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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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Rafaqat S, Khurshid H, Hafeez R, Arif M, Zafar A, Gilani M, Ashraf H, Rafaqat S. Role of Interleukins in Pancreatic Cancer: A Literature Review. J Gastrointest Cancer 2024; 55:1498-1510. [PMID: 39256264 DOI: 10.1007/s12029-024-01111-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 08/31/2024] [Indexed: 09/12/2024]
Abstract
PURPOSE This review article summarizes the pathophysiological aspects of interleukins (ILs) including IL-1, IL-2, IL-3, IL-4, IL-5, IL-6, IL-7, IL-8, IL-9, and IL-10 in pancreatic cancer (PC). METHODS Science Direct, PubMed, and Google Scholar were used for the literature review. The search was conducted until August 12, 2024, and particular keywords such as "Pancreatic Cancer," "Interleukins," "Pathophysiological Aspects," "Immunosuppression," "Invasiveness," and "Metastasis" were used. Focusing on interleukins related to pancreatic cancer, 61 original studies were included: 32 studies for human patients, 16 studies for animal models, and 13 studies for both animal models and human patients. All types of PC were considered. The timeframe of 1991 to 2024 was chosen for clinical studies. RESULTS In epithelial pancreatic tumors, IL-1 is a major inflammation factor. Serum concentrations of soluble interleukin-2-receptor were considerably greater in patients with PC and chronic pancreatitis than in healthy individuals. In comparison to controls, pancreatic cancer patients had considerably greater levels of macrophage colony-stimulating factor and significantly lower levels of stem cell factor and IL-3. The tissues and cells of pancreatic cancer have higher concentrations of IL-4 receptors. IL-5 has a role in the accumulation of pancreatic fibrosis. For individuals with pancreatic ductal adenocarcinoma (PDAC), a high serum level of IL-6 may be a separate risk factor for the development of widespread liver metastases. PDAC patients' peripheral blood mononuclear cells exhibit a substantial upregulation of IL-7 receptor. The role of IL-8 in the growth and spread of PC in humans. The miR-200a/β-catenin axis may be the mechanism by which IL-9 stimulates the proliferation and metastasis of PC cells. Blocking IL-10 in the local microenvironment appears to result in a significant reversal of tumor-induced immunosuppression. CONCLUSION The article concludes that interleukins 1, 2, 3, 4, 5, 6, 7, 8, 9, and 10 played significant roles in the pathogenesis of PC.
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Affiliation(s)
- Saira Rafaqat
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan.
| | - Huma Khurshid
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Ramsha Hafeez
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Mehnaz Arif
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Ayesha Zafar
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Mahrukh Gilani
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Habiba Ashraf
- Department of Zoology, Lahore College for Women University, Lahore, 54000, Pakistan
| | - Sana Rafaqat
- Department of Biotechnology (Human Genetics), Lahore College for Women University, Lahore, 54000, Pakistan
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Bukys T, Kurlinkus B, Sileikis A, Vitkus D. The Prospect of Improving Pancreatic Cancer Diagnostic Capabilities by Implementing Blood Biomarkers: A Study of Evaluating Properties of a Single IL-8 and in Conjunction with CA19-9, CEA, and CEACAM6. Biomedicines 2024; 12:2344. [PMID: 39457656 PMCID: PMC11505492 DOI: 10.3390/biomedicines12102344] [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: 09/18/2024] [Revised: 10/07/2024] [Accepted: 10/11/2024] [Indexed: 10/28/2024] Open
Abstract
Background/Objectives: This study aims to evaluate the possible clinical application of interleukin 8 (IL-8) as a single biomarker and its capabilities in combination with carbohydrate antigen (CA19-9), carcinoembryonic antigen (CEA), and carcinoembryonic antigen cell adhesion molecule 6 (CEACAM6) as diagnostic and prognostic tools for pancreatic ductal adenocarcinoma (PDAC). Methods: A total of 170 serum samples from patients with PDAC (n = 100), chronic pancreatitis (CP) (n = 39), and healthy individuals (n = 31) were analysed. IL-8 and CEACAM6 were measured by an enzyme-linked immunosorbent assay (ELISA). CA19-9 and CEA were determined by chemiluminescent microparticle immunoassay, and bilirubin was quantified using a diazonium salt reaction. Receiver operating characteristic curve analysis, logistic regression, and Kaplan-Meier analyses were performed to evaluate the properties of a single IL-8 and in combination with other biomarkers. Results: The concentrations of IL-8 were statistically significantly higher in the PDAC group compared to the CP and control groups. Heterogeneous levels of IL-8 correlated with PDAC stages (p = 0.007). IL-8 had good and satisfactory diagnostic efficacy in differentiating PDAC from controls (0.858; p < 0.001) and patients with CP (0.696; p < 0.001), respectively. High and low expressions of IL-8 were not significantly associated with overall survival (OS) or disease-free survival (DFS). A combination of IL-8, CEACAM6, and CA19-9 reached the highest AUC values for differentiating PDAC from the control group. The best classification score between PDAC and the control group with CP patients was obtained by merging IL-8 and CA19-9 (0.894; p < 0.001). Conclusions: These results provide compelling evidence of IL-8 as a promising diagnostic biomarker. Nonetheless, due to the high complexity of PDAC, only the conjunction of IL-8, CA19-9, and CEACAM6 integrates sufficient diagnostic capabilities.
