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1
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Sharma R, Komal K, Kumar S, Ghosh R, Pandey P, Gupta GD, Kumar M. Advances in pancreatic cancer diagnosis: from DNA methylation to AI-assisted imaging. Expert Rev Mol Diagn 2025:1-13. [PMID: 40388321 DOI: 10.1080/14737159.2025.2509022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/22/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
INTRODUCTION Pancreatic Cancer (PC) is a highly aggressive tumor that is mainly diagnosed at later stages. Various imaging technologies, such as CT, MRI, and EUS, possess limitations in early PC diagnosis. Therefore, this review article explores the various innovative biomarkers for PC detection, such as DNA methylation, Noncoding RNAs, and proteomic biomarkers, and the role of AI in PC detection at early stages. AREA COVERED Innovative biomarkers, such as DNA methylation genes, show higher specificity and sensitivity in PC diagnosis. Additionally, various non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs, show high diagnostic accuracy and serve as diagnostic and prognostic biomarkers. Additionally, proteomic biomarkers retain higher diagnostic accuracy in different body fluids. Apart from this, the utilization of AI showed that AI surpassed the radiologist's diagnostic performance in PC detection. EXPERT OPINION The combination of AI and advanced biomarkers can revolutionize early PC detection. However, large-scale, prospective studies are needed to validate its clinical utility. Further. standardization of biomarker panels and AI algorithms is a vital step toward their reliable applications in early PC detection, ultimately improving patient outcomes. [Figure: see text].
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Affiliation(s)
- Rohit Sharma
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Kumari Komal
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Sourabh Kumar
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Rashmi Ghosh
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Prachi Pandey
- Department of Quality Assurance, ISF College Pharmacy, Moga, India
| | | | - Manish Kumar
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
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2
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Juthani R, Manne A. Blood-based biomarkers in pancreatic ductal adenocarcinoma: developments over the last decade and what holds for the future- a review. Front Oncol 2025; 15:1555963. [PMID: 40330826 PMCID: PMC12052548 DOI: 10.3389/fonc.2025.1555963] [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: 01/06/2025] [Accepted: 03/24/2025] [Indexed: 05/08/2025] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) accounts for a significant burden of global cancer deaths worldwide. The dismal outcomes associated with PDAC can be overcome by detecting the disease early and developing tools that predict response to treatment, allowing the selection of the most optimal treatment. Over the last couple of years, significant progress has been made in the development of novel biomarkers that aid in diagnosis, prognosis, treatment selection, and monitoring response. Blood-based biomarkers offer an alternative to tissue-based diagnosis and offer immense potential in managing PDAC. In this review, we have discussed the advances in blood-based biomarkers in PDAC, such as DNA (mutations and methylations), RNA, protein biomarkers and circulating tumor cells (CTC) over the last decade and also elucidated all aspects of practical implementation of these biomarkers in clinical practice. We have also discussed implementing multiomics utilizing more than one biomarker and targeted therapies that have been developed using these biomarkers.
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Affiliation(s)
- Ronit Juthani
- Department of Medicine, Saint Vincent Hospital, Worcester, MA, United States
| | - Ashish Manne
- Department of Internal Medicine, Division of Medical Oncology at the Arthur G. James Cancer Hospital and Richard J. Solove Research Institute, The Ohio State University Comprehensive Cancer Center, Columbus, OH, United States
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3
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Lokau J, Bollmann M, Garbers Y, Feist E, Lohmann CH, Bertrand J, Garbers C. Transforming growth factor beta induces interleukin-11 expression in osteoarthritis. Cytokine 2025; 187:156863. [PMID: 39879889 DOI: 10.1016/j.cyto.2025.156863] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/16/2024] [Revised: 01/04/2025] [Accepted: 01/19/2025] [Indexed: 01/31/2025]
Abstract
Interleukin-11 (IL-11) is a member of the IL-6 family of cytokines and possesses both pro- and anti-inflammatory properties. IL-11 activates its target cells via binding to a membrane-bound IL-11R and subsequent formation of a homodimer of the signal-transducing receptor gp130. Thus, the expression pattern of the IL-11R determines which cells can be activated by IL-11. However, knowledge about IL-11 target cells and cells that secrete IL-11 are sparse, and the overall roles of IL-11 in inflammatory diseases are largely unexplored. In this study, we show that high amounts of IL-11 can be detected via ELISA in the synovial fluid of osteoarthritis (OA) patients in comparison to rheumatoid arthritis (RA) patients. Using primary cells and tissue of OA patients, we show that IL-11 is expressed by chondrocytes in cartilage, but not in the synovium. We further identify the cytokine transforming growth factor β 1(TGF-β1) as a potent inducer of IL-11 secretion in both primary chondrocytes and fibroblasts, and TGF-β1 and IL-11 levels correlate significantly in the synovial fluid of OA patients. Using immunohistochemistry, we show that both cartilage and synovium express IL-11R, and the amount of IL-11R is independent of the disease severity. Primary chondrocytes and fibroblasts from OA patients respond to IL-11 stimulation with potent activation of the Jak/STAT3 signaling cascade, suggesting that these cell types are not only the source, but also the targets of IL-11 in OA patients. Our results uncover IL-11 as a potential new target for therapy in OA.
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Affiliation(s)
- Juliane Lokau
- Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany; Department of Pathology, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany
| | - Miriam Bollmann
- Department of Orthopaedic Surgery, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany
| | - Yvonne Garbers
- Faculty of Management, Culture and Technology (Lingen campus), Osnabrück University of Applied Sciences, 49809 Lingen, (Ems), Germany
| | - Eugen Feist
- Department of Rheumatology and Clinical Immunology, Charité-Universitätsmedizin Berlin, and Experimental Rheumatology, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany
| | - Christoph H Lohmann
- Department of Orthopaedic Surgery, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany
| | - Jessica Bertrand
- Department of Orthopaedic Surgery, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany
| | - Christoph Garbers
- Institute of Clinical Biochemistry, Hannover Medical School, 30625 Hannover, Germany; Department of Pathology, Otto-von-Guericke-University Magdeburg, 39120 Magdeburg, Germany.
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4
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Chen X, Sun F, Wang X, Feng X, Aref AR, Tian Y, Ashrafizadeh M, Wu D. Inflammation, microbiota, and pancreatic cancer. Cancer Cell Int 2025; 25:62. [PMID: 39987122 PMCID: PMC11847367 DOI: 10.1186/s12935-025-03673-6] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2024] [Accepted: 02/04/2025] [Indexed: 02/24/2025] Open
Abstract
Pancreatic cancer (PC) is a malignancy of gastrointestinal tract threatening the life of people around the world. In spite of the advances in the treatment of PC, the overall survival of this disease in advanced stage is less than 12%. Moreover, PC cells have aggressive behaviour in proliferation and metastasis as well as capable of developing therapy resistance. Therefore, highlighting the underlying molecular mechanisms in PC pathogenesis can provide new insights for its treatment. In the present review, inflammation and related pathways as well as role of gut microbiome in the regulation of PC pathogenesis are highlighted. The various kinds of interleukins and chemokines are able to regulate angiogenesis, metastasis, proliferation, inflammation and therapy resistance in PC cells. Furthermore, a number of molecular pathways including NF-κB, TLRs and TGF-β demonstrate dysregulation in PC aggravating inflammation and tumorigenesis. Therapeutic regulation of these pathways can reverse inflammation and progression of PC. Both chronic and acute pancreatitis have been shown to be risk factors in the development of PC, further highlighting the role of inflammation. Finally, the composition of gut microbiota can be a risk factor for PC development through affecting pathways such as NF-κB to mediate inflammation.
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Affiliation(s)
- XiaoLiang Chen
- Department of General Surgery and Integrated Traditional Chinese and Western Medicine Oncology, Tiantai People'S Hospital of Zhejiang Province(Tiantai Branch of Zhejiang Provincial People'S Hospital), Hangzhou Medical College, Taizhou, Zhejiang, China
| | - Feixia Sun
- Nursing Department, Shandong First Medical University Affiliated Occupational Disease Hospital (Shandong Provincial Occupational Disease Hospital), Jinan, China
| | - Xuqin Wang
- Department of Oncology, Chongqing General Hospital, Chongqing University, Chongqing, 401120, China
| | - Xiaoqiang Feng
- Center of Stem Cell and Regenerative Medicine, Gaozhou People's Hospital, Gaozhou, 525200, Guangdong, China
| | - Amir Reza Aref
- VitroVision Department, DeepkinetiX, Inc, Boston, MA, USA
| | - Yu Tian
- Research Center, the Huizhou Central People'S Hospital, Guangdong Medical University, Huizhou, Guangdong, China.
- School of Public Health, Benedictine University, No. 5700 College Road, Lisle, IL, 60532, USA.
| | - Milad Ashrafizadeh
- Department of Radiation Oncology, Shandong Cancer Hospital and Institute, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, 250000, Shandong, China.
| | - Dengfeng Wu
- Department of Emergency, The People'S Hospital of Gaozhou, No. 89 Xiguan Road, Gaozhou, 525200, Guangdong, China.
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5
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Di Marco F, Cufaro MC, Damiani V, Dufrusine B, Pizzinato E, Di Ferdinando F, Sala G, Lattanzio R, Dainese E, Federici L, Ponsaerts P, De Laurenzi V, Cicalini I, Pieragostino D. Proteomic meta-analysis unveils new frontiers for biomarkers research in pancreatic carcinoma. Oncogenesis 2025; 14:3. [PMID: 39956821 PMCID: PMC11830788 DOI: 10.1038/s41389-025-00547-4] [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: 08/01/2024] [Revised: 12/20/2024] [Accepted: 02/06/2025] [Indexed: 02/18/2025] Open
Abstract
Pancreatic carcinoma (PC) is the sixth leading cause of cancer death in both sexes in 2022, responsible for almost 5% of all cancer deaths worldwide; it is characterized by a poor prognosis since most patients present with an unresectable and metastatic tumor. To date, the decreasing trend in mortality rates related to the most common cancers has contributed to making pancreatic cancer a serious public health problem. In the last few years, scientific research has led to many advances in diagnostic approaches, perioperative management, radiotherapy techniques, and systemic therapies for advanced disease, but only with modest incremental progress in PC patient outcomes. Most of the causes of this high mortality are, unfortunately, late diagnosis and an important therapeutic resistance; for this reason, the most recent high-throughput proteomics technologies focus on the identification of novel biomarkers and molecular profiling to generate new insights in the study of PC, to improve diagnosis and prognosis and to monitor the therapies progress. In this work, we present and discuss the integration of results from different revised studies on protein biomarkers in a global proteomic meta-analysis to understand which path to pursue scientific research. In particular, cancer signaling, inflammatory response, and cell migration and signaling have emerged as the main pathways described in PC, as well as scavenging of free radicals and metabolic alteration concurrently highlighted new research insights on this disease. Interestingly, from the study of upstream regulators, some were found to be shared by collecting data relating to both biological fluid and tissue biomarkers, side by side: specifically, TNF, LPS, p38-MAPK, AGT, miR-323-5p, and miR-34a-5p. By integrating many biological components with their interactions and environmental relationships, it's possible to achieve an in-depth description of the pathological condition in PC and define correlations between concomitant symptoms and tumor genesis and progression. In conclusion, our work may represent a strategy to combine the results from different studies on various biological samples in a more comprehensive way.
