β) plays an important role in pancreatic pathology, especially carcinogenesis, but its role in pNET development remains unknown. The aim of this study was to analyze the association between IL1β polymorphisms and susceptibility to pNETs. IL1β -511 C/T and +3954 C/T single-nucleotide polymorphisms (SNPs) were analyzed by real-time polymerase chain reaction-SNP analysis. IL1β serum values in pNET patients were also determined. Association between high-expression C/T -511 IL1β genotype and susceptibility to pNET (p=0.042) was found, especially with functional pNET (p=0.014), where it was associated with the T allele (p=0.016). Combination of genotype analyses confirmed carriers of -511/+3954 CTCT to be at risk of developing functional pNETs (p=0.006) and carriers of -511/+3954 CTCC at risk of developing nonfunctional pNETs (p=0.019). IL1β serum levels of all patients were below the limit of detection. Our results suggest IL1β involvement in pNET development, and we also found association between the IL1β -511 SNP and susceptibility to pNET, especially functional pNETs. Nonfunctional pNETs seem to have inferior prognosis when compared with functional pNETs. It is possible that they differ in tumor microenvironment and that nonfunctional tumors share similarities with adenocarcinoma. We believe that our findings will contribute to understanding of the etiology and possible novel prognostic markers for pNETs when future studies investigating the serum and tumor tissue IL1β levels are done.
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Affiliation(s)
- Maja Cigrovski Berković
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital “Sestre milosrdnice,” Zagreb, Croatia
| | - Tina Catela Ivković
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
| | - Jasminka Marout
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital “Sestre milosrdnice,” Zagreb, Croatia
| | - Vanja Zjačić-Rotkvić
- Department of Endocrinology, Diabetes, and Metabolism, University Hospital “Sestre milosrdnice,” Zagreb, Croatia
| | - Sanja Kapitanović
- Laboratory for Personalized Medicine, Division of Molecular Medicine, Ruđer Bošković Institute, Zagreb, Croatia
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Identification of possible genetic polymorphisms involved in cancer cachexia: a systematic review. J Genet 2011; 90:165-77. [PMID: 21677406 DOI: 10.1007/s12041-011-0027-4] [Citation(s) in RCA: 38] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Cancer cachexia is a polygenic and complex syndrome. Genetic variations in regulation of the inflammatory response, muscle and fat metabolic pathways, and pathways in appetite regulation are likely to contribute to the susceptibility or resistance to developing cancer cachexia. A systematic search of Medline and EmBase databases, covering 1986-2008 was performed for potential candidate genes/genetic polymorphisms relating to cancer cachexia. Related genes were then identified using pathway functional analysis software. All candidate genes were reviewed for functional polymorphisms or clinically significant polymorphisms associated with cachexia using the OMIM and GeneRIF databases. Genes with variants which had functional or clinical associations with cachexia and replicated in at least one study were entered into pathway analysis software to reveal possible network associations between genes. A total of 184 polymorphisms with functional or clinical relevance to cancer cachexia were identified in 92 candidate genes. Of these, 42 polymorphisms (in 33 genes) were replicated in more than one study with 13 polymorphisms found to influence two or more hallmarks of cachexia (i.e. inflammation, loss of fat mass and/or lean mass and reduced survival). Thirty-three genes were found to be significantly interconnected in two major networks with four genes (ADIPOQ, IL6, NFKB1 and TLR4) interlinking both networks. Selection of candidate genes and polymorphisms is a key element of multigene study design. The present study provides an initial framework to select genes/polymorphisms for further study in cancer cachexia, and to develop their potential as susceptibility biomarkers of developing cachexia.