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Affiliation(s)
- Tomas Bukys
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania;
| | - Benediktas Kurlinkus
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania; (B.K.); (A.S.)
| | - Audrius Sileikis
- Clinic of Gastroenterology, Nephrourology and Surgery, Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania; (B.K.); (A.S.)
| | - Dalius Vitkus
- Department of Physiology, Biochemistry, Microbiology and Laboratory Medicine, Institute of Biomedical Sciences, Faculty of Medicine, Vilnius University, LT-03101 Vilnius, Lithuania;
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Bidan N, Dunsmore G, Ugrinic M, Bied M, Moreira M, Deloménie C, Ginhoux F, Blériot C, de la Fuente M, Mura S. Multicellular tumor spheroid model to study the multifaceted role of tumor-associated macrophages in PDAC. Drug Deliv Transl Res 2024; 14:2085-2099. [PMID: 38062286 DOI: 10.1007/s13346-023-01479-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 11/07/2023] [Indexed: 06/27/2024]
Abstract
While considerable efforts have been made to develop new therapies, progress in the treatment of pancreatic cancer has so far fallen short of patients' expectations. This is due in part to the lack of predictive in vitro models capable of accounting for the heterogeneity of this tumor and its low immunogenicity. To address this point, we have established and characterized a 3D spheroid model of pancreatic cancer composed of tumor cells, cancer-associated fibroblasts, and blood-derived monocytes. The fate of the latter has been followed from their recruitment into the tumor spheroid to their polarization into a tumor-associated macrophage (TAM)-like population, providing evidence for the formation of an immunosuppressive microenvironment.This 3D model well reproduced the multiple roles of TAMs and their influence on drug sensitivity and cell migration. Furthermore, we observed that lipid-based nanosystems consisting of sphingomyelin and vitamin E could affect the phenotype of macrophages, causing a reduction of characteristic markers of TAMs. Overall, this optimized triple coculture model gives a valuable tool that could find useful application for a more comprehensive understanding of TAM plasticity as well as for more predictive drug screening. This could increase the relevance of preclinical studies and help identify effective treatments.
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Affiliation(s)
- Nadège Bidan
- Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91400, Orsay, France
| | | | - Martina Ugrinic
- Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91400, Orsay, France
| | - Mathilde Bied
- Inserm U1015, Gustave Roussy, 94800, Villejuif, France
| | - Marco Moreira
- Inserm U1015, Gustave Roussy, 94800, Villejuif, France
| | - Claudine Deloménie
- Inserm US31, CNRS UAR3679, Ingénierie Et Plateformes Au Service de L'Innovation Thérapeutique (UMS-IPSIT), Université Paris-Saclay, 91400, Orsay, France
| | | | - Camille Blériot
- Inserm U1015, Gustave Roussy, 94800, Villejuif, France
- CNRS UMR8253, Institut Necker Enfants Malades, 75015, Paris, France
| | - Maria de la Fuente
- Nano-Oncology and Translational Therapeutics Group, Health Research Institute of Santiago de Compostela (IDIS), Complexo Hospitalario Universitario de Santiago de Compostela SERGAS, 15706, Santiago de Compostela, Spain
- Biomedical Research Networking Center On Oncology (CIBERONC), 28029, Madrid, Spain
- DIVERSA Technologies SL, 15782, Santiago de Compostela, Spain
| | - Simona Mura
- Université Paris-Saclay, CNRS, Institut Galien Paris-Saclay, 91400, Orsay, France.
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Lyu J, Jiang M, Zhu Z, Wu H, Kang H, Hao X, Cheng S, Guo H, Shen X, Wu T, Chang J, Wang C. Identification of biomarkers and potential therapeutic targets for pancreatic cancer by proteomic analysis in two prospective cohorts. CELL GENOMICS 2024; 4:100561. [PMID: 38754433 PMCID: PMC11228889 DOI: 10.1016/j.xgen.2024.100561] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 12/12/2023] [Accepted: 04/21/2024] [Indexed: 05/18/2024]
Abstract
Pancreatic cancer (PC) is the deadliest malignancy due to late diagnosis. Aberrant alterations in the blood proteome might serve as biomarkers to facilitate early detection of PC. We designed a nested case-control study of incident PC based on a prospective cohort of 38,295 elderly Chinese participants with ∼5.7 years' follow-up. Forty matched case-control pairs passed the quality controls for the proximity extension assay of 1,463 serum proteins. With a lenient threshold of p < 0.005, we discovered regenerating family member 1A (REG1A), REG1B, tumor necrosis factor (TNF), and phospholipase A2 group IB (PLA2G1B) in association with incident PC, among which the two REG1 proteins were replicated using the UK Biobank Pharma Proteomics Project, with effect sizes increasing steadily as diagnosis time approaches the baseline. Mendelian randomization analysis further supported the potential causal effects of REG1 proteins on PC. Taken together, circulating REG1A and REG1B are promising biomarkers and potential therapeutic targets for the early detection and prevention of PC.
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Affiliation(s)
- Jingjing Lyu
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Minghui Jiang
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Ziwei Zhu
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Hongji Wu
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Haonan Kang
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xingjie Hao
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Shanshan Cheng
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Huan Guo
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Xia Shen
- Greater Bay Area Institute of Precision Medicine (Guangzhou), Fudan University, Guangzhou, China
| | - Tangchun Wu
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Occupational and Environmental Health, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Jiang Chang
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Health Toxicology, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
| | - Chaolong Wang
- Ministry of Education Key Laboratory of Environment and Health, State Key Laboratory of Environmental Health (Incubating), School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China; Department of Epidemiology and Biostatistics, School of Public Health, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China.