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Affiliation(s)
- Federica Di Marco
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Maria Concetta Cufaro
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Verena Damiani
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Beatrice Dufrusine
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Erika Pizzinato
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Telematic University of "Leonardo Da Vinci", Torrevecchia Teatina, Chieti, Italy
| | - Fabio Di Ferdinando
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Gianluca Sala
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Rossano Lattanzio
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Enrico Dainese
- Department of Bioscience and Technology for Food Agriculture and Environment, University of Teramo, Teramo, Italy
| | - Luca Federici
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Peter Ponsaerts
- Laboratory of Experimental Hematology, Vaccine and Infectious Disease Institute (Vaxinfectio), University of Antwerp, Antwerpen, Belgium
| | - Vincenzo De Laurenzi
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
| | - Ilaria Cicalini
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy.
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy.
| | - Damiana Pieragostino
- Centre for Advanced Studies and Technology (CAST), "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
- Department of Innovative Technologies in Medicine and Dentistry, "G. d' Annunzio" University of Chieti-Pescara, Chieti, Italy
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6
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Lim WW, Leung JH, Xie C, Cheng AWT, Su L, Lum LN, Toh A, Kong SC, Takano AM, Hausenloy DJ, Chua YC. Circulating Interleukins as Biomarkers in Non-Small Cell Lung Cancer Patients: A Pilot Study Compared to Normal Individuals. Diseases 2024; 12:221. [PMID: 39329890 PMCID: PMC11430979 DOI: 10.3390/diseases12090221] [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: 08/28/2024] [Revised: 09/17/2024] [Accepted: 09/17/2024] [Indexed: 09/28/2024] Open
Abstract
Identifying biomarkers in non-small cell lung cancer (NSCLC) can improve diagnosis and patient stratification. We evaluated plasmas and sera for interleukins (IL)-11, IL-6, IL-8, IL-17A, and IL-33 as biomarkers in primary NSCLC patients undergoing surgical treatment against normal volunteers. Exhaled-breath condensates (EBCs), a potential source without invasive procedures, were explored in normal individuals. Due to separate recruitment criteria and intrinsic cohort differences, the NSCLC and control cohorts were not well matched for age (median age: 65 vs. 40 years; p < 0.0001) and smoking status (p = 0.0058). Interleukins were first assessed through conventional ELISA. IL-11 was elevated in NSCLC plasma compared to controls (49.71 ± 16.90 vs. 27.67 ± 14.06 pg/mL, respectively, p < 0.0001) but undetectable in sera and EBCs by conventional ELISA. Therefore, high-sensitivity PCR-based IL-11 ELISA was repeated, albeit with concentration discrepancies. IL11 gene and protein upregulation by RT-qPCR and immunohistochemistry, respectively, were validated in NSCLC tumors. The lack of detection sensitivity across IL-6, IL-8, IL-17A, and IL-33 suggests the need for further, precise assays. Surprisingly, biomarker concentrations can be dissimilar across paired plasmas and sera. Our results identified a need to optimize detection limits for biomarker detection and caution against over-reliance on just one form of blood sample for biomarker assessment.
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Affiliation(s)
- Wei-Wen Lim
- National Heart Research Institute of Singapore, National Heart Center Singapore, Singapore 169609, Singapore
- Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore 169857, Singapore
| | - Jason H Leung
- Department of Cardiothoracic Surgery, National Heart Center Singapore, Singapore 169609, Singapore
| | - Chen Xie
- National Heart Research Institute of Singapore, National Heart Center Singapore, Singapore 169609, Singapore
| | - Angelina W T Cheng
- National Heart Research Institute of Singapore, National Heart Center Singapore, Singapore 169609, Singapore
| | - Liping Su
- National Heart Research Institute of Singapore, National Heart Center Singapore, Singapore 169609, Singapore
| | - Luh-Nah Lum
- Clinical and Translational Research Office, National Heart Center Singapore, Singapore 169609, Singapore
| | - Aishah Toh
- Clinical and Translational Research Office, National Heart Center Singapore, Singapore 169609, Singapore
| | - Siew-Ching Kong
- Clinical and Translational Research Office, National Heart Center Singapore, Singapore 169609, Singapore
| | - Angela M Takano
- Department of Anatomical Pathology, Singapore General Hospital, Singapore 169608, Singapore
| | - Derek J Hausenloy
- National Heart Research Institute of Singapore, National Heart Center Singapore, Singapore 169609, Singapore
- Program in Cardiovascular and Metabolic Disorders, Duke-National University of Singapore, Singapore 169857, Singapore
- Yong Loo Lin School of Medicine, National University Singapore, Singapore 117597, Singapore
- The Hatter Cardiovascular Institute, University College London, London WC1E 6HX, UK
| | - Yang C Chua
- Department of Cardiothoracic Surgery, National Heart Center Singapore, Singapore 169609, Singapore
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7
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Sun X, Wang S, Wong CC. Mass spectrometry–based proteomics technology in pancreatic cancer research. JOURNAL OF PANCREATOLOGY 2024; 7:145-163. [DOI: 10.1097/jp9.0000000000000152] [Citation(s) in RCA: 1] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/03/2025] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) has become a significant health concern with increasing incidence and mortality rates over the past few decades. Researchers have turned their attention to cutting-edge mass spectrometry (MS) technology due to its high-throughput and accurate detection capacity, which plays a vital role in understanding the mechanisms and discovering biomarkers for pancreatic diseases. In this review, we comprehensively investigate various methodologies of quantitative and qualitative proteomics MS technologies, alongside bioinformatical platforms employed in pancreatic cancer research. The integration of these optimized approaches provides novel insights into the molecular mechanisms underlying tumorigenesis and disease progression, ultimately facilitating the discovery of potential diagnostic, prognostic biomarkers, and therapeutic targets. The robust MS-based strategy shows promise in paving the way for early diagnosis and personalized medicine for pancreatic cancer patients.
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Affiliation(s)
- Xue Sun
- First School of Clinical Medicine, Peking University Health Science Center, Peking University, Beijing 100871, China
- School of Pharmacy, University of Wisconsin-Madison, Madison, Wisconsin 53705, United States
| | - Siyuan Wang
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
| | - Catherine C.L. Wong
- First School of Clinical Medicine, Peking University Health Science Center, Peking University, Beijing 100871, China
- State Key Laboratory of Complex Severe and Rare Diseases, Clinical Research Institute, Peking Union Medical College Hospital, Chinese Academy of Medical Science & Peking Union Medical College, Beijing 100730, China
- Tsinghua-Peking University Joint Center for Life Sciences, Tsinghua University, Beijing 100084, China
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8
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Stuart SF, Curpen P, Gomes AJ, Lan MC, Nie S, Williamson NA, Kannourakis G, Morokoff AP, Achuthan AA, Luwor RB. Interleukin-11/IL-11 Receptor Promotes Glioblastoma Cell Proliferation, Epithelial-Mesenchymal Transition, and Invasion. Brain Sci 2024; 14:89. [PMID: 38248304 PMCID: PMC10813507 DOI: 10.3390/brainsci14010089] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/30/2023] [Revised: 12/22/2023] [Accepted: 12/29/2023] [Indexed: 01/23/2024] Open
Abstract
Glioblastoma is highly proliferative and invasive. However, the regulatory cytokine networks that promote glioblastoma cell proliferation and invasion into other areas of the brain are not fully defined. In the present study, we define a critical role for the IL-11/IL-11Rα signalling axis in glioblastoma proliferation, epithelial to mesenchymal transition, and invasion. We identified enhanced IL-11/IL-11Rα expression correlated with reduced overall survival in glioblastoma patients using TCGA datasets. Proteomic analysis of glioblastoma cell lines overexpressing IL-11Rα displayed a proteome that favoured enhanced proliferation and invasion. These cells also displayed greater proliferation and migration, while the knockdown of IL-11Rα reversed these tumourigenic characteristics. In addition, these IL-11Rα overexpressing cells displayed enhanced invasion in transwell invasion assays and in 3D spheroid invasion assays, while knockdown of IL-11Rα resulted in reduced invasion. Furthermore, IL-11Rα-overexpressing cells displayed a more mesenchymal-like phenotype compared to parental cells and expressed greater levels of the mesenchymal marker Vimentin. Overall, our study identified that the IL-11/IL-11Rα pathway promotes glioblastoma cell proliferation, EMT, and invasion.
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Affiliation(s)
- Sarah F. Stuart
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; (S.F.S.); (A.J.G.); (A.P.M.)
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia;
| | - Peter Curpen
- Townsville Hospital and Health Service, James Cook University, Townsville, QLD 4814, Australia;
| | - Adele J. Gomes
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; (S.F.S.); (A.J.G.); (A.P.M.)
| | - Michelle C. Lan
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; (S.F.S.); (A.J.G.); (A.P.M.)
| | - Shuai Nie
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3052, Australia; (S.N.); (N.A.W.)
| | - Nicholas A. Williamson
- Melbourne Mass Spectrometry and Proteomics Facility, Bio21 Molecular Science & Biotechnology Institute, The University of Melbourne, Melbourne, VIC 3052, Australia; (S.N.); (N.A.W.)
| | - George Kannourakis
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia;
- Federation University, Ballarat, VIC 3350, Australia
| | - Andrew P. Morokoff
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; (S.F.S.); (A.J.G.); (A.P.M.)
- Department of Neurosurgery, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia
| | - Adrian A. Achuthan
- Department of Medicine, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia;
| | - Rodney B. Luwor
- Department of Surgery, The University of Melbourne, The Royal Melbourne Hospital, Parkville, VIC 3050, Australia; (S.F.S.); (A.J.G.); (A.P.M.)
- Fiona Elsey Cancer Research Institute, Ballarat, VIC 3350, Australia;
- Federation University, Ballarat, VIC 3350, Australia
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9
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Kazakov AS, Deryusheva EI, Rastrygina VA, Sokolov AS, Permyakova ME, Litus EA, Uversky VN, Permyakov EA, Permyakov SE. Interaction of S100A6 Protein with the Four-Helical Cytokines. Biomolecules 2023; 13:1345. [PMID: 37759746 PMCID: PMC10526228 DOI: 10.3390/biom13091345] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/27/2023] [Revised: 08/19/2023] [Accepted: 08/31/2023] [Indexed: 09/29/2023] Open
Abstract
S100 is a family of over 20 structurally homologous, but functionally diverse regulatory (calcium/zinc)-binding proteins of vertebrates. The involvement of S100 proteins in numerous vital (patho)physiological processes is mediated by their interaction with various (intra/extra)cellular protein partners, including cell surface receptors. Furthermore, recent studies have revealed the ability of specific S100 proteins to modulate cell signaling via direct interaction with cytokines. Previously, we revealed the binding of ca. 71% of the four-helical cytokines via the S100P protein, due to the presence in its molecule of a cytokine-binding site overlapping with the binding site for the S100P receptor. Here, we show that another S100 protein, S100A6 (that has a pairwise sequence identity with S100P of 35%), specifically binds numerous four-helical cytokines. We have studied the affinity of the recombinant forms of 35 human four-helical cytokines from all structural families of this fold to Ca2+-loaded recombinant human S100A6, using surface plasmon resonance spectroscopy. S100A6 recognizes 26 of the cytokines from all families of this fold, with equilibrium dissociation constants from 0.3 nM to 12 µM. Overall, S100A6 interacts with ca. 73% of the four-helical cytokines studied to date, with a selectivity equivalent to that for the S100P protein, with the differences limited to the binding of interleukin-2 and oncostatin M. The molecular docking study evidences the presence in the S100A6 molecule of a cytokine-binding site, analogous to that found in S100P. The findings argue the presence in some of the promiscuous members of the S100 family of a site specific to a wide range of four-helical cytokines. This unique feature of the S100 proteins potentially allows them to modulate the activity of the numerous four-helical cytokines in the disorders accompanied by an excessive release of the cytokines.