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Hussain A, Priyani A, Sadrieh L, Brahmbhatt K, Ahmed M, Sharma C. Concurrent Sulforaphane and Eugenol Induces Differential Effects on Human Cervical Cancer Cells. Integr Cancer Ther 2011; 11:154-65. [DOI: 10.1177/1534735411400313] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/07/2023] Open
Abstract
Background. The concept of combination of chemoprevention holds great potential for cancer management as lower, clinically tolerable doses of individual agents could be achieved through therapeutic synergy. However, elucidation of their possible interactions—additive, synergistic, or antagonistic—must be thoroughly studied before considering for clinical use. Methods. To evaluate the effect of combination treatment of sulforaphane (SFN) and eugenol on HeLa cells, the authors performed cell viability assay, apoptosis assay, and reverse transcription polymerase chain reaction for gene expression analysis. Calculations of combination effects were expressed as a combination index (CI) with CI < 1, CI = 1, or CI > 1 representing synergism, additivity, or antagonism, respectively. Results. Simultaneous treatment with variable dose combinations of SFN and eugenol resulted in differential effects with an antagonistic effect at lower and synergistic at higher sub-lethal doses as reflected in cell cytotoxicity and apoptosis induction. Importantly, gemcitabine used in conjunction with the low- and high-dose combinations showed no significant cell death at lower doses suggesting that cell cytotoxicity is proportional to gemcitabine alone, whereas at higher sublethal doses of SFN and eugenol, it was found to act in a synergistic manner with gemcitabine. Furthermore, SFN and eugenol combinations at synergistic dose significantly downregulated the expression of Bcl-2, COX-2 and IL-β but not the antagonistic combinations. Conclusion. This study clearly indicates that 2 (or more) chemopreventive agents can act antagonistically or synergistically necessitating elucidation of possible mechanistic interactions for favorable and reliable outcomes of dietary components in the field of cancer prevention.
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CLINICAL RELEVANCE OF IL-1β PROMOTER POLYMORPHISMS (−1470, −511, AND −31) IN PATIENTS WITH MAJOR TRAUMA. Shock 2010; 33:576-82. [DOI: 10.1097/shk.0b013e3181cc0a8e] [Citation(s) in RCA: 28] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
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Allen IC, TeKippe EM, Woodford RMT, Uronis JM, Holl EK, Rogers AB, Herfarth HH, Jobin C, Ting JPY. The NLRP3 inflammasome functions as a negative regulator of tumorigenesis during colitis-associated cancer. ACTA ACUST UNITED AC 2010; 207:1045-56. [PMID: 20385749 PMCID: PMC2867287 DOI: 10.1084/jem.20100050] [Citation(s) in RCA: 656] [Impact Index Per Article: 43.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
Colitis-associated cancer (CAC) is a major complication of inflammatory bowel diseases. We show that components of the inflammasome are protective during acute and recurring colitis and CAC in the dextran sulfate sodium (DSS) and azoxymethane + DSS models. Mice lacking the inflammasome adaptor protein PYCARD (ASC) and caspase-1 demonstrate increased disease outcome, morbidity, histopathology, and polyp formation. The increased tumor burden is correlated with attenuated levels of IL-1β and IL-18 at the tumor site. To decipher the nucleotide-binding domain, leucine-rich-repeat-containing (NLR) component that is involved in colitis and CAC, we assessed Nlrp3 and Nlrc4 deficient mice. Nlrp3−/− mice showed an increase in acute and recurring colitis and CAC, although the disease outcome was less severe in Nlrp3−/− mice than in Pycard−/− or Casp1−/− animals. No significant differences were observed in disease progression or outcome in Nlrc4−/− mice compared with similarly treated wild-type animals. Bone marrow reconstitution experiments show that Nlrp3 gene expression and function in hematopoietic cells, rather than intestinal epithelial cells or stromal cells, is responsible for protection against increased tumorigenesis. These data suggest that the inflammasome functions as an attenuator of colitis and CAC.