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Szymoński K, Skirlińska-Nosek K, Lipiec E, Sofińska K, Czaja M, Wilkosz N, Krupa M, Wanat F, Ulatowska-Białas M, Adamek D. Combined analytical approach empowers precise spectroscopic interpretation of subcellular components of pancreatic cancer cells. Anal Bioanal Chem 2023; 415:7281-7295. [PMID: 37906289 PMCID: PMC10684650 DOI: 10.1007/s00216-023-04997-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2023] [Revised: 09/27/2023] [Accepted: 10/09/2023] [Indexed: 11/02/2023]
Abstract
The lack of specific and sensitive early diagnostic options for pancreatic cancer (PC) results in patients being largely diagnosed with late-stage disease, thus inoperable and burdened with high mortality. Molecular spectroscopic methodologies, such as Raman or infrared spectroscopies, show promise in becoming a leader in screening for early-stage cancer diseases, including PC. However, should such technology be introduced, the identification of differentiating spectral features between various cancer types is required. This would not be possible without the precise extraction of spectra without the contamination by necrosis, inflammation, desmoplasia, or extracellular fluids such as mucous that surround tumor cells. Moreover, an efficient methodology for their interpretation has not been well defined. In this study, we compared different methods of spectral analysis to find the best for investigating the biomolecular composition of PC cells cytoplasm and nuclei separately. Sixteen PC tissue samples of main PC subtypes (ductal adenocarcinoma, intraductal papillary mucinous carcinoma, and ampulla of Vater carcinoma) were collected with Raman hyperspectral mapping, resulting in 191,355 Raman spectra and analyzed with comparative methodologies, specifically, hierarchical cluster analysis, non-negative matrix factorization, T-distributed stochastic neighbor embedding, principal components analysis (PCA), and convolutional neural networks (CNN). As a result, we propose an innovative approach to spectra classification by CNN, combined with PCA for molecular characterization. The CNN-based spectra classification achieved over 98% successful validation rate. Subsequent analyses of spectral features revealed differences among PC subtypes and between the cytoplasm and nuclei of their cells. Our study establishes an optimal methodology for cancer tissue spectral data classification and interpretation that allows precise and cognitive studies of cancer cells and their subcellular components, without mixing the results with cancer-surrounding tissue. As a proof of concept, we describe findings that add to the spectroscopic understanding of PC.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Medical College, Jagiellonian University, Kraków, Poland.
- Department of Pathomorphology, University Hospital, Kraków, Poland.
| | - Katarzyna Skirlińska-Nosek
- Faculty of Physics, Astronomy and Applied Computer Science, M. Smoluchowski Institute of Physics, Jagiellonian University, Kraków, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
| | - Ewelina Lipiec
- Faculty of Physics, Astronomy and Applied Computer Science, M. Smoluchowski Institute of Physics, Jagiellonian University, Kraków, Poland
| | - Kamila Sofińska
- Faculty of Physics, Astronomy and Applied Computer Science, M. Smoluchowski Institute of Physics, Jagiellonian University, Kraków, Poland
| | - Michał Czaja
- Faculty of Physics, Astronomy and Applied Computer Science, M. Smoluchowski Institute of Physics, Jagiellonian University, Kraków, Poland
- Doctoral School of Exact and Natural Sciences, Jagiellonian University, Kraków, Poland
| | - Natalia Wilkosz
- Faculty of Physics, Astronomy and Applied Computer Science, M. Smoluchowski Institute of Physics, Jagiellonian University, Kraków, Poland
- AGH University of Krakow, Faculty of Physics and Applied Computer Science, Kraków, Poland
| | - Matylda Krupa
- Department of Pathomorphology, Medical College, Jagiellonian University, Kraków, Poland
| | - Filip Wanat
- Department of Pathomorphology, Medical College, Jagiellonian University, Kraków, Poland
| | - Magdalena Ulatowska-Białas
- Department of Pathomorphology, Medical College, Jagiellonian University, Kraków, Poland
- Department of Pathomorphology, University Hospital, Kraków, Poland
| | - Dariusz Adamek
- Department of Pathomorphology, Medical College, Jagiellonian University, Kraków, Poland
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7
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Szymoński K, Chmura Ł, Lipiec E, Adamek D. Vibrational spectroscopy – are we close to finding a solution for early pancreatic cancer diagnosis? World J Gastroenterol 2023; 29:96-109. [PMID: 36683712 PMCID: PMC9850953 DOI: 10.3748/wjg.v29.i1.96] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2022] [Revised: 10/03/2022] [Accepted: 10/31/2022] [Indexed: 01/04/2023] Open
Abstract
Pancreatic cancer (PC) is an aggressive and lethal neoplasm, ranking seventh in the world for cancer deaths, with an overall 5-year survival rate of below 10%. The knowledge about PC pathogenesis is rapidly expanding. New aspects of tumor biology, including its molecular and morphological heterogeneity, have been reported to explain the complicated “cross-talk” that occurs between the cancer cells and the tumor stroma or the nature of pancreatic ductal adenocarcinoma-associated neural remodeling. Nevertheless, currently, there are no specific and sensitive diagnosis options for PC. Vibrational spectroscopy (VS) shows a promising role in the development of early diagnosis technology. In this review, we summarize recent reports about improvements in spectroscopic methodologies, briefly explain and highlight the drawbacks of each of them, and discuss available solutions. The important aspects of spectroscopic data evaluation with multivariate analysis and a convolutional neural network methodology are depicted. We conclude by presenting a study design for systemic verification of the VS-based methods in the diagnosis of PC.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow 33-332, Poland
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
| | - Łukasz Chmura
- Department of Pathomorphology, Jagiellonian University Medical College, Cracow 33-332, Poland
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
| | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, Cracow 30-348, Poland
| | - Dariusz Adamek
- Department of Pathomorphology, University Hospital in Cracow, Cracow 31-501, Poland
- Department of Neuropathology, Jagiellonian University Medical College, Cracow 33-332, Poland
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Evidence of Stem Cells Mobilization in the Blood of Patients with Pancreatitis: A Potential Link with Disease Severity. Stem Cells Int 2022; 2022:5395248. [PMID: 35846982 PMCID: PMC9286984 DOI: 10.1155/2022/5395248] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/15/2022] [Accepted: 06/27/2022] [Indexed: 11/17/2022] Open
Abstract
A growing number of studies indicate the potential involvement of various populations of bone marrow-derived stem cells (BMSCs) in tissue repair. However, the mobilization of BMSCs to the peripheral blood (PB) in acute and chronic pancreatitis (AP and CP) has not been investigated. A total of 78 patients were assigned into AP, CP, and healthy control groups in this study. Using flow cytometry, we found that VSELs, EPCs, and CD133+SCs were mobilized to the PB of patients with both AP and CP. Interestingly, AP and CP patients exhibited lower absolute number of circulating MSCs in the PB compared to healthy individuals. SC mobilization to the PB was more evident in patients with AP than CP and in patients with moderate/severe AP than mild AP. Using ELISA, we found a significantly increased HGF concentration in the PB of patients with AP and SDF1α in the PB of patients with CP. We noted a significant positive correlation between SDF1α concentration and the mobilized population of CD133+SCs in AP and between C5a and the mobilized population of VSELs moderate/severe AP. Thus, bone marrow-derived SCs may play a role in the regeneration of pancreatic tissue in both AP and CP, and mobilization of VSELs to the PB depends on the severity of AP.