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Affiliation(s)
- Alexey S. Kazakov
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Evgenia I. Deryusheva
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Victoria A. Rastrygina
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Andrey S. Sokolov
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Maria E. Permyakova
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Ekaterina A. Litus
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Vladimir N. Uversky
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
- Department of Molecular, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
- USF Health Byrd Alzheimer’s Research Institute, Morsani College of Medicine, University of South Florida, Tampa, FL 33612, USA
| | - Eugene A. Permyakov
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
| | - Sergei E. Permyakov
- Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institute for Biological Instrumentation, Institutskaya str., 7, Pushchino, Moscow Region 142290, Russia; (A.S.K.); (E.I.D.); (V.A.R.); (A.S.S.); (M.E.P.); (E.A.L.); (E.A.P.)
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10
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Croft W, Pearce H, Margielewska-Davies S, Lim L, Nicol SM, Zayou F, Blakeway D, Marcon F, Powell-Brett S, Mahon B, Merard R, Zuo J, Middleton G, Roberts K, Brown RM, Moss P. Spatial determination and prognostic impact of the fibroblast transcriptome in pancreatic ductal adenocarcinoma. eLife 2023; 12:e86125. [PMID: 37350578 PMCID: PMC10361717 DOI: 10.7554/elife.86125] [Citation(s) in RCA: 5] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/11/2023] [Accepted: 06/22/2023] [Indexed: 06/24/2023] Open
Abstract
Pancreatic ductal adenocarcinoma has a poor clinical outcome and responses to immunotherapy are suboptimal. Stromal fibroblasts are a dominant but heterogenous population within the tumor microenvironment and therapeutic targeting of stromal subsets may have therapeutic utility. Here, we combine spatial transcriptomics and scRNA-Seq datasets to define the transcriptome of tumor-proximal and tumor-distal cancer-associated fibroblasts (CAFs) and link this to clinical outcome. Tumor-proximal fibroblasts comprise large populations of myofibroblasts, strongly expressed podoplanin, and were enriched for Wnt ligand signaling. In contrast, inflammatory CAFs were dominant within tumor-distal subsets and expressed complement components and the Wnt-inhibitor SFRP2. Poor clinical outcome was correlated with elevated HIF-1α and podoplanin expression whilst expression of inflammatory and complement genes was predictive of extended survival. These findings demonstrate the extreme transcriptional heterogeneity of CAFs and its determination by apposition to tumor. Selective targeting of tumor-proximal subsets, potentially combined with HIF-1α inhibition and immune stimulation, may offer a multi-modal therapeutic approach for this disease.
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Affiliation(s)
- Wayne Croft
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
- Centre for Computational Biology, University of BirminghamBirminghamUnited Kingdom
| | - Hayden Pearce
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Sandra Margielewska-Davies
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Lindsay Lim
- Cancer Research Horizons, The Francis Crick InstituteLondonUnited Kingdom
| | - Samantha M Nicol
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Fouzia Zayou
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Daniel Blakeway
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Francesca Marcon
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Sarah Powell-Brett
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Brinder Mahon
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Reena Merard
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Jianmin Zuo
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
| | - Gary Middleton
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Keith Roberts
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Rachel M Brown
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
| | - Paul Moss
- Institute of Immunology and Immunotherapy, College of Medical and Dental Sciences, University of BirminghamBirminghamUnited Kingdom
- University Hospitals Birmingham NHS Foundation Trust, Queen Elizabeth Hospital BirminghamBirminghamUnited Kingdom
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11
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Rehabilitation Training Can Significantly Increase the Serum IL-11 Levels and Improve the Prognosis in Ischemic Stroke Patients. Mediators Inflamm 2023; 2023:1865760. [PMID: 36875689 PMCID: PMC9977548 DOI: 10.1155/2023/1865760] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Revised: 10/26/2022] [Accepted: 11/24/2022] [Indexed: 02/24/2023] Open
Abstract
We aimed to explore the expression of IL-11 in ischemic stroke patients and its correlation with rehabilitation training and prognosis. The present randomized control study recruited ischemic stroke patients who were admitted during March 2014 to November 2020. All patients underwent computer tomography (CT) and magnetic resonance imaging (MRI) examination. All patients were randomly divided into two groups, including rehabilitation training (RT) group and control group. The patients in the RT group were received rehabilitation training within 2 days after the vital signs were stable while control group received routine nursing. The serum interleukin- (IL-) 11 levels were measured by enzyme-linked immunosorbent assay (ELISA) when patients were just hospitalized and 6 h, 24 h, 48 h, 72 h, and 90 h after treatment. Demographic, clinical statistics, imaging data, and the National Institutes of Health Stroke Scores (NIHSS) were recorded. The modified Rankin Scale (mRS) scores were measured after 90 days treatment to assess the prognosis of ischemic patients. The serum IL-11 levels of the RT group elevated more quickly during the study time compared with the control group. In addition, the NIHSS and mRS scores of ischemic stroke patients in the RT group were significantly lower than that in the control group. The NIHSS score, the proportion receiving rehabilitation training, and the levels of IL-11, triglyceride (TG), and high-density leptin cholesterol (HDLC) of ischemic stroke patients in the mRS score ≥ 3 group were remarkably elevated than that in the mRS score ≤ 2 group. However, the serum IL-11 levels of ischemic stroke patients were obviously decreased in the mRS score ≥ 3 group. IL-11 could be a potential diagnostic biomarker of poor prognosis of ischemic stroke patients. Furthermore, IL-11, NIHSS score, and rehabilitation training were the risk factors for poor prognosis of ischemic stroke patients. This study demonstrated that the ischemic stroke patients in the RT group had higher serum IL-11 levels and better prognosis. This study might provide a new approach to improve the prognosis of patients with ischemic stroke. This trial is registered with ChiCTR-PNR-16007706.
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12
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Inflammatory Cytokines and Radiotherapy in Pancreatic Ductal Adenocarcinoma. Biomedicines 2022; 10:biomedicines10123215. [PMID: 36551971 PMCID: PMC9775272 DOI: 10.3390/biomedicines10123215] [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: 11/16/2022] [Revised: 12/06/2022] [Accepted: 12/08/2022] [Indexed: 12/14/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) remains a therapeutic challenge in clinical oncology. Surgery is the only potentially curative treatment. However, the majority of PDAC patients present with locally advanced/unresectable or metastatic disease, where palliative multiagent chemotherapy is the first-line treatment with the therapeutic intent to delay progression and prolong survival. For locally advanced/unresectable pancreatic cancer patients who are treated with chemotherapy, consolidative radiotherapy in the form concurrent chemoradiation or stereotactic ablative radiotherapy improves locoregional control and pain/symptom control. To improve clinical outcomes of PDAC patients, there is a dire need for discoveries that will shed more light on the pathophysiology of the disease and lead to the development of more efficacious treatment strategies. Inflammatory cytokines are known to play a role in mediating tumor progression, chemoresistance, and radioresistance in PDAC. A PubMed search on published articles related to radiotherapy, inflammatory cytokines, and pancreatic cancer patients in the English language was performed. This article primarily focuses on reviewing the clinical literature that examines the association of inflammatory cytokines with clinical outcomes and the effects of radiotherapy on inflammatory cytokines in PDAC patients.
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13
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van der Sijde F, Dik WA, Mustafa DAM, Vietsch EE, Besselink MG, Debets R, Koerkamp BG, Haberkorn BCM, Homs MYV, Janssen QP, Luelmo SAC, Mekenkamp LJM, Oostvogels AAM, Smits-te Nijenhuis MAW, Wilmink JW, van Eijck CHJ, the Dutch Pancreatic Cancer Group. Serum cytokine levels are associated with tumor progression during FOLFIRINOX chemotherapy and overall survival in pancreatic cancer patients. Front Immunol 2022; 13:898498. [PMID: 36091056 PMCID: PMC9454314 DOI: 10.3389/fimmu.2022.898498] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2022] [Accepted: 07/26/2022] [Indexed: 11/13/2022] Open
Abstract
BackgroundBiomarkers predicting treatment response may be used to stratify patients with pancreatic ductal adenocarcinoma (PDAC) for available therapies. The aim of this study was to evaluate the association of circulating cytokines with FOLFIRINOX response and with overall survival (OS).MethodsSerum samples were collected before start and after the first cycle of FOLFIRINOX from patients with PDAC (n=83) of all disease stages. Overall, 34 circulating cytokines were analyzed with a multiplex immunoassay. In addition, changes in peripheral blood immune cell counts were determined by flow cytometry to correlate with differences in cytokine levels. Chemotherapy response was determined by CT scans with the RECIST 1.1 criteria, as disease control (n=64) or progressive disease (n=19) within eight cycles of FOLFIRINOX.ResultsPatients with high serum IL-1RA concentrations after one cycle of chemotherapy were less likely to have tumor progression during FOLFIRINOX (OR 0.25, P=0.040). Increase of circulating IL-1RA concentrations correlated with increase of total, classical (CD14+CD16-), and non-classical monocytes (CD14-CD16+), and dendritic cells. In multivariable cox regression, including the variables chemotherapy response outcome and baseline CA19-9 level, serum concentrations of IL-7 (HR 2.14, P=0.010), IL-18 (HR 2.00, P=0.020), and MIP-1β (HR 0.51, P=0.025) after one cycle of FOLFIRINOX showed correlations with OS.ConclusionsCirculating IL-1RA, IL-7, IL-18, and MIP-1β concentrations are biomarkers associated with FOLFIRINOX response in PDAC patients, suggesting an important role for specific immune cells in chemotherapy response and PDAC progression. Cytokine-based treatment might improve patient outcome and should be evaluated in future studies.