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Affiliation(s)
- Irving C Allen
- Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Chapel Hill, NC 27599, USA
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Yu J, Zeng Z, Wang S, Tian L, Wu J, Xue L, Lee CW, Zhang M, Goggins WB, Chen M, Hu P, Sung JJY. IL-1B-511 polymorphism is associated with increased risk of certain subtypes of gastric cancer in Chinese: a case-control study. Am J Gastroenterol 2010; 105:557-64. [PMID: 19904240 DOI: 10.1038/ajg.2009.644] [Citation(s) in RCA: 17] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES The association of interleukin-1B (IL-1B)-511 polymorphism with gastric cancer is still controversial, and the association of IL-1B-511 polymorphism with subtypes of gastric cancer is still largely unknown. We investigated whether the association between IL-1B-511 polymorphism and gastric cancer risk varies by clinically important tumor characteristics and the prognostic value of this polymorphism in a large population-based case-control study among Chinese. METHODS A population-based case-control study was conducted between 1999 and 2006 in Guangdong Province, China. A total of 1,010 gastric cancer patients and 1,500 healthy controls were enrolled in this study. Polymorphism in IL-1B-511 was analyzed by PCR-restriction fragment length polymorphism on 501 gastric cancers and 500 healthy controls. RESULTS Compared with the CC genotype, carriers of IL-1B-511 TT genotype had an increased gastric cancer risk (odds ratio (OR)=1.97, 95% confidence interval (CI)=1.29-3.01, P=0.0016). TT genotype was significantly associated with intestinal type of gastric cancer (OR=3.16, 95% CI=1.74-5.71, P=0.0001) but not with diffuse or mixed-type gastric cancer. The test for OR heterogeneity between the intestinal-type and non-intestinal-type gastric cancers was statistically significant (P=0.02). In subgroup analyses, TT genotype was found to be associated with poorly differentiated gastric cancer (OR=3.31, 95% CI=1.43-3.60, P<0.0001), but not with moderately or well-differentiated gastric cancer. IL-1B-511 genotypes were not associated with the prognosis of gastric cancer patients. CONCLUSIONS IL-1B polymorphism influences certain subtypes of gastric cancer according to the clinical and pathological features. Understanding the etiologic heterogeneity of gastric cancer may result in improvements in controlling this disorder.
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Affiliation(s)
- Jun Yu
- Department of Medicine and Therapeutics, Li Ka Shing Institute of Health Sciences, The Chinese University of Hong Kong, Hong Kong, China.
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Bartosch-Härlid A, Andersson R. Cachexia in pancreatic cancer – Mechanisms and potential intervention. E-SPEN, THE EUROPEAN E-JOURNAL OF CLINICAL NUTRITION AND METABOLISM 2009; 4:e337-e343. [DOI: 10.1016/j.eclnm.2009.10.002] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/08/2023]
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Saini A, Faulkner S, Al-Shanti N, Stewart C. Powerful signals for weak muscles. Ageing Res Rev 2009; 8:251-67. [PMID: 19716529 DOI: 10.1016/j.arr.2009.02.001] [Citation(s) in RCA: 68] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2009] [Accepted: 02/10/2009] [Indexed: 12/19/2022]
Abstract
The aim of the present review is to summarise, evaluate and critique the different mechanisms involved in anabolic growth of skeletal muscle and the catabolic processes involved in cancer cachexia and sarcopenia of ageing. This is highly relevant, since they represent targets for future promising clinical investigations. Sarcopenia is an inevitable process associated with a gradual reduction in muscle mass and strength, associated with a reduction in motor unit number and atrophy of muscle fibres, especially the fast type IIa fibres. The loss of muscle mass with ageing is clinically important because it leads to diminished functional ability and associated complications. Cachexia is widely recognised as severe and rapid wasting accompanying disease states such as cancer or immunodeficiency disease. One of the main characteristics of cancer cachexia is asthenia or lack of strength, which is directly related to the muscle loss. Indeed, apart from the speed of loss, muscle wasting during cancer and ageing share many common metabolic pathways and mediators. In healthy young individuals, muscles maintain their mass and function because of a balance between protein synthesis and protein degradation associated with rates of anabolic and catabolic processes, respectively. Muscles grow (hypertrophy) when protein synthesis exceeds protein degradation. Conversely, muscles shrink (atrophy) when protein degradation dominates. These processes are not occurring independently of each other, but are finely coordinated by a web of intricate signalling networks. Such signalling networks are in charge of executing environmental and cellular cues that ultimately determine whether muscle proteins are synthesised or degraded. Increasing our understanding for the pathways involved in hypertrophy and atrophy and particularly the interaction of these pathways is essential in designing therapeutic strategies for both prevention and treatment of muscle wasting conditions with age and with disease.