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9
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Nagata N, Nishijima S, Kojima Y, Hisada Y, Imbe K, Miyoshi-Akiyama T, Suda W, Kimura M, Aoki R, Sekine K, Ohsugi M, Miki K, Osawa T, Ueki K, Oka S, Mizokami M, Kartal E, Schmidt TSB, Molina-Montes E, Estudillo L, Malats N, Trebicka J, Kersting S, Langheinrich M, Bork P, Uemura N, Itoi T, Kawai T. Metagenomic Identification of Microbial Signatures Predicting Pancreatic Cancer From a Multinational Study. Gastroenterology 2022; 163:222-238. [PMID: 35398347 DOI: 10.1053/j.gastro.2022.03.054] [Citation(s) in RCA: 97] [Impact Index Per Article: 32.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/15/2021] [Revised: 02/23/2022] [Accepted: 03/29/2022] [Indexed: 12/26/2022]
Abstract
BACKGROUND & AIMS To identify gut and oral metagenomic signatures that accurately predict pancreatic ductal carcinoma (PDAC) and to validate these signatures in independent cohorts. METHODS We conducted a multinational study and performed shotgun metagenomic analysis of fecal and salivary samples collected from patients with treatment-naïve PDAC and non-PDAC controls in Japan, Spain, and Germany. Taxonomic and functional profiles of the microbiomes were characterized, and metagenomic classifiers to predict PDAC were constructed and validated in external datasets. RESULTS Comparative metagenomics revealed dysbiosis of both the gut and oral microbiomes and identified 30 gut and 18 oral species significantly associated with PDAC in the Japanese cohort. These microbial signatures achieved high area under the curve values of 0.78 to 0.82. The prediction model trained on the Japanese gut microbiome also had high predictive ability in Spanish and German cohorts, with respective area under the curve values of 0.74 and 0.83, validating its high confidence and versatility for PDAC prediction. Significant enrichments of Streptococcus and Veillonella spp and a depletion of Faecalibacterium prausnitzii were common gut signatures for PDAC in all the 3 cohorts. Prospective follow-up data revealed that patients with certain gut and oral microbial species were at higher risk of PDAC-related mortality. Finally, 58 bacteriophages that could infect microbial species consistently enriched in patients with PDAC across the 3 countries were identified. CONCLUSIONS Metagenomics targeting the gut and oral microbiomes can provide a powerful source of biomarkers for identifying individuals with PDAC and their prognoses. The identification of shared gut microbial signatures for PDAC in Asian and European cohorts indicates the presence of robust and global gut microbial biomarkers.
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Affiliation(s)
- Naoyoshi Nagata
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan.
| | - Suguru Nishijima
- Computational Bio-Big Data Open Innovation Lab, National Institute of Advanced Industrial Science and Technology, Tokyo, Japan; Graduate School of Advanced Science and Engineering, Waseda University, Tokyo, Japan; Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany.
| | - Yasushi Kojima
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Yuya Hisada
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Koh Imbe
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tohru Miyoshi-Akiyama
- Pathogenic Microbe Laboratory, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Wataru Suda
- Laboratory for Microbiome Sciences, RIKEN Center for Integrative Medical Sciences, Yokohama, Japan
| | - Moto Kimura
- Department of Clinical Research Strategic Planning Center for Clinical Sciences, National Center for Global Health and Medicine, Tokyo, Japan
| | - Ryo Aoki
- Institute of Health Sciences, Ezaki Glico Co., Ltd., Osaka, Japan
| | - Katsunori Sekine
- Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital, Tokyo, Japan
| | - Mitsuru Ohsugi
- Department of Diabetes, Endocrinology, and Metabolism, Center Hospital, National Center for Global Health and Medicine, Tokyo, Japan; Diabetes and Metabolism Information Center, Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Kuniko Miki
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Tokyo, Japan
| | - Tsuyoshi Osawa
- Division of Nutriomics and Oncology, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Kohjiro Ueki
- Diabetes Research Center, Research Institute, National Center for Global Health and Medicine, Tokyo, Japan
| | - Shinichi Oka
- AIDS Clinical Center, National Center for Global Health and Medicine, Tokyo, Japan
| | - Masashi Mizokami
- Genome Medical Sciences Project, Research Institute, National Center for Global Health and Medicine, Chiba, Japan
| | - Ece Kartal
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Thomas S B Schmidt
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany
| | - Esther Molina-Montes
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, and CIBERONC, Spain
| | - Lidia Estudillo
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, and CIBERONC, Spain
| | - Nuria Malats
- Genetic and Molecular Epidemiology Group, Spanish National Cancer Research Center (CNIO), Madrid, and CIBERONC, Spain
| | - Jonel Trebicka
- Section for Translational Hepatology, Department of Internal Medicine I, Goehte University Frankfurt, Frankfurt, Germany; European Foundation for the Study of Chronic Liver Failure, Barcelona, Spain
| | - Stephan Kersting
- Department of Surgery, University Hospital of Erlangen, Erlangen, Germany; Department of Surgery, University Clinic Greifswald, Greifswald, Germany
| | - Melanie Langheinrich
- Department of Surgery, University Hospital of Erlangen, Erlangen, Germany; Department of Surgery, University Clinic Greifswald, Greifswald, Germany
| | - Peer Bork
- Structural and Computational Biology Unit, European Molecular Biology Laboratory, Heidelberg, Germany; Department of Bioinformatics, Biocenter, University of Würzburg, Würzburg, Germany
| | - Naomi Uemura
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan; Department of Gastroenterology and Hepatology, National Center for Global Health and Medicine, Kohnodai Hospital, Tokyo, Japan
| | - Takao Itoi
- Department of Gastroenterology and Hepatology, Tokyo Medical University, Tokyo, Japan
| | - Takashi Kawai
- Department of Gastroenterological Endoscopy, Tokyo Medical University, Tokyo, Japan
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Szymoński K, Milian-Ciesielska K, Lipiec E, Adamek D. Current Pathology Model of Pancreatic Cancer. Cancers (Basel) 2022; 14:2321. [PMID: 35565450 PMCID: PMC9105915 DOI: 10.3390/cancers14092321] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/06/2022] [Revised: 04/29/2022] [Accepted: 05/05/2022] [Indexed: 02/01/2023] Open
Abstract
Pancreatic cancer (PC) is one of the most aggressive and lethal malignant neoplasms, ranking in seventh place in the world in terms of the incidence of death, with overall 5-year survival rates still below 10%. The knowledge about PC pathomechanisms is rapidly expanding. Daily reports reveal new aspects of tumor biology, including its molecular and morphological heterogeneity, explain complicated "cross-talk" that happens between the cancer cells and tumor stroma, or the nature of the PC-associated neural remodeling (PANR). Staying up-to-date is hard and crucial at the same time. In this review, we are focusing on a comprehensive summary of PC aspects that are important in pathologic reporting, impact patients' outcomes, and bring meaningful information for clinicians. Finally, we show promising new trends in diagnostic technologies that might bring a difference in PC early diagnosis.