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Affiliation(s)
- Fleur van der Sijde
- Erasmus MC Cancer Institute, Department of Surgery, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Willem A. Dik
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Dana A. M. Mustafa
- Tumor Immuno-Pathology Laboratory, Department of Pathology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Eveline E. Vietsch
- Erasmus MC Cancer Institute, Department of Surgery, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Marc G. Besselink
- Cancer Center Amsterdam, Department of Surgery, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Reno Debets
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Bas Groot Koerkamp
- Erasmus MC Cancer Institute, Department of Surgery, University Medical Center Rotterdam, Rotterdam, Netherlands
| | | | - Marjolein Y. V. Homs
- Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Quisette P. Janssen
- Erasmus MC Cancer Institute, Department of Surgery, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Saskia A. C. Luelmo
- Department of Medical Oncology, Leiden University Medical Center, Leiden, Netherlands
| | | | - Astrid A. M. Oostvogels
- Laboratory of Tumor Immunology, Department of Medical Oncology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Marja A. W. Smits-te Nijenhuis
- Laboratory of Medical Immunology, Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, Netherlands
| | - Johanna W. Wilmink
- Cancer Center Amsterdam, Department of Medical Oncology, Amsterdam UMC, University of Amsterdam, Amsterdam, Netherlands
| | - Casper H. J. van Eijck
- Erasmus MC Cancer Institute, Department of Surgery, University Medical Center Rotterdam, Rotterdam, Netherlands
- *Correspondence: Casper H. J. van Eijck,
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14
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Leung JH, Ng B, Lim WW. Interleukin-11: A Potential Biomarker and Molecular Therapeutic Target in Non-Small Cell Lung Cancer. Cells 2022; 11:cells11142257. [PMID: 35883698 PMCID: PMC9318853 DOI: 10.3390/cells11142257] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/22/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 02/01/2023] Open
Abstract
Non-small cell lung cancer (NSCLC) accounts for 85% of lung cancer and is a fast progressive disease when left untreated. Identification of potential biomarkers in NSCLC is an ongoing area of research that aims to detect, diagnose, and prognosticate patients early to optimize treatment. We review the role of interleukin-11 (IL11), a stromal-cell derived pleiotropic cytokine with profibrotic and cellular remodeling properties, as a potential biomarker in NSCLC. This review identifies the need for biomarkers in NSCLC, the potential sources of IL11, and summarizes the available information leveraging upon published literature, publicly available datasets, and online tools. We identify accumulating evidence suggesting IL11 to be a potential biomarker in NSCLC patients. Further in-depth studies into the pathophysiological effects of IL11 on stromal-tumor interaction in NSCLC are warranted and current available literature highlights the potential value of IL11 detection as a diagnostic and prognostic biomarker in NSCLC.
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Affiliation(s)
- Jason Hongting Leung
- Department of Cardiothoracic Surgery, National Heart Center Singapore, Singapore 169609, Singapore
- Correspondence:
| | - Benjamin Ng
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609, Singapore; (B.N.); (W.-W.L.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169609, Singapore
| | - Wei-Wen Lim
- National Heart Research Institute Singapore, National Heart Center Singapore, Singapore 169609, Singapore; (B.N.); (W.-W.L.)
- Cardiovascular and Metabolic Disorders Program, Duke-National University of Singapore Medical School, Singapore 169609, Singapore
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15
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Majumder S, Shivaji UN, Kasturi R, Sigamani A, Ghosh S, Iacucci M. Inflammatory bowel disease-related colorectal cancer: Past, present and future perspectives. World J Gastrointest Oncol 2022; 14:547-567. [PMID: 35321275 PMCID: PMC8919014 DOI: 10.4251/wjgo.v14.i3.547] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/15/2021] [Revised: 04/21/2021] [Accepted: 02/27/2022] [Indexed: 02/06/2023] Open
Abstract
Inflammatory bowel disease-related colorectal cancer (IBD-CRC) is one of the most serious complications of IBD contributing to significant mortality in this cohort of patients. IBD is often associated with diet and lifestyle-related gut microbial dysbiosis, the interaction of genetic and environmental factors, leading to chronic gut inflammation. According to the “common ground hypothesis”, microbial dysbiosis and intestinal barrier impairment are at the core of the chronic inflammatory process associated with IBD-CRC. Among the many underlying factors known to increase the risk of IBD-CRC, perhaps the most important factor is chronic persistent inflammation. The persistent inflammation in the colon results in increased proliferation of cells necessary for repair but this also increases the risk of dysplastic changes due to chromosomal and microsatellite instability. Multiple pathways have been identified, regulated by many positive and negative factors involved in the development of cancer, which in this case follows the ‘inflammation-dysplasia-carcinoma’ sequence. Strategies to lower this risk are extremely important to reduce morbidity and mortality due to IBD-CRC, among which colonoscopic surveillance is the most widely accepted and implemented modality, forming part of many national and international guidelines. However, the effectiveness of surveillance in IBD has been a topic of much debate in recent years for multiple reasons — cost-benefit to health systems, resource requirements, and also because of studies showing conflicting long-term data. Our review provides a comprehensive overview of past, present, and future perspectives of IBD-CRC. We explore and analyse evidence from studies over decades and current best practices followed globally. In the future directions section, we cover emerging novel endoscopic techniques and artificial intelligence that could play an important role in managing the risk of IBD-CRC.
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Affiliation(s)
- Snehali Majumder
- Department of Clinical Research, Narayana Health, Bangalore 560099, Karnataka, India
| | - Uday Nagesh Shivaji
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Rangarajan Kasturi
- Department of Gastroenterology, Narayana Health, Bangalore 560099, India
| | - Alben Sigamani
- Department of Clinical Research, Narayana Health, Bangalore 560099, Karnataka, India
| | - Subrata Ghosh
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
| | - Marietta Iacucci
- National Institute for Health Research Birmingham Biomedical Research Centre, University Hospitals Birmingham, Birmingham B15 2TH, United Kingdom
- Institute of Immunology and Immunotherapy, University of Birmingham, Birmingham B15 2TH, United Kingdom
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16
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Kazakov AS, Sokolov AS, Permyakova ME, Litus EA, Uversky VN, Permyakov EA, Permyakov SE. Specific cytokines of interleukin-6 family interact with S100 proteins. Cell Calcium 2021; 101:102520. [PMID: 34933172 DOI: 10.1016/j.ceca.2021.102520] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/18/2021] [Revised: 12/10/2021] [Accepted: 12/12/2021] [Indexed: 02/07/2023]
Abstract
Cytokines of interleukin-6 (IL-6) family are important signaling proteins involved in various physiological and pathological processes. Earlier, we described interactions between IL-11 and S100P/B proteins from the family of S100 proteins engaged in the pathogenesis of numerous diseases. We probed here interactions between seven IL-6 family cytokines (IL-6, IL-11, OSM, LIF, CNTF, CT-1, and CLCF1) and fourteen S100 proteins (S100A1/A4/A6/A7/A8/A9/A10/A11/A12/A13/A14/A15/B/P). Surface plasmon resonance spectroscopy revealed formation of calcium-dependent complexes between IL-11, OSM, CNTF, CT-1, and CLCF1 and distinct subsets of S100A1/A6/B/P proteins with equilibrium dissociation constants of 19 nM - 12 µM. The existence of a network of interactions between Ca2+-loaded S100 proteins and IL-6 family cytokines suggest regulation of these cytokines by the extracellular forms of S100 proteins.
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Affiliation(s)
- Alexey S Kazakov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, Pushchino, Moscow region 142290 Russia
| | - Andrey S Sokolov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, Pushchino, Moscow region 142290 Russia
| | - Maria E Permyakova
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, Pushchino, Moscow region 142290 Russia
| | - Ekaterina A Litus
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, Pushchino, Moscow region 142290 Russia
| | - Vladimir N Uversky
- Department of Molecular Medicine and Byrd Alzheimer's Research Institute, Morsani College of Medicine, University of South Florida, 12901 Bruce B. Downs Blvd., Tampa, FL MDC07, USA.
| | - Eugene A Permyakov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, Pushchino, Moscow region 142290 Russia
| | - Sergei E Permyakov
- Institute for Biological Instrumentation, Pushchino Scientific Center for Biological Research of the Russian Academy of Sciences, Institutskaya str., 7, Pushchino, Moscow region 142290 Russia.
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17
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Fan T, Pan S, Yang S, Hao B, Zhang L, Li D, Geng Q. Clinical Significance and Immunologic Landscape of a Five-IL(R)-Based Signature in Lung Adenocarcinoma. Front Immunol 2021; 12:693062. [PMID: 34497605 PMCID: PMC8419226 DOI: 10.3389/fimmu.2021.693062] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2021] [Accepted: 08/03/2021] [Indexed: 01/05/2023] Open
Abstract
Interleukins (ILs) and interleukin receptors (ILRs) play important role in the antitumor immune response. However, the expression signature and clinical characteristics of the IL(R) family in lung adenocarcinoma (LUAD) remains unclear. The main purpose of this study was to explore the expression profile of IL(R) family genes and construct an IL(R)-based prognostic signature in LUAD. Five public datasets of 1,312 patients with LUAD were enrolled in this study. Samples from The Cancer Genome Atlas (TCGA) were used as the training set, and samples from the other four cohorts extracted from Gene Expression Omnibus (GEO) database were used as the validation set. Additionally, the profile of IL(R) family signature was explored, and the association between this signature and immunotherapy response was also analyzed. Meanwhile, the prognostic value was compared between this IL(R)-based signature and different immunotherapy markers. A signature based on five identified IL(R)s (IL7R, IL5RA, IL20RB, IL11, IL22RA1) was constructed using the TCGA dataset through univariate/multivariable Cox proportional hazards regression and least absolute shrinkage and selection operator (LASSO) Cox analysis. These cases with LUAD were stratified into high- and low-risk group according to the risk score. This signature showed a strong prognostic ability, which was verified by the five independent cohorts and clinical subtypes. The IL(R)-based models presented unique characteristics in terms of immune cell infiltration and immune inflammation profile in tumor microenvironment (TME). Biological pathway analysis confirmed that high-risk patients showed significant T- and B-cell immunosuppression and rapid tumor cell proliferation. More importantly, we researched the relationship between this IL(R)-based signature and immune checkpoints, tumor mutation burden (TMB), tumor purity and ploidy, and tumor immune dysfunction and exclusion (TIDE) score, which confirmed that this signature gave the best prognostic value. We first provided a robust prognostic IL(R)-based signature, which had the potential as a predictor for immunotherapy response to realize individualized treatment of LUAD.
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Affiliation(s)
- Tao Fan
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shize Pan
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Shuo Yang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan, China
| | - Bo Hao
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Lin Zhang
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Donghang Li
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
| | - Qing Geng
- Department of Thoracic Surgery, Renmin Hospital of Wuhan University, Wuhan, China
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18
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van der Sijde F, Mustafa DAM, Vietsch EE, Katsikis PD, van Eijck CHJ. Circulating Immunological Biomarkers: Prognosis of Pancreatic Cancer Patients Reflected by the Immune System. Pancreas 2021; 50:933-941. [PMID: 34643608 DOI: 10.1097/mpa.0000000000001862] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/26/2022]
Abstract
ABSTRACT To date, little advances have been made toward new and more effective therapies for pancreatic ductal adenocarcinoma (PDAC). Discovery of prognostic and predictive biomarkers is needed to stratify patients for available treatments and to elucidate how new therapies could be developed. Recent studies have made clear that the immune system is not only affected in the microenvironment of the primary tumor and it is also systemically disrupted in PDAC patients. Under normal circumstances, the immune system is in perfect balance with both proinflammatory and anti-inflammatory components present. In this review, we focus on circulating immunological characteristics including immune cells and their subtypes, cytokines, and immune checkpoints in the peripheral blood not only to understand the poor prognosis of PDAC patients but also to find new leads for new innovative therapies.