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Affiliation(s)
- Amarjit Saini
- Institute for Biomedical Research into Human Movement and Health, Manchester Metropolitan University, Manchester, United Kingdom.
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Savinkova LK, Ponomarenko MP, Ponomarenko PM, Drachkova IA, Lysova MV, Arshinova TV, Kolchanov NA. TATA box polymorphisms in human gene promoters and associated hereditary pathologies. BIOCHEMISTRY (MOSCOW) 2009; 74:117-29. [PMID: 19267666 DOI: 10.1134/s0006297909020011] [Citation(s) in RCA: 40] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/23/2022]
Abstract
TATA-binding protein (TBP) is the first basal factor that recognizes and binds a TATA box on TATA-containing gene promoters transcribed by RNA polymerase II. Data available in the literature are indicative of admissible variability of the TATA box. The TATA box flanking sequences can influence TBP affinity as well as the level of basal and activated transcription. The possibility of mediated involvement in in vivo gene expression regulation of the TBP interactions with variant TATA boxes is supported by data on TATA box polymorphisms and associated human hereditary pathologies. A table containing data on TATA element polymorphisms in human gene promoters (about 40 mutations have been described), associated with particular pathologies, their short functional characteristics, and manifestation mechanisms of TATA-box SNPs is presented. Four classes of polymorphisms are considered: TATA box polymorphisms that weaken and enhance promoter, polymorphisms causing TATA box emergence and disappearance, and human virus TATA box polymorphisms. The described examples are indicative of the polymorphism-associated severe pathologies like thalassemia, the increased risk of hepatocellular carcinoma, sensitivity to H. pylori infection, oral cavity and lung cancers, arterial hypertension, etc.
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Affiliation(s)
- L K Savinkova
- Institute of Cytology and Genetics, Siberian Branch of the Russian Academy of Sciences, Novosibirsk, Russia.
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Milne RL, Greenhalf W, Murta-Nascimento C, Real FX, Malats N. The inherited genetic component of sporadic pancreatic adenocarcinoma. Pancreatology 2009; 9:206-14. [PMID: 19352090 DOI: 10.1159/000210261] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Pancreatic cancer, like many other complex diseases, has genetic and environmental components to its etiology. It is likely that relatively common genetic variants with modest effects on pancreatic cancer risk play an important role in both familial and sporadic forms of the disease, either individually or in interaction with environmental factors. The relatively high frequency of such variants means that they could potentially explain a substantial portion of disease risk. Here we summarize the findings published to date from genetic association studies. In general, very few low-penetrance variants have been identified and those that have require replication in independent studies. Possible gene-environment interactions arising from these studies also require replication. More comprehensive approaches are needed to make progress, including global analyses of biologically sound pathways and genome-wide association studies. Large sample sizes are required to do this appropriately and multi-study consortia make this possible. A number of consortia of pre-existing studies have already been formed, and these will facilitate the identification of further low-penetrance variants and gene-environment interaction. However, these approaches do not substitute for the design of novel, sufficiently powered studies that apply uniform criteria to case selection, the acquisition of environmental exposure information, and to biological sample collection.