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Affiliation(s)
- Krzysztof Szymoński
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
- Department of Pathomorphology, University Hospital, 30-688 Cracow, Poland;
| | | | - Ewelina Lipiec
- M. Smoluchowski Institute of Physics, Jagiellonian University, 30-348 Cracow, Poland;
| | - Dariusz Adamek
- Department of Pathomorphology, Jagiellonian University Medical College, 31-531 Cracow, Poland;
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11
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Tanţău A, Leucuţa DC, Tanţău M, Boţan E, Zaharie R, Mândruţiu A, Tomuleasa IC. Inflammation, Tumoral Markers and Interleukin-17, -10, and -6 Profiles in Pancreatic Adenocarcinoma and Chronic Pancreatitis. Dig Dis Sci 2021; 66:3427-3438. [PMID: 33184795 DOI: 10.1007/s10620-020-06700-w] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/15/2020] [Accepted: 10/27/2020] [Indexed: 12/14/2022]
Abstract
BACKGROUND Interleukin profiles can be used as biochemical markers regarding the early diagnosis of pancreatic cancer. AIMS To assess CRP, CA 19-9, CEA levels, and interleukin-6, -10, and -17 profiles in pancreatic ductal adenocarcinoma, chronic pancreatitis was compared with a control group, and the correlation with pancreatic cancer survival. METHODS A total of 87 patients were prospective divided in pancreatic cancer (n = 53), chronic pancreatitis (n = 22) ,and control group (n = 12). The diagnosis of PDAC was made histologically. The diagnosis of chronic pancreatitis was based on medical history, imaging methods, and endoscopic ultrasound. Systemic concentrations of interleukins were measured using ELISA kits. The patients were followed at 1, 3, and 6 months. RESULTS CRP, CA 19-9, and CEA were higher in the pancreatic cancer group (p < 0.001). Interleukin-10 was significantly higher in the pancreatic cancer and chronic pancreatitis groups (p < 0.001). Interleukin-17 was statistically higher in the pancreatic cancer group (p < 0.0001). The cut-off of interleukin-17 of 0.273 had a sensitivity of 90.9 and a specificity of 80.9 with a curve under ROC of 0.80 in order to differentiate between pancreatic cancer and chronic pancreatitis. The serum levels of interleukins are not correlated with the stage of the disease. CRP, CA 19-9, CEA, and interleukin-6, -10, and -17 were lower in patients with survival more than 6 months. CONCLUSIONS We detected high levels of interleukin-6, -10, and -17 in chronic pancreatitis and pancreatic cancer. Serum interleukin-17 levels can discriminate between pancreatic cancer and chronic pancreatitis. The prognostic role of interleukins needs to be established.
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Affiliation(s)
- Alina Tanţău
- The 4th Medical Clinic, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400015, Cluj-Napoca City, Cluj, Romania
- Department of Gastroenterology and Hepatology Medical Center, 400132, Cluj-Napoca City, Cluj, Romania
| | - Daniel-Corneliu Leucuţa
- Medical Informatics and Biostatistics Department, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012, Cluj-Napoca City, Cluj, Romania.
| | - Marcel Tanţău
- The 3rd Medical Clinic, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012, Cluj-Napoca City, Cluj, Romania
- Department of Internal Medicine and Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400158, Cluj-Napoca City, Cluj, Romania
| | - Emil Boţan
- Anatomopathology Department, "Regina Maria" Medical Center, 400117, Cluj-Napoca City, Cluj, Romania
| | - Roxana Zaharie
- The 3rd Medical Clinic, "Iuliu Hatieganu" University of Medicine and Pharmacy, 400012, Cluj-Napoca City, Cluj, Romania
- Department of Internal Medicine and Gastroenterology, "Prof. Dr. Octavian Fodor" Regional Institute of Gastroenterology and Hepatology, 400158, Cluj-Napoca City, Cluj, Romania
| | - Alina Mândruţiu
- Department of Gastroenterology and Hepatology Medical Center, 400132, Cluj-Napoca City, Cluj, Romania
| | - Ionuţ-Ciprian Tomuleasa
- Hematology Department, "Prof. Dr. Ion Chiricuţă" Institute of Oncology Cluj-Napoca, 400015, Cluj-Napoca City, Cluj, Romania
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Zampogiannis A, Piperi C, Baka M, Zoi I, Papavassiliou AG, Moschovi M. Low IL-23 levels in peripheral blood and bone marrow at diagnosis of acute leukemia in children increased with the elimination of leukemic burden. J Cell Mol Med 2021; 25:7426-7435. [PMID: 34235838 PMCID: PMC8335666 DOI: 10.1111/jcmm.16772] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/31/2021] [Revised: 06/17/2021] [Accepted: 06/21/2021] [Indexed: 12/24/2022] Open
Abstract
IL-23 is an IL-12 cytokine family member with pleiotropic functions that regulates tumour growth in various cancer types, exhibiting both anti-tumorigenic and pro-tumorigenic properties. Preclinical studies have shown a potential anti-leukemic action on childhood B-ALL cells. The study involved 65 children with acute leukemia [59 patients with acute lymphoblastic leukemia (ALL) and 6 patients with acute myeloid leukemia (AML)] and 27 healthy controls. Using an enzyme-linked immunosorbent assay, we aimed to determine the IL-23 levels in the peripheral blood (PB) and bone marrow (BM) of patients at diagnosis and at the end of the induction therapy (EIT). PB IL-23 levels were lower in leukemia patients compared to the healthy controls. In all acute leukemia patients, IL-23 levels were significantly lower at diagnosis both in PB (P = .015) and in BM (P = .037) compared to the PB and BM concentrations at the EIT. The same pattern was present in both subgroups of ALL and AML patients. The high leukemic burden at diagnosis was related with lower IL-23 levels, which were increased with the disease remission. Considering the anti-leukemic potential of this cytokine, the elevation of the IL-23 concentration at the disease remission indicates a beneficial role of IL-23 in paediatric acute leukemia.