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Affiliation(s)
| | | | | | - Peter D Katsikis
- Department of Immunology, Erasmus MC, University Medical Center Rotterdam, Rotterdam, the Netherlands
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19
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O'Neill RS, Stoita A. Biomarkers in the diagnosis of pancreatic cancer: Are we closer to finding the golden ticket? World J Gastroenterol 2021; 27:4045-4087. [PMID: 34326612 PMCID: PMC8311531 DOI: 10.3748/wjg.v27.i26.4045] [Citation(s) in RCA: 51] [Impact Index Per Article: 12.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/26/2021] [Revised: 03/24/2021] [Accepted: 06/15/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) is a leading cause of cancer related mortality on a global scale. The disease itself is associated with a dismal prognosis, partly due to its silent nature resulting in patients presenting with advanced disease at the time of diagnosis. To combat this, there has been an explosion in the last decade of potential candidate biomarkers in the research setting in the hope that a diagnostic biomarker may provide a glimmer of hope in what is otherwise quite a substantial clinical dilemma. Currently, serum carbohydrate antigen 19-9 is utilized in the diagnostic work-up of patients diagnosed with PC however this biomarker lacks the sensitivity and specificity associated with a gold-standard marker. In the search for a biomarker that is both sensitive and specific for the diagnosis of PC, there has been a paradigm shift towards a focus on liquid biopsy and the use of diagnostic panels which has subsequently proved to have efficacy in the diagnosis of PC. Currently, promising developments in the field of early detection on PC using diagnostic biomarkers include the detection of microRNA (miRNA) in serum and circulating tumour cells. Both these modalities, although in their infancy and yet to be widely accepted into routine clinical practice, possess merit in the early detection of PC. We reviewed over 300 biomarkers with the aim to provide an in-depth summary of the current state-of-play regarding diagnostic biomarkers in PC (serum, urinary, salivary, faecal, pancreatic juice and biliary fluid).
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Affiliation(s)
- Robert S O'Neill
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St George and Sutherland Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
| | - Alina Stoita
- Department of Gastroenterology, St Vincent's Hospital Sydney, Sydney 2010, Australia
- St Vincent’s Clinical School, Faculty of Medicine, University of New South Wales, Sydney 2010, Australia
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Maroni P, Bendinelli P, Ferraretto A, Lombardi G. Interleukin 11 (IL-11): Role(s) in Breast Cancer Bone Metastases. Biomedicines 2021; 9:biomedicines9060659. [PMID: 34201209 PMCID: PMC8228851 DOI: 10.3390/biomedicines9060659] [Citation(s) in RCA: 18] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/13/2021] [Revised: 06/04/2021] [Accepted: 06/05/2021] [Indexed: 12/11/2022] Open
Abstract
Bone metastases represent the main problem related to the progression of breast cancer, as they are the main cause of death for these patients. Unfortunately, to date, bone metastases are incurable and represent the main challenge for the researcher. Chemokines and cytokines affect different stages of the metastatic process, and in bone metastases, interleukin (IL) -6, IL-8, IL-1β, and IL-11 participate in the interaction between cancer cells and bone cells. This review focuses on IL-11, a pleiotropic cytokine that, in addition to its well-known effects on several tissues, also mediates certain signals in cancer cells. In particular, as IL-11 works on bone remodeling, it plays a relevant role in the osteolytic vicious cycle of bone resorption and tumour growth, which characterizes bone metastasis. IL-11 appears as a candidate for anti-metastatic therapy. Even if different therapeutic approaches have considered IL-11 and the downstream-activated gp130 signaling pathways activated downstream of gp130, further studies are needed to decipher the contribution of the different cytokines and their mechanisms of action in breast cancer progression to define therapeutic strategies.
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Affiliation(s)
- Paola Maroni
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Correspondence: ; Tel.: +39-02-6621-4759
| | - Paola Bendinelli
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, 20133 Milano, Italy;
| | - Anita Ferraretto
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Dipartimento di Scienze Biomediche per la Salute, Università degli Studi di Milano, Via L. Mangiagalli 31, 20133 Milano, Italy;
| | - Giovanni Lombardi
- Laboratory of Experimental Biochemistry & Molecular Biology, IRCCS Istituto Ortopedico Galeazzi, Via R. Galeazzi 4, 20161 Milano, Italy; (A.F.); or (G.L.)
- Department of Athletics, Strength and Conditioning, Poznań University of Physical Education, Królowej Jadwigi 27/39, 61-871 Poznań, Poland
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Non-Invasive Biomarkers for Earlier Detection of Pancreatic Cancer-A Comprehensive Review. Cancers (Basel) 2021; 13:cancers13112722. [PMID: 34072842 PMCID: PMC8198035 DOI: 10.3390/cancers13112722] [Citation(s) in RCA: 19] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2021] [Revised: 05/20/2021] [Accepted: 05/27/2021] [Indexed: 12/24/2022] Open
Abstract
Simple Summary Pancreatic ductal adenocarcinoma (PDAC), which represents approximately 90% of all pancreatic cancers, is an extremely aggressive and lethal disease. It is considered a silent killer due to a largely asymptomatic course and late clinical presentation. Earlier detection of the disease would likely have a great impact on changing the currently poor survival figures for this malignancy. In this comprehensive review, we assessed over 4000 reports on non-invasive PDAC biomarkers in the last decade. Applying the Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool, we selected and reviewed in more detail 49 relevant studies reporting on the most promising candidate biomarkers. In addition, we also highlight the present challenges and complexities of translating novel biomarkers into clinical use. Abstract Pancreatic ductal adenocarcinoma (PDAC) carries a deadly diagnosis, due in large part to delayed presentation when the disease is already at an advanced stage. CA19-9 is currently the most commonly utilized biomarker for PDAC; however, it lacks the necessary accuracy to detect precursor lesions or stage I PDAC. Novel biomarkers that could detect this malignancy with improved sensitivity (SN) and specificity (SP) would likely result in more curative resections and more effective therapeutic interventions, changing thus the present dismal survival figures. The aim of this study was to systematically and comprehensively review the scientific literature on non-invasive biomarkers in biofluids such as blood, urine and saliva that were attempting earlier PDAC detection. The search performed covered a period of 10 years (January 2010—August 2020). Data were extracted using keywords search in the three databases: MEDLINE, Web of Science and Embase. The Quality Assessment of Diagnostic Accuracy Studies (QUADAS-2) tool was applied for study selection based on establishing the risk of bias and applicability concerns in Patient Selection, Index test (biomarker assay) and Reference Standard (standard-of-care diagnostic test). Out of initially over 4000 published reports, 49 relevant studies were selected and reviewed in more detail. In addition, we discuss the present challenges and complexities in the path of translating the discovered biomarkers into the clinical setting. Our systematic review highlighted several promising biomarkers that could, either alone or in combination with CA19-9, potentially improve earlier detection of PDAC. Overall, reviewed biomarker studies should aim to improve methodological and reporting quality, and novel candidate biomarkers should be investigated further in order to demonstrate their clinical usefulness. However, challenges and complexities in the path of translating the discovered biomarkers from the research laboratory to the clinical setting remain and would have to be addressed before a more realistic breakthrough in earlier detection of PDAC is achieved.
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Emerging roles for the IL-6 family of cytokines in pancreatic cancer. Clin Sci (Lond) 2020; 134:2091-2115. [PMID: 32808663 PMCID: PMC7434989 DOI: 10.1042/cs20191211] [Citation(s) in RCA: 71] [Impact Index Per Article: 14.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 07/29/2020] [Accepted: 08/07/2020] [Indexed: 12/13/2022]
Abstract
Pancreatic cancer has one of the poorest prognoses of all malignancies, with little improvement in clinical outcome over the past 40 years. Pancreatic ductal adenocarcinoma is responsible for the vast majority of pancreatic cancer cases, and is characterised by the presence of a dense stroma that impacts therapeutic efficacy and drives pro-tumorigenic programs. More specifically, the inflammatory nature of the tumour microenvironment is thought to underlie the loss of anti-tumour immunity and development of resistance to current treatments. Inflammatory pathways are largely mediated by the expression of, and signalling through, cytokines, chemokines, and other cellular messengers. In recent years, there has been much attention focused on dual targeting of cancer cells and the tumour microenvironment. Here we review our current understanding of the role of IL-6, and the broader IL-6 cytokine family, in pancreatic cancer, including their contribution to pancreatic inflammation and various roles in pancreatic cancer pathogenesis. We also summarise potential opportunities for therapeutic targeting of these pathways as an avenue towards combating poor patient outcomes.
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Zhang WH, Wang WQ, Han X, Gao HL, Li TJ, Xu SS, Li S, Xu HX, Li H, Ye LY, Lin X, Wu CT, Long J, Yu XJ, Liu L. Advances on diagnostic biomarkers of pancreatic ductal adenocarcinoma: A systems biology perspective. Comput Struct Biotechnol J 2020; 18:3606-3614. [PMID: 33304458 PMCID: PMC7710502 DOI: 10.1016/j.csbj.2020.11.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/26/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.
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Affiliation(s)
- Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Han
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuai-Shuai Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Long-Yun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Lin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Long
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Pountos I, Walters G, Panteli M, Einhorn TA, Giannoudis PV. Inflammatory Profile and Osteogenic Potential of Fracture Haematoma in Humans. J Clin Med 2019; 9:jcm9010047. [PMID: 31878248 PMCID: PMC7019316 DOI: 10.3390/jcm9010047] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/23/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/15/2022] Open
Abstract
Fracture haematoma forms immediately after fracture and is considered essential for the bone healing process. Its molecular composition has been briefly investigated with our current understanding being based on animal studies. This study aims to analyse the inflammatory cytokine content of fracture haematoma in humans and determine its effect on osteoprogenitor cells. Twenty-three patients were recruited following informed consent. Peripheral blood, fracture haematoma and bone were collected. A Luminex assay on the levels of 34 cytokines was performed and autologous peripheral blood samples served as control. Mesenchymal Stem Cells (MSCs) were isolated following collagenase digestion and functional assays were performed. Gene expression analysis of 84 key osteogenic molecules was performed. Thirty-three inflammatory cytokines were found to be significantly raised in fracture haematoma when compared to peripheral serum (p < 0.05). Amongst the most raised molecules were IL-8, IL-11 and MMP1, -2 and -3. Fracture haematoma did not significantly affect MSC proliferation, but ALP activity and calcium deposition were significantly increased in the MSCs undergoing osteogenic differentiation. Medium supplementations with fracture haematoma resulted in a statistically significant upregulation of osteogenic genes including the EGF, FGF2 and VEGFA. This seems to be the pathway involved in the osteogenic effect of fracture haematoma on bone cells. In conclusion, fracture haematoma is found to be a medium rich in inflammatory and immunomodulatory mediators. At the same time, it contains high levels of anti-inflammatory molecules, regulates osteoclastogenesis, induces angiogenesis and the production of the extracellular matrix. It appears that fracture haematoma does not affect osteoprogenitor cells proliferation as previously thought, but induces an osteogenic phenotype.
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Affiliation(s)
- Ippokratis Pountos
- Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds LS 2 9JT, UK; (G.W.); (M.P.); (P.V.G.)
- Correspondence: ; Tel.: +44-113-3922750
| | - Gavin Walters
- Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds LS 2 9JT, UK; (G.W.); (M.P.); (P.V.G.)
| | - Michalis Panteli
- Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds LS 2 9JT, UK; (G.W.); (M.P.); (P.V.G.)
| | - Thomas A. Einhorn
- Department of Orthopaedic Surgery, NYU Langone Health, New York, NY 10016, USA;
| | - Peter V. Giannoudis
- Academic Department of Trauma & Orthopaedics, School of Medicine, University of Leeds, Leeds LS 2 9JT, UK; (G.W.); (M.P.); (P.V.G.)