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Affiliation(s)
- R L Milne
- Spanish National Cancer Research Centre, Madrid, Spain
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Deans DAC, Tan BHL, Ross JA, Rose-Zerilli M, Wigmore SJ, Howell WM, Grimble RF, Fearon KCH. Cancer cachexia is associated with the IL10 -1082 gene promoter polymorphism in patients with gastroesophageal malignancy. Am J Clin Nutr 2009; 89:1164-72. [PMID: 19244371 DOI: 10.3945/ajcn.2008.27025] [Citation(s) in RCA: 41] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/14/2022] Open
Abstract
BACKGROUND The genetic predisposition of the host to local or systemic inflammation may contribute to the effect of cancer cachexia. OBJECTIVE We investigated the relation between cytokine polymorphisms (IL1B -511, IL6 -174, IL10 -1082, TNFA -308, and LTA +252) and markers of nutritional status among patients with gastroesophageal cancer to determine whether any such association was reflected by cytokine concentrations in the tumor or plasma compartments. DESIGN Patients (n = 203) with a diagnosis of gastroesophageal cancer underwent nutritional assessment (body mass index, anthropometric measures, dysphagia scoring, and estimation of dietary intake). Single nucleotide polymorphism genotyping was performed by TaqMan allelic discrimination genotyping. Serum cytokine and C-reactive protein concentrations were determined by enzyme-linked immunosorbent assay. Tumor tissue cytokine protein concentrations (n = 56) were determined by using the Cytometric Bead Array System. RESULTS IL10 GG and IL6 CC polymorphisms were associated with elevated serum C-reactive protein concentrations, and the IL6 CC genotype was also associated with elevated tumor tissue cytokine concentrations. At diagnosis, the IL10 GG, but not the IL6, genotype was linked with increased total weight loss: 4.9% for AA, 7.1% for AG, and 12.0% for GG (P = 0.007). Serum C-reactive protein concentrations correlated with increased weight loss (r = 0.24, P < 0.001). Compared with other genotypes, the IL10 GG genotype retained an independent association in determining the extent of weight loss on multivariate analysis (95% CI: 0.52, 3.43; P = 0.008). Possession of the GG allele was associated with a 2.3 times increased risk of developing cachexia (95% CI: 1.2, 4.3; P = 0.014). CONCLUSION These data suggest that the IL10 genotype of the host can influence the development of cachexia among patients with gastroesophageal malignancy.
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Affiliation(s)
- D A Chris Deans
- Department of Clinical and Surgical Sciences, Medical School, University of Edinburgh, Edinburgh, UK
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Braumann C, Gutt CN, Scheele J, Menenakos C, Willems W, Mueller JM, Jacobi CA. Taurolidine reduces the tumor stimulating cytokine interleukin-1beta in patients with resectable gastrointestinal cancer: a multicentre prospective randomized trial. World J Surg Oncol 2009; 7:32. [PMID: 19309495 PMCID: PMC2667516 DOI: 10.1186/1477-7819-7-32] [Citation(s) in RCA: 12] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2008] [Accepted: 03/23/2009] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND The effect of additional treatment strategies with antineoplastic agents on intraperitoneal tumor stimulating interleukin levels are unclear. Taurolidine and Povidone-iodine have been mainly used for abdominal lavage in Germany and Europe. METHODS In the settings of a multicentre (three University Hospitals) prospective randomized controlled trial 120 patients were randomly allocated to receive either 0.5% taurolidine/2,500 IU heparin (TRD) or 0.25% povidone-iodine (control) intraperitoneally for resectable colorectal, gastric or pancreatic cancers. Due to the fact that IL-1beta (produced by macrophages) is preoperatively indifferent in various gastrointestinal cancer types our major outcome criterion was the perioperative (overall) level of IL-1beta in peritoneal fluid. RESULTS Cytokine values were significantly lower after TRD lavage for IL-1beta, IL-6, and IL-10. Perioperative complications did not differ. The median follow-up was 50.0 months. The overall mortality rate (28 vs. 25, p = 0.36), the cancer-related death rate (17 vs. 19, p = .2), the local recurrence rate (7 vs. 12, p = .16), the distant metastasis rate (13 vs. 18, p = 0.2) as well as the time to relapse were not statistically significant different. CONCLUSION Reduced cytokine levels might explain a short term antitumorigenic intraperitoneal effect of TRD. But, this study analyzed different types of cancer. Therefore, we set up a multicentre randomized trial in patients undergoing curative colorectal cancer resection. TRIAL REGISTRATION ISRCTN66478538.
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Affiliation(s)
- Chris Braumann
- Department of General, Visceral, Vascular and Thoracic Surgery, Universitaetsmedizin Berlin, Charité Campus Mitte, Humboldt University, Charitéplatz 1, 10117 Berlin, Germany.