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Affiliation(s)
- Archontis Zampogiannis
- Pediatric Hematology‐Oncology UnitMedical School"Agia Sophia" Children's HospitalNational and Kapodistrian University of AthensAthensGreece
| | - Christina Piperi
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | - Margarita Baka
- Department of Pediatric Hematology‐Oncology"P&A Kyriakou" Children's HospitalAthensGreece
| | - Iliana Zoi
- Department of Biological ChemistryMedical SchoolNational and Kapodistrian University of AthensAthensGreece
| | | | - Maria Moschovi
- Pediatric Hematology‐Oncology UnitMedical School"Agia Sophia" Children's HospitalNational and Kapodistrian University of AthensAthensGreece
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13
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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: 48] [Impact Index Per Article: 12.0] [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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14
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Lee SWL, Seager RJ, Litvak F, Spill F, Sieow JL, Leong PH, Kumar D, Tan ASM, Wong SC, Adriani G, Zaman MH, Kamm ARD. Integrated in silico and 3D in vitro model of macrophage migration in response to physical and chemical factors in the tumor microenvironment. Integr Biol (Camb) 2021; 12:90-108. [PMID: 32248236 DOI: 10.1093/intbio/zyaa007] [Citation(s) in RCA: 41] [Impact Index Per Article: 10.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2019] [Revised: 01/30/2020] [Accepted: 03/10/2020] [Indexed: 12/18/2022]
Abstract
Macrophages are abundant in the tumor microenvironment (TME), serving as accomplices to cancer cells for their invasion. Studies have explored the biochemical mechanisms that drive pro-tumor macrophage functions; however the role of TME interstitial flow (IF) is often disregarded. Therefore, we developed a three-dimensional microfluidic-based model with tumor cells and macrophages to study how IF affects macrophage migration and its potential contribution to cancer invasion. The presence of either tumor cells or IF individually increased macrophage migration directedness and speed. Interestingly, there was no additive effect on macrophage migration directedness and speed under the simultaneous presence of tumor cells and IF. Further, we present an in silico model that couples chemokine-mediated signaling with mechanosensing networks to explain our in vitro observations. In our model design, we propose IL-8, CCL2, and β-integrin as key pathways that commonly regulate various Rho GTPases. In agreement, in vitro macrophage migration remained elevated when exposed to a saturating concentration of recombinant IL-8 or CCL2 or to the co-addition of a sub-saturating concentration of both cytokines. Moreover, antibody blockade against IL-8 and/or CCL2 inhibited migration that could be restored by IF, indicating cytokine-independent mechanisms of migration induction. Importantly, we demonstrate the utility of an integrated in silico and 3D in vitro approach to aid the design of tumor-associated macrophage-based immunotherapeutic strategies.
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Affiliation(s)
- Sharon Wei Ling Lee
- BioSystems and Micromechanics IRG, Singapore-MIT Alliance for Research and Technology, Singapore, 138602, Singapore.,Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117597, Singapore.,Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - R J Seager
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA
| | - Felix Litvak
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA
| | - Fabian Spill
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA.,Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,School of Mathematics, University of Birmingham, Birmingham, B15 2TT, UK
| | - Je Lin Sieow
- Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Penny Hweixian Leong
- Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Dillip Kumar
- Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Alrina Shin Min Tan
- Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Siew Cheng Wong
- Department of Microbiology and Immunology, Yong Loo Lin School of Medicine, National University of Singapore (NUS), Singapore, 117597, Singapore.,Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Giulia Adriani
- Singapore Immunology Network (SIgN), Agency for Science, Technology, and Research (A*STAR), Singapore
| | - Muhammad Hamid Zaman
- Department of Biomedical Engineering, Boston University, Boston, MA, 02215, USA.,Howard Hughes Medical Institute, Boston University, Boston, MA, 02215, USA
| | - And Roger D Kamm
- Department of Mechanical Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA.,Department of Biological Engineering, Massachusetts Institute of Technology, Cambridge, MA, 02139, USA
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15
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Review of clinical and emerging biomarkers for early diagnosis and treatment management of pancreatic cancer: towards personalised medicine. JOURNAL OF RADIOTHERAPY IN PRACTICE 2021. [DOI: 10.1017/s1460396921000182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/07/2022]
Abstract
Abstract
Background:
Pancreatic cancer is the 12th most commonly diagnosed cancer and the 3rd leading cause of cancer mortality and accounts for approximately 2·7% of all newly diagnosed cancer cases and 6·4% of all cancer mortalities in Canada. It has a very poor survival rate mainly due to the difficulty of detecting the disease at an early stage. Consequently, in the advancement of disease management towards the concept of precision medicine that takes individual patient variabilities into account, several investigators have focused on the identification of effective clinical biomarkers with high specificity and sensitivity, capable of early diagnosis of symptomatic patients and early detection of the disease in asymptomatic individuals at high risk for developing pancreatic cancer.