- NIHR Leeds Biomedical Research Center, Chapel Allerton Hospital, LS7 4SA Leeds, West Yorkshire, Leeds LS7 4SA, UK
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Ansari D, Torén W, Zhou Q, Hu D, Andersson R. Proteomic and genomic profiling of pancreatic cancer. Cell Biol Toxicol 2019; 35:333-343. [PMID: 30771135 PMCID: PMC6757097 DOI: 10.1007/s10565-019-09465-9] [Citation(s) in RCA: 32] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2018] [Accepted: 02/05/2019] [Indexed: 02/06/2023]
Abstract
Pancreatic cancer remains the most fatal human tumor type. The aggressive tumor biology coupled with the lack of early detection strategies and effective treatment are major reasons for the poor survival rate. Collaborative research efforts have been devoted to understand pancreatic cancer at the molecular level. Large-scale genomic studies have generated important insights into the genetic drivers of pancreatic cancer. In the post-genomic era, protein sequencing of tumor tissue, cell lines, pancreatic juice, and blood from patients with pancreatic cancer has provided a fundament for the development of new diagnostic and prognostic biomarkers. The integration of mass spectrometry and genomic sequencing strategies may help characterize protein identities and post-translational modifications that relate to a specific mutation. Consequently, proteomic and genomic techniques have become a compulsory requirement in modern medicine and health care. These types of proteogenomic studies may usher in a new era of precision diagnostics and treatment in patients with pancreatic cancer.
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Affiliation(s)
- Daniel Ansari
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden.
| | - William Torén
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
| | - Qimin Zhou
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
- School of Ophthalmology and Optometry, Eye Hospital, Wenzhou Medical University, Wenzhou, China
| | - Dingyuan Hu
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
- Department of Gastroenterology, The Second Affiliated Hospital and Yuying Children's Hospital of Wenzhou Medical University, Wenzhou, China
| | - Roland Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, SE-221 85, Lund, Sweden
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Gan J, Wang W, Yang Z, Pan J, Zheng L, Yin L. Prognostic value of pretreatment serum lactate dehydrogenase level in pancreatic cancer patients: A meta-analysis of 18 observational studies. Medicine (Baltimore) 2018; 97:e13151. [PMID: 30431587 PMCID: PMC6257391 DOI: 10.1097/md.0000000000013151] [Citation(s) in RCA: 22] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Several studies were conducted to investigate the prognostic value of pretreatment serum lactate dehydrogenase (LDH) level in pancreatic cancer (PC), but the results were inconsistent. This study aims to comprehensively assess the prognostic value of pretreatment serum LDH level in PC patients by combining the data of the published literatures on this topic. METHODS Embase, PubMed, and Web of Science were completely retrieved until June, 2018. The observational studies focusing on the prognostic value of pretreatment serum LDH level in PC patients were eligible. STATA version 12.0 was used to undertake the statistical analysis. RESULTS Eighteen studies with a total of 3345 patients were included in this meta-analysis. The meta-analysis was conducted to generate pooled hazard ratios (HRs) and 95% confidence interval (CI) for overall survival (OS). Our analysis results suggested that high serum LDH level predicted worse OS (HR 1.57, 95% CI 1.30-1.90, P < .001) in PC patients. Moreover, for patients with advanced PC, the prognostic relevance of pretreatment serum LDH level not only existed in those receiving palliative chemotherapy (HR 1.72, 95% CI 1.35-2.18, P < .001), but also in those who were precluded from chemotherapy (HR 1.91, 95% CI 1.4219-2.58, P < .001). CONCLUSION The meta-analysis results demonstrated that pretreatment serum LDH level is closely associated with OS, and it may be a useful biomarker for assessing the prognosis of PC patients.
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Xu Y, Ye J, Wang M, Wang Y, Ji Q, Huang Y, Zeng T, Wang Z, Ye D, Jiang H, Liu J, Lin Y, Wan J. Increased interleukin-11 levels in thoracic aorta and plasma from patients with acute thoracic aortic dissection. Clin Chim Acta 2018; 481:193-199. [PMID: 29555322 DOI: 10.1016/j.cca.2018.03.014] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2017] [Revised: 02/13/2018] [Accepted: 03/15/2018] [Indexed: 12/13/2022]
Abstract
BACKGROUND Interleukin (IL) 11 is closely related to tumor and hematological system diseases. Recent studies have demonstrated that IL-11 also participates in cardiovascular diseases, including ischemia-reperfusion mediated heart injury and acute myocardial infarction. This study aimed to investigate whether IL-11 is involved in acute thoracic aortic dissection (TAD). METHODS Aortic tissue samples from normal donors and acute TAD patients were collected, and the expression of IL-11 in all aortic tissue was analyzed. In addition, blood samples from patients with chest pain were collected and divided into a non-AD (NAD) group and a TAD group according to the results of computed tomography angiography of the thoracic aorta. The plasma IL-11, IL-17 and interferon (IFN) γ in all blood samples were measured. RESULTS Compared with aortic tissue of normal controls, IL-11 was significantly increased in aortic tissue of acute TAD patients, especially in the torn section. The IL-11 was derived from aorta macrophages in TAD. In addition, the plasma IL-11, IL-17 and IFN-γ were significantly higher in acute TAD patients than in NAD patients, and the correlation analysis showed that IL-11 levels were positively correlated with levels of IFN-γ, IL-17, glucose, systolic blood pressure, diastolic blood pressure, white blood cells, C-reactive proteins and D-dimers. Binary logistic regression analyses showed that elevated IL11 in patients who may have diagnostic value of TAD, but less that D-dimer. CONCLUSION IL-11 was increased in thoracic aorta and plasma of TAD patients and may be a promising biomarker for diagnosis in patients with TAD.
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Affiliation(s)
- Yao Xu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Jing Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Menglong Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Yuan Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Qingwei Ji
- Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China; Emergency & Critical Care Center, Beijing Anzhen Hospital, Capital Medical University, Beijing Institute of Heart, Lung, and Blood Vessel Diseases, Beijing 100029, China
| | - Ying Huang
- Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
| | - Tao Zeng
- Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China
| | - Zhen Wang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Di Ye
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Huimin Jiang
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Jianfang Liu
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China
| | - Yingzhong Lin
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Department of Cardiology, The People's Hospital of Guangxi Zhuang Autonomous Region, Nanning 530021, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
| | - Jun Wan
- Department of Cardiology, Renmin Hospital of Wuhan University, Wuhan 430060, China; Cardiovascular Research Institute, Wuhan University, Wuhan 430060, China; Hubei Key Laboratory of Cardiology, Wuhan 430060, China.
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Ma J, Song X, Xu X, Mou Y. Cancer-Associated Fibroblasts Promote the Chemo-resistance in Gastric Cancer through Secreting IL-11 Targeting JAK/STAT3/Bcl2 Pathway. Cancer Res Treat 2018; 51:194-210. [PMID: 29690750 PMCID: PMC6333970 DOI: 10.4143/crt.2018.031] [Citation(s) in RCA: 56] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/09/2018] [Accepted: 04/15/2018] [Indexed: 12/19/2022] Open
Abstract
Purpose Our aim was to detect the potential role of interleukin 11 (IL-11) in the development of chemo-resistance in gastric cancer and to reveal the mechanism involved in the process. Materials and Methods Here, we used flow cytometry to examine the percentage of cancer-associated-fibroblasts in tumor samples from chemo-resistant and -sensitive gastric cancer patients. Using MTT assay, we detected the cell viability under different conditions. Using quantitative real-time polymerase chain reaction and Western blotting, we determined the target expressions in mRNA and protein levels. We also performed immunohistochemistry and immunofluorescence to detect the target proteins under different conditions. Animal models were constructed to verify the potential role of IL-11 in chemo-resistant develop in vivo. Results Herein, we observed enriched cancer associated fibroblasts in drug resistant tumor tissues from gastric patients. Those fibroblasts facilitate the chemotherapeutic drugs resistance development through the secretion of IL-11, which activates the IL-11/IL-11R/gp130/JAK/STAT3 anti-apoptosis signaling pathway in gastric cancer cells. We found that the combination of chemotherapeutic drugs and JAK inhibitor overcomes the resistance and increases the survival of mice with gastric cancer xenografts. Conclusion Ourresults demonstrated that IL-11 contributed to the obtain ofresistance to chemotherapy drugs through gp130/JAK/STAT3/Bcl2 pathway, and targeting the IL-11 signaling pathway induced by fibroblasts might be a promising strategy to overcome the multi-drugs resistant cancer in clinic.
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Affiliation(s)
- Jun Ma
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China
| | - Xiao Song
- Department of General Surgery, Ningbo No. 2 Hospital, Ningbo, China
| | - Xiaowu Xu
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China
| | - Yiping Mou
- Department of Gastrointestinal and Pancreatic Surgery, Zhejiang Provincial People's Hospital, People's Hospital of Hangzhou Medical College, Hangzhou, China.,Key Laboratory of Gastroenterology of Zhejiang Province, Hangzhou, China
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IL-6 family cytokines: Key inflammatory mediators as biomarkers and potential therapeutic targets. Cytokine Growth Factor Rev 2018; 41:10-17. [PMID: 29699936 DOI: 10.1016/j.cytogfr.2018.04.004] [Citation(s) in RCA: 156] [Impact Index Per Article: 22.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2018] [Revised: 04/14/2018] [Accepted: 04/16/2018] [Indexed: 02/07/2023]
Abstract
IL-6 is a critical cytokine in acute phase response and involved in the pathogenesis of several chronic inflammatory diseases including cancer. Studies have highlighted that levels of IL-6 and its family members can be useful for diagnosis, prognosis of relapse-free survival and recurrence. IL-6 family cytokines have been identified as cancer biomarkers through screening of inflammatory mediators in different fluids including saliva, serum, and bronchoalveolar lavage fluid (BALF). IL-6 can be modulated by chemopreventive drugs, small molecules, monoclonal antibodies and immune checkpoint inhibitors. Unveiling the different sources of IL-6, the interaction between IL-6 and its cellular targets, the IL-6-dependent tumor resistance mechanisms, and the identification of novel regulators of IL-6 are some of the highly complex topics included in this review and their understanding could aid cancer biomarkers and therapy development.
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Jimenez-Luna C, Torres C, Ortiz R, Dieguez C, Martinez-Galan J, Melguizo C, Prados JC, Caba O. Proteomic biomarkers in body fluids associated with pancreatic cancer. Oncotarget 2018; 9:16573-16587. [PMID: 29662668 PMCID: PMC5893263 DOI: 10.18632/oncotarget.24654] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/23/2017] [Accepted: 02/25/2018] [Indexed: 12/12/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant disease that represents the fourth leading cancer-related death worldwide. There has been very little improvement in survival rates over recent years, and surgical resection remains the only reliable curative approach. Factors that contribute to this dismal prognosis for PC include its rapid progression and invasion, the absence of specific symptoms, and the little impact of available chemotherapy. Importantly, the management of this malignancy is also limited by the lack of highly specific and sensitive biomarkers for its diagnosis and follow-up, and their identification is therefore considered a promising strategy to improve outcomes in these patients. Numerous translational studies have explored the usefulness of body fluids as a non-invasive source of PC-specific biomarkers, and innovations in proteomic methods and technologies have provided a myriad of protein biomarkers for different cancers. The adoption of a proteomic approach has improved understanding of the biology of PC and contributed to the potential identification of protein biomarkers for this disease. This review considers the most recent research efforts to develop novel proteomic biomarkers in body fluids for PC.