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Abstract
PURPOSE OF REVIEW To review current knowledge of the relationship between cytokines, the acute phase response (APR) and the development of cachexia. RECENT FINDINGS Cytokines important in the initiation of the APR are also important in the genesis of cachexia. The presence of an APR or high circulating levels of pro-inflammatory cytokines are known to be related to adverse outcome in cancer patients. Studies of host cytokine genotype have demonstrated that specific host cytokine polymorphisms are associated with both the development of cachexia and reduced patient survival. The desire to be able to predict accurately survival in cancer patients has led to the description of various APR-based prognostic scoring systems. SUMMARY Cachexia is an important clinical problem affecting up to two thirds of cancer patients. It results from anorexia and metabolic change and leads to loss of both adipose tissue and lean body mass, particularly in the skeletal muscle compartment. An APR is seen in half of cancer patients at presentation, and is most often determined clinically by raised plasma C-reactive protein concentrations. Adverse outcome and shortened survival have been linked to the presence of an APR. This article explores the cause and consequences of the APR in cancer cachexia.
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Clinical significance of interleukin-6 (IL-6) gene polymorphism and IL-6 serum level in pancreatic adenocarcinoma and chronic pancreatitis. Dig Dis Sci 2009; 54:683-9. [PMID: 18661238 DOI: 10.1007/s10620-008-0390-z] [Citation(s) in RCA: 81] [Impact Index Per Article: 5.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/15/2007] [Accepted: 06/17/2008] [Indexed: 12/13/2022]
Abstract
The aim of our study was to assess the clinical significance of -174G/C Il-6 gene polymorphism and Il-6 serum level in patients with pancreatic adenocarcinoma (PA) and chronic pancreatitis (CP). The study included 41 with pancreatic adenocarcinoma, 56 with chronic pancreatitis, and 50 healthy volunteers, hospitalized between 2003 and 2006. Il-6 serum levels were measured with an enzyme-linked immunoassay and Il-6 gene polymorphism was studied in DNA isolated from peripheral blood. In PA and CP patients Il-6 serum levels were significantly higher than in the control group (P < 0.01). The levels of Il-6 in the patients with tumor size >or=3.5 cm were higher than that in patients with smaller tumors (P < 0.01). The elevated Il-6 levels were also correlated with the presence of liver metastases (P < 0.01). Mean Il-6 serum level was significantly higher in patients homozygous G/G for -174 Il-6 gene compared with patients with at least one C allele. Our findings indicate that -174G/C Il-6 gene polymorphism influences circulating Il-6 levels. Increased Il-6 serum levels may be correlated with tumor size and the presence of liver metastases in patients with pancreatic adenocarcinoma.
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Ren JL, Pan JS, Lu YP, Sun P, Han J. Inflammatory signaling and cellular senescence. Cell Signal 2009; 21:378-383. [PMID: 18992324 PMCID: PMC2870712 DOI: 10.1016/j.cellsig.2008.10.011] [Citation(s) in RCA: 105] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2008] [Revised: 09/29/2008] [Accepted: 10/21/2008] [Indexed: 01/22/2023]
Abstract
Inflammation acts as a double-edged sword in the pathogenesis of cancer. Inflammatory responses play a key role in eliminating potentially cancerous cells; however, an inflammatory microenvironment also promotes the development of cancer. Proinflammatory cytokines, the key mediators of inflammation, also play a dual role in oncogenesis. While they can promote neoplastic progression, recent studies have revealed an unexpected function of the inflammatory pathways in inhibiting cancer development. These studies demonstrate that cells undergoing senescence, a cellular program serving as a barrier to cancer development, produce increased amount of inflammatory cytokines. These inflammatory cytokines play an essential role in the initiation and maintenance of cellular senescence, and are responsible for triggering an innate immune response that clears the senescent tumor cells in vivo. The purpose of the present review is to discuss the dual roles of the inflammatory cytokines produced by senescent cells in the pathogenesis of cancer, and the signaling pathway mediating their role in cellular senescence.
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Affiliation(s)
- Jian-Lin Ren
- Department of Gastroenterology, Zhongshan Hospital, Xiamen University, Xiamen, China
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