Materials and methods:
We searched several databases from August to December 2020 for relevant studies published in English between 2000 and 2020 and reporting on biomarkers for the management of pancreatic cancer. In this narrative review paper, we describe 13 clinical and emerging biomarkers for pancreatic cancers used in screening for early detection and diagnosis, to identify patients’ risk for metastatic disease and subsequent relapse, to monitor patient response to specific treatment and to provide clinicians the possibility of prospectively identifying groups of patients who will benefit from a particular treatment.
Conclusions:
Current and emerging biomarkers for pancreatic cancer with high specificity and sensitivity has the potential to account for individual patient variabilities, for early detection of disease before the onset of metastasis to improve treatment outcome and patients’ survival, help screen high-risk populations, predict prognosis, provide accurate information of patient response to specific treatment and improve patients monitoring during treatment. Thus, the future holds promise for the use of effective clinical biomarkers or a panel of biomarkers for personalised patient-specific targeted medicine for pancreatic cancer.
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Liu B, Wang F, Chen L, Xin Y, Liu L, Wu D, Li W. Effects of High-Fat Diet on Carcinogen-Induced Pancreatic Cancer and Intestinal Microbiota in C57BL/6 Wild-Type Mice. Pancreas 2021; 50:564-570. [PMID: 33939670 DOI: 10.1097/mpa.0000000000001797] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/19/2022]
Abstract
OBJECTIVES High-fat diet has been considered a risk factor for the development of pancreatic cancer. It is also shown to significantly impact composition and dysbiosis of gut microbiota in both humans and animals. However, there is little information on the effect of high-fat diet on the development of pancreatic cancer or upon the gut microbiota of patients with pancreatic cancer in humans or animal models. METHODS In this study, the effect of high-fat diet on cancer pathology and the gut microbiota was investigated by a carcinogen-induced pancreatic cancer mouse model. RESULTS Compared with carcinogen alone, mice with high-fat diet and carcinogen showed more obvious pathological changes in pancreatic tissue; increased levels of proinflammatory cytokine tumor necrosis factor-α, interleukin-6, interleukin-10, and carbohydrate antigen 242; and increased expression of cancer-associated biomarkers mucin-4 and claudin-4 in pancreatic tissue. Moreover, there is a significant change in the gut microbiota between the carcinogen group and the carcinogen with high-fat diet group. We identified that Johnsonella ignava especially existed in the carcinogen with high-fat diet group, which may contribute to pancreatic cancer development. CONCLUSIONS Our results revealed that high-fat diet changed the composition of the gut microbiota and was involved in carcinogen-induced pancreatic cancer progression.
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Affiliation(s)
- Beibei Liu
- From the Department of Surgery, Cell Biology, University of Oklahoma Health Sciences Center, Oklahoma City, OK
| | | | | | - Yi Xin
- Biochemistry and Molecular Biology, Dalian Medical University, Dalian, China
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Cheng YH, Chiang EPI, Syu JN, Chao CY, Lin HY, Lin CC, Yang MD, Tsai SY, Tang FY. Treatment of 13-cis retinoic acid and 1,25-dihydroxyvitamin D3 inhibits TNF-alpha-mediated expression of MMP-9 protein and cell invasion through the suppression of JNK pathway and microRNA 221 in human pancreatic adenocarcinoma cancer cells. PLoS One 2021; 16:e0247550. [PMID: 33730072 PMCID: PMC7968633 DOI: 10.1371/journal.pone.0247550] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/09/2020] [Accepted: 02/09/2021] [Indexed: 12/28/2022] Open
Abstract
Human pancreatic ductal adenocarcinoma (PDAC) is a deadly cancer type with a very high mortality rate. Inflammatory cytokine such as tumor necrosis factor- alpha (TNF-α) plays a pivotal role in the progression of PDAC. Recently, suppression of cell invasion by preventive agents has received considerable attention in the prevention of metastatic tumors. Several clinical studies suggested that natural forms or analogues of fat-soluble vitamins such as vitamin A and vitamin D can work as anti-cancer agents to inhibit the development of cancer. In this study, our results demonstrated that co-treatment of 13-cis retinoic acid (13-cis RA) and 1,25-dihydroxyvitamin D3 (1,25-VD3) significantly inhibited TNF-α mediated cell invasion in PDAC in vitro. Cotreatment of 13-cis RA and 1,25-VD3 also inhibited TNF-α mediated expression of matrix metalloproteinase-9 (MMP-9) protein through blocking c-Jun N-terminal kinase (JNK) and nuclear factor kappa B (NF-κB) signaling pathways. Our results demonstrated that treatment of TNF-α lead to a decreased expression of tissue inhibitor of metalloproteinase- 3 (TIMP-3) protein and an induction of MMP-9 protein and cell invasion through an upregulation of microRNA-221 (miR-221) in human PDAC cells. Moreover, treatment of SP600125 (a specific inhibitor of JNK pathway) or cotreatment of 13-cis RA and 1,25-VD3 significantly induced a decreased expression of miR-221 and an increased expression of TIMP-3 protein. These results suggest that 13-cis RA and 1,25-VD3 significantly suppress TNF-α mediated cell invasion and therefore potentially act as preventive agents against PDAC.