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Affiliation(s)
- Cristina Jimenez-Luna
- Institute of Biopathology and Regenerative Medicine (IBIMER), Granada University, Granada, Spain
| | - Carolina Torres
- Department of Medicine, Division of Gastroenterology and Hepatology, University of Illinois at Chicago, Chicago, IL, USA
| | - Raul Ortiz
- Department of Health Sciences, Jaen University, Jaen, Spain
| | - Carmelo Dieguez
- Department of Gastroenterology, San Cecilio University Hospital, Granada, Spain
| | | | - Consolacion Melguizo
- Institute of Biopathology and Regenerative Medicine (IBIMER), Granada University, Granada, Spain
| | - Jose C. Prados
- Institute of Biopathology and Regenerative Medicine (IBIMER), Granada University, Granada, Spain
| | - Octavio Caba
- Department of Health Sciences, Jaen University, Jaen, Spain
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31
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Yu L, Wang S, Lin X, Lu Y, Gu P. MicroRNA-124a inhibits cell proliferation and migration in liver cancer by regulating interleukin-11. Mol Med Rep 2017; 17:3972-3978. [PMID: 29286137 DOI: 10.3892/mmr.2017.8348] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/26/2017] [Accepted: 12/12/2017] [Indexed: 11/05/2022] Open
Abstract
Liver cancer is the sixth most common malignant tumour and ranks in the top three cancers with regard to mortality due to metastasis and postsurgical recurrence. It is significant to understand the mechanisms underlying liver cancer for diagnosis and treatment. Cumulative evidence suggests that the abnormal regulation of microRNAs (miRNAs/miRs) may contribute to the development and metastasis of cancer. miR‑124a acts as a tumour suppressor in osteosarcoma, endometrial carcinoma, prostate cancer, and glioblastoma. However, the effects of miR‑124a in liver cancer and its biological mechanism are not fully understood. It has been demonstrated that miR‑124a is downregulated and interleukin (IL)‑11 is upregulated in the liver cancer tissues. In the present study, miR‑124a upregulation inhibited cell proliferation, migration and promoted cell apoptosis. Through a dual‑luciferase reporter assay, it was verified that IL‑11 is a direct target of miR‑124a. Furthermore, the overexpression of miR‑124a repressed the secretion of IL‑11 from hepatoma cells. Finally, it was identified that mimics of miR‑124a increased the expression of tissue inhibitor of matrix metalloproteinase‑2 (TIMP‑2) and Caspase‑3 and decreased the expression levels of matrix metalloproteinase 2 (MMP2), MMP9, B‑cell lymphoma 2, signal transducer and activator of transcription 3 (STAT3), and phosphorylated‑STAT3. In conclusion, the results indicated that miR‑124a has an important role as a tumour suppressor gene by targeting IL‑11. These findings may provide novel insights for clinical treatments to prevent the development of liver cancer.
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Affiliation(s)
- Liedao Yu
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Shuo Wang
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Xiangjin Lin
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Yang Lu
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
| | - Pengcheng Gu
- Department of Orthopedics Surgery, The First Affiliated Hospital of Zhejiang University, Hangzhou, Zhejiang 310006, P.R. China
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Bressy C, Lac S, Nigri J, Leca J, Roques J, Lavaut MN, Secq V, Guillaumond F, Bui TT, Pietrasz D, Granjeaud S, Bachet JB, Ouaissi M, Iovanna J, Vasseur S, Tomasini R. LIF Drives Neural Remodeling in Pancreatic Cancer and Offers a New Candidate Biomarker. Cancer Res 2017; 78:909-921. [PMID: 29269518 DOI: 10.1158/0008-5472.can-15-2790] [Citation(s) in RCA: 79] [Impact Index Per Article: 9.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2015] [Revised: 08/28/2017] [Accepted: 12/18/2017] [Indexed: 01/11/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is characterized by extensive stroma and pathogenic modifications to the peripheral nervous system that elevate metastatic capacity. In this study, we show that the IL6-related stem cell-promoting factor LIF supports PDAC-associated neural remodeling (PANR). LIF was overexpressed in tumor tissue compared with healthy pancreas, but its receptors LIFR and gp130 were expressed only in intratumoral nerves. Cancer cells and stromal cells in PDAC tissues both expressed LIF, but only stromal cells could secrete it. Biological investigations showed that LIF promoted the differentiation of glial nerve sheath Schwann cells and induced their migration by activating JAK/STAT3/AKT signaling. LIF also induced neuronal plasticity in dorsal root ganglia neurons by increasing the number of neurites and the soma area. Notably, injection of LIF-blocking antibody into PDAC-bearing mice reduced intratumoral nerve density, supporting a critical role for LIF function in PANR. In serum from human PDAC patients and mouse models of PDAC, we found that LIF titers positively correlated with intratumoral nerve density. Taken together, our findings suggest LIF as a candidate serum biomarker and diagnostic tool and a possible therapeutic target for limiting the impact of PANR in PDAC pathophysiology and metastatic progression.Significance: This study suggests a target to limit neural remodeling in pancreatic cancer, which contributes to poorer quality of life and heightened metastatic progression in patients. Cancer Res; 78(4); 909-21. ©2017 AACR.
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Affiliation(s)
- Christian Bressy
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Sophie Lac
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Jérémy Nigri
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Julie Leca
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Julie Roques
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Marie-Nöelle Lavaut
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.,Department of Pathology, Hospital North and Mediterranean University, Marseille, France
| | - Véronique Secq
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.,Department of Pathology, Hospital North and Mediterranean University, Marseille, France
| | - Fabienne Guillaumond
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Thi-Thien Bui
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Daniel Pietrasz
- INSERM UMRS 775, University PARIS DESCARTES, Paris, France.,Department of Hepatobiliary and Digestive Surgery, Groupe Hospitalier Pitié Salpêtrière, Paris, France
| | - Samuel Granjeaud
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Jean-Baptiste Bachet
- INSERM UMRS 775, University PARIS DESCARTES, Paris, France.,Department of Hepatobiliary and Digestive Surgery, Groupe Hospitalier Pitié Salpêtrière, Paris, France.,Department of Hepatogastroentérology, Groupe Hospitalier Pitié Salpêtrière, Paris, France
| | - Mehdi Ouaissi
- Aix-Marseille University, INSERM, CRO2, UMR 911, Marseille, France
| | - Juan Iovanna
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Sophie Vasseur
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France
| | - Richard Tomasini
- CRCM, INSERM, U1068; Paoli-Calmettes Institute; Aix-Marseille University, UM 105; CNRS, UMR7258, Marseille, France.
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33
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Lokau J, Agthe M, Flynn CM, Garbers C. Proteolytic control of Interleukin-11 and Interleukin-6 biology. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2017. [DOI: 10.1016/j.bbamcr.2017.06.008] [Citation(s) in RCA: 27] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
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Tao M, Liu L, Shen M, Zhi Q, Gong FR, Zhou BP, Wu Y, Liu H, Chen K, Shen B, Wu MY, Shou LM, Li W. Inflammatory stimuli promote growth and invasion of pancreatic cancer cells through NF-κB pathway dependent repression of PP2Ac. Cell Cycle 2016; 15:381-93. [PMID: 26761431 DOI: 10.1080/15384101.2015.1127468] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/17/2023] Open
Abstract
Previous studies have indicated that inflammatory stimulation represses protein phosphatase 2A (PP2A), a well-known tumor suppressor. However, whether PP2A repression participates in pancreatic cancer progression has not been verified. We used lipopolysaccharide (LPS) and macrophage-conditioned medium (MCM) to establish in vitro inflammation models, and investigated whether inflammatory stimuli affect pancreatic cancer cell growth and invasion PP2A catalytic subunit (PP2Ac)-dependently. Via nude mouse models of orthotopic tumor xenografts and dibutyltin dichloride (DBTC)-induced chronic pancreatitis, we evaluated the effect of an inflammatory microenvironment on PP2Ac expression in vivo. We cloned the PP2Acα and PP2Acβ isoform promoters to investigate the PP2Ac transcriptional regulation mechanisms. MCM accelerated pancreatic cancer cell growth; MCM and LPS promoted cell invasion. DBTC promoted xenograft growth and metastasis, induced tumor-associated macrophage infiltration, promoted angiogenesis, activated the nuclear factor-κB (NF-κB) pathway, and repressed PP2Ac expression. In vitro, LPS and MCM downregulated PP2Ac mRNA and protein. PP2Acα overexpression attenuated JNK, ERK, PKC, and IKK phosphorylation, and impaired LPS/MCM-stimulated cell invasion and MCM-promoted cell growth. LPS and MCM activated the NF-κB pathway in vitro. LPS and MCM induced IKK and IκB phosphorylation, leading to p65/RelA nuclear translocation and transcriptional activation. Overexpression of the dominant negative forms of IKKα attenuated LPS and MCM downregulation of PP2Ac, suggesting inflammatory stimuli repress PP2Ac expression NF-κB pathway-dependently. Luciferase reporter gene assay verified that LPS and MCM downregulated PP2Ac transcription through an NF-κB-dependent pathway. Our study presents a new mechanism in inflammation-driven cancer progression through NF-κB pathway-dependent PP2Ac repression.
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Affiliation(s)
- Min Tao
- a Department of Oncology , the First Affiliated Hospital of Soochow University , Suzhou , China.,b PREMED Key Laboratory for Precision Medicine, Soochow University , Suzhou , China.,c Jiangsu Institute of Clinical Immunology , Suzhou , China.,d Institute of Medical Biotechnology, Soochow University , Suzhou , China
| | - Lu Liu
- a Department of Oncology , the First Affiliated Hospital of Soochow University , Suzhou , China
| | - Meng Shen
- e Department of General Surgery , the First Affiliated Hospital of Soochow University , Suzhou , China
| | - Qiaoming Zhi
- e Department of General Surgery , the First Affiliated Hospital of Soochow University , Suzhou , China
| | - Fei-Ran Gong
- f Department of Hematology , the First Affiliated Hospital of Soochow University , Suzhou , China
| | - Binhua P Zhou
- g Markey Cancer Center, University of Kentucky College of Medicine , Lexington , KY , USA.,h Departments of Molecular and Cellular Biochemistry , University of Kentucky College of Medicine , Lexington , KY , USA
| | - Yadi Wu
- g Markey Cancer Center, University of Kentucky College of Medicine , Lexington , KY , USA.,i Molecular and Biomedical Pharmacology, University of Kentucky College of Medicine , Lexington , KY , USA
| | - Haiyan Liu
- j Laboratory of Cellular and Molecular Tumor Immunology, Institute of Biology and Medical Sciences, Soochow University , Suzhou , Jiangsu Province , China
| | - Kai Chen
- a Department of Oncology , the First Affiliated Hospital of Soochow University , Suzhou , China
| | - Bairong Shen
- k Center for Systems Biology, Soochow University , Suzhou , China
| | - Meng-Yao Wu
- a Department of Oncology , the First Affiliated Hospital of Soochow University , Suzhou , China
| | - Liu-Mei Shou
- a Department of Oncology , the First Affiliated Hospital of Soochow University , Suzhou , China.,l Department of Oncology , the First Affiliated Hospital of Zhejiang Chinese Medicine University , Hangzhou , China
| | - Wei Li
- a Department of Oncology , the First Affiliated Hospital of Soochow University , Suzhou , China.,b PREMED Key Laboratory for Precision Medicine, Soochow University , Suzhou , China.,c Jiangsu Institute of Clinical Immunology , Suzhou , China.,k Center for Systems Biology, Soochow University , Suzhou , China
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35
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Cancer-associated fibroblasts treated with cisplatin facilitates chemoresistance of lung adenocarcinoma through IL-11/IL-11R/STAT3 signaling pathway. Sci Rep 2016; 6:38408. [PMID: 27922075 PMCID: PMC5138853 DOI: 10.1038/srep38408] [Citation(s) in RCA: 106] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2016] [Accepted: 11/09/2016] [Indexed: 12/13/2022] Open
Abstract
Cancer-associated fibroblasts (CAF) are recognized as one of the key determinants in the malignant progression of lung adenocarcinoma. And its contributions to chemoresistance acquisition of lung cancer has raised more and more attention. In our study, cancer associated fibroblasts treated with cisplatin conferred chemoresistance to lung cancer cells. Meanwhile, Interleukin-11(IL-11) was significantly up-regulated in the CAF stimulated by cisplatin. As confirmed in lung adenocarcinoma cells in vivo and in vitro, IL-11 could protect cancer cells from cisplatin-induced apoptosis and thus promote their chemoresistance. Furthermore, it was also observed that IL-11 induced STAT3 phosphorylation and increased anti-apoptotic protein Bcl-2 and Survivin expression in cancer cells. The effect could be abrogated by suppressing STAT3 phosphorylation or silencing IL-11Rα expression in cancer cells. In conclusion, chemotherapy-induced IL-11 upregulation in CAF promotes lung adenocarcinoma cell chemoresistance by activating IL-11R/STAT3 anti-apoptotic signaling pathway.
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36
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Expression, Purification, and Characterization of Interleukin-11 Orthologues. Molecules 2016; 21:molecules21121632. [PMID: 27916836 PMCID: PMC6274577 DOI: 10.3390/molecules21121632] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/10/2016] [Revised: 11/22/2016] [Accepted: 11/24/2016] [Indexed: 11/17/2022] Open
Abstract
Interleukin-11 (IL-11) is a multifunctional cytokine implicated in several normal and pathological processes. The decoding of IL-11 function and development of IL-11-targeted drugs dictate the use of laboratory animals and need of the better understanding of species specificity of IL-11 signaling. Here, we present a method for the recombinant interleukin-11 (rIL-11) production from the important model animals, mouse and macaque. The purified mouse and macaque rIL-11 interact with extracellular domain of human IL-11 receptor subunit α and activate STAT3 signaling in HEK293 cells co-expressing human IL-11 receptors with efficacies resembling those of human rIL-11. Hence, the evolutionary divergence does not impair IL-11 signaling. Furthermore, compared to human rIL-11 its macaque orthologue is 8-fold more effective STAT3 activator, which favors its use for treatment of thrombocytopenia as a potent substitute for human rIL-11. Compared to IL-6, IL-11 signaling exhibits lower species specificity, likely due to less conserved intrinsic disorder propensity within IL-6 orthologues. The developed express method for preparation of functionally active macaque/mouse rIL-11 samples is suited for exploration of the molecular mechanisms underlying IL-11 action and for development of the drug candidates for therapy of oncologic/hematologic/inflammatory diseases related to IL-11 signaling.
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Permyakov EA, Uversky VN, Permyakov SE. Interleukin-11: A Multifunctional Cytokine with Intrinsically Disordered Regions. Cell Biochem Biophys 2016; 74:285-96. [DOI: 10.1007/s12013-016-0752-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/12/2016] [Accepted: 06/13/2016] [Indexed: 12/14/2022]
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38
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A panoramic review and in silico analysis of IL-11 structure and function. Cytokine Growth Factor Rev 2016; 32:41-61. [PMID: 27312790 DOI: 10.1016/j.cytogfr.2016.06.002] [Citation(s) in RCA: 50] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2016] [Revised: 05/21/2016] [Accepted: 06/03/2016] [Indexed: 12/15/2022]
Abstract
Human Interleukin (IL)-11 is a multifunctional cytokine, recognized for its thrombopoietic effects for more than two decades; clinically, IL-11 is used in the treatment of thrombocytopenia. IL-11 shares structural and functional similarities with IL-6, a related family member. In recent years, there has been a renewed interest in IL-11, because its distinct biological activities associated with cancers of epithelial origin and inflammatory disorders have been revealed. Although the crystal structure of IL-11 was resolved more than two years, a better understanding of the mechanisms of IL-11 action is required to further extend the clinical use of IL-11. This review will discuss the available structural, functional, and bioinformatics knowledge concerning IL-11 and will summarize its relationship with several diseases.
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Kazakov AS, Sokolov AS, Vologzhannikova AA, Permyakova ME, Khorn PA, Ismailov RG, Denessiouk KA, Denesyuk AI, Rastrygina VA, Baksheeva VE, Zernii EY, Zinchenko DV, Glazatov VV, Uversky VN, Mirzabekov TA, Permyakov EA, Permyakov SE. Interleukin-11 binds specific EF-hand proteins via their conserved structural motifs. J Biomol Struct Dyn 2016; 35:78-91. [PMID: 26726132 DOI: 10.1080/07391102.2015.1132392] [Citation(s) in RCA: 25] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Interleukin-11 (IL-11) is a hematopoietic cytokine engaged in numerous biological processes and validated as a target for treatment of various cancers. IL-11 contains intrinsically disordered regions that might recognize multiple targets. Recently we found that aside from IL-11RA and gp130 receptors, IL-11 interacts with calcium sensor protein S100P. Strict calcium dependence of this interaction suggests a possibility of IL-11 interaction with other calcium sensor proteins. Here we probed specificity of IL-11 to calcium-binding proteins of various types: calcium sensors of the EF-hand family (calmodulin, S100B and neuronal calcium sensors: recoverin, NCS-1, GCAP-1, GCAP-2), calcium buffers of the EF-hand family (S100G, oncomodulin), and a non-EF-hand calcium buffer (α-lactalbumin). A specific subset of the calcium sensor proteins (calmodulin, S100B, NCS-1, GCAP-1/2) exhibits metal-dependent binding of IL-11 with dissociation constants of 1-19 μM. These proteins share several amino acid residues belonging to conservative structural motifs of the EF-hand proteins, 'black' and 'gray' clusters. Replacements of the respective S100P residues by alanine drastically decrease its affinity to IL-11, suggesting their involvement into the association process. Secondary structure and accessibility of the hinge region of the EF-hand proteins studied are predicted to control specificity and selectivity of their binding to IL-11. The IL-11 interaction with the EF-hand proteins is expected to occur under numerous pathological conditions, accompanied by disintegration of plasma membrane and efflux of cellular components into the extracellular milieu.
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Affiliation(s)
- Alexei S Kazakov
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Andrei S Sokolov
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Alisa A Vologzhannikova
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Maria E Permyakova
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Polina A Khorn
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Ramis G Ismailov
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Konstantin A Denessiouk
- b Faculty of Science and Engineering , Åbo Akademi University , Biskopsgatan 8, Åbo 20500 , Finland
| | - Alexander I Denesyuk
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.,b Faculty of Science and Engineering , Åbo Akademi University , Biskopsgatan 8, Åbo 20500 , Finland
| | - Victoria A Rastrygina
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Viktoriia E Baksheeva
- c Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Leninskye Gory, House 1, Building 40, Moscow 119992 , Russia
| | - Evgeni Yu Zernii
- c Belozersky Institute of Physico-Chemical Biology, Lomonosov Moscow State University , Leninskye Gory, House 1, Building 40, Moscow 119992 , Russia
| | - Dmitry V Zinchenko
- d Branch of Shemyakin and Ovchinnikov , Institute of Bioorganic Chemistry of the Russian Academy of Sciences , Institutskaya str. 6, Pushchino, Moscow Region 142290 , Russia
| | | | - Vladimir N Uversky
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia.,f Department of Molecular Medicine and USF Health Byrd Alzheimer's Research Institute, Morsani College of Medicine , University of South Florida , Tampa , FL 33612 , USA
| | - Tajib A Mirzabekov
- g Antherix , Institutskaya str. 7, Pushchino, Moscow Region 142290 , Russia.,h Biomirex Inc. , 304 Pleasant Street, Watertown , MA 02472 , USA
| | - Eugene A Permyakov
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
| | - Sergei E Permyakov
- a Institute for Biological Instrumentation of the Russian Academy of Sciences , Institutskaya str., 7, Pushchino, Moscow Region 142290 , Russia
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40
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Kazakov AS, Sokolov AS, Rastrygina VA, Solovyev VV, Ismailov RG, Mikhailov RV, Ulitin AB, Yakovenko AR, Mirzabekov TA, Permyakov EA, Permyakov SE. High-affinity interaction between interleukin-11 and S100P protein. Biochem Biophys Res Commun 2015; 468:733-8. [DOI: 10.1016/j.bbrc.2015.11.024] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2015] [Accepted: 11/03/2015] [Indexed: 12/31/2022]
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41
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Cantharidin represses invasion of pancreatic cancer cells through accelerated degradation of MMP2 mRNA. Sci Rep 2015; 5:11836. [PMID: 26135631 PMCID: PMC4488834 DOI: 10.1038/srep11836] [Citation(s) in RCA: 31] [Impact Index Per Article: 3.1] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/14/2015] [Accepted: 05/22/2015] [Indexed: 12/22/2022] Open
Abstract
Cantharidin is an active constituent of mylabris, a traditional Chinese medicine, and is a potent and selective inhibitor of protein phosphatase 2A (PP2A) that plays an important role in cell cycle control, apoptosis, and cell-fate determination. In the present study, we found that cantharidin repressed the invasive ability of pancreatic cancer cells and downregulated matrix metalloproteinase 2 (MMP2) expression through multiple pathways, including ERK, JNK, PKC, NF-κB, and β-catenin. Interestingly, transcriptional activity of the MMP2 promoter increased after treatment with PP2A inhibitors, suggesting the involvement of a posttranscriptional mechanism. By using an mRNA stability assay, we found accelerated degradation of MMP2 mRNA after treatment of cantharidin. Microarray analyses revealed that multiple genes involved in the 3' → 5' decay pathway were upregulated, especially genes participating in cytoplasmic deadenylation. The elevation of these genes were further demonstrated to be executed through ERK, JNK, PKC, NF-κB, and β-catenin pathways. Knockdown of PARN, RHAU, and CNOT7, three critical members involved in cytoplasmic deadenylation, attenuated the downregulation of MMP2. Hence, we present the mechanism of repressed invasion by cantharidin and other PP2A inhibitors through increased degradation of MMP2 mRNA by elevated cytoplasmic deadenylation.
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