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Affiliation(s)
- Yen-Huang Cheng
- Department of Emergency Medicine, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - En-Pei Isabel Chiang
- Department of Food Science and Biotechnology, National Chung Hsing University, Taichung, Taiwan
- Innovation and Development Center of Sustainable Agriculture (IDCSA), National Chung Hsing University, Taichung, Taiwan
| | - Jia-Ning Syu
- Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan
| | - Che-Yi Chao
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
- Department of Medical Research, China Medical University Hospital, China Medical University, Taichung, Taiwan
| | - Hung-Yu Lin
- Research Assistant Center, Show Chwan Memorial Hospital, Changhua, Taiwan
| | - Cheng-Chieh Lin
- School of Medicine, College of Medicine, China Medical University, Taichung, Taiwan
- Department of Family Medicine, China Medical University Hospital, Taichung, Taiwan
- Department of Healthcare Administration, College of Health Science, Asia University, Taichung, Taiwan
| | - Mei-Due Yang
- Department of Surgery, China Medical University Hospital, Taichung, Taiwan
| | - Shu-Yao Tsai
- Department of Food Nutrition and Health Biotechnology, Asia University, Taichung, Taiwan
| | - Feng-Yao Tang
- Biomedical Science Laboratory, Department of Nutrition, China Medical University, Taichung, Taiwan
- * E-mail:
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18
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Willenbrock F, Cox CM, Parkes EE, Wilhelm-Benartzi CS, Abraham AG, Owens R, Sabbagh A, Jones CM, Hughes DLI, Maughan T, Hurt CN, O'Neill EE, Mukherjee S. Circulating biomarkers and outcomes from a randomised phase 2 trial of gemcitabine versus capecitabine-based chemoradiotherapy for pancreatic cancer. Br J Cancer 2021; 124:581-586. [PMID: 33100327 PMCID: PMC7851394 DOI: 10.1038/s41416-020-01120-z] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2020] [Revised: 09/30/2020] [Accepted: 10/02/2020] [Indexed: 12/11/2022] Open
Abstract
BACKGROUND The Phase 2 SCALOP trial compared gemcitabine with capecitabine-based consolidation chemoradiotherapy (CRT) in locally advanced pancreatic cancer (LAPC). METHODS Thirty-five systematically identified circulating biomarkers were analysed in plasma samples from 60 patients enroled in SCALOP. Each was measured in triplicate at baseline (prior to three cycles of gemcitabine-capecitabine induction chemotherapy) and, for a subset, prior to CRT. Association with overall survival (OS) was determined using univariable Cox regression and optimal thresholds delineating low to high values identified using time-dependent ROC curves. Independence from known prognostic factors was assessed using Spearman correlation and the Wilcoxon rank sum test prior to multivariable Cox regression modelling including independent biomarkers and known prognostic factors. RESULTS Baseline circulating levels of C-C motif chemokine ligand 5 (CCL5) were significantly associated with OS, independent of other clinicopathological characteristics. Patients with low circulating CCL5 (CCL5low) had a median OS of 18.5 (95% CI 11.76-21.32) months compared to 11.3 (95% CI 9.86-15.51) months in CCL5high; hazard ratio 1.95 (95% CI 1.04-8.65; p = 0.037). CONCLUSIONS CCL5 is an independent prognostic biomarker in LAPC. Given the known role of CCL5 in tumour invasion, metastasis and the induction of an immunosuppressive micro-environment, targeting of CCL5-mediated pathways may offer therapeutic potential in pancreatic cancer. CLINICAL TRIAL REGISTRATION The SCALOP trial was registered with ISRCTN, number 96169987 (registered 29 May 2008).
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Affiliation(s)
| | | | | | | | | | - Robert Owens
- Oxford University Hospital NHS Trust, Oxford, UK
| | - Ahmad Sabbagh
- Weston Park Cancer Centre, Sheffield Teaching Hospitals NHS Foundation Trust, Sheffield, UK
| | | | | | - Tim Maughan
- Department of Oncology, University of Oxford, Oxford, UK
| | | | - Eric E O'Neill
- Department of Oncology, University of Oxford, Oxford, UK
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19
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Mirlekar B, Pylayeva-Gupta Y. IL-12 Family Cytokines in Cancer and Immunotherapy. Cancers (Basel) 2021; 13:E167. [PMID: 33418929 PMCID: PMC7825035 DOI: 10.3390/cancers13020167] [Citation(s) in RCA: 168] [Impact Index Per Article: 42.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2020] [Revised: 12/22/2020] [Accepted: 12/29/2020] [Indexed: 12/16/2022] Open
Abstract
The IL-12 family cytokines are a group of unique heterodimeric cytokines that include IL-12, IL-23, IL-27, IL-35 and, most recently, IL-39. Recent studies have solidified the importance of IL-12 cytokines in shaping innate and adaptive immune responses in cancer and identified multipronged roles for distinct IL-12 family members, ranging from effector to regulatory immune functions. These cytokines could serve as promising candidates for the development of immunomodulatory therapeutic approaches. Overall, IL-12 can be considered an effector cytokine and has been found to engage anti-tumor immunity by activating the effector Th1 response, which is required for the activation of cytotoxic T and NK cells and tumor clearance. IL-23 and IL-27 play dual roles in tumor immunity, as they can both activate effector immune responses and promote tumor growth by favoring immune suppression. IL-35 is a potent regulatory cytokine and plays a largely pro-tumorigenic role by inhibiting effector T cells. In this review, we summarize the recent findings on IL-12 family cytokines in the control of tumor growth with an emphasis primarily on immune regulation. We underscore the clinical implications for the use of these cytokines either in the setting of monotherapy or in combination with other conventional therapies for the more effective treatment of malignancies.
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Affiliation(s)
- Bhalchandra Mirlekar
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;
| | - Yuliya Pylayeva-Gupta
- Lineberger Comprehensive Cancer Center, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA;
- Department of Genetics, The University of North Carolina at Chapel Hill School of Medicine, Chapel Hill, NC 27599, USA
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20
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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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21
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Nakajima K, Ino Y, Yamazaki-Itoh R, Naito C, Shimasaki M, Takahashi M, Esaki M, Nara S, Kishi Y, Shimada K, Hiraoka N. IAP inhibitor, Embelin increases VCAM-1 levels on the endothelium, producing lymphocytic infiltration and antitumor immunity. Oncoimmunology 2020; 9:1838812. [PMID: 33178497 PMCID: PMC7595596 DOI: 10.1080/2162402x.2020.1838812] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022] Open
Abstract
There is an increasing unmet need for successful immunotherapeutic interventions. Lymphocyte extravasation via tumor tissue endothelial cells (TECs) is required for lymphocyte infiltration into tumor sites. This study aimed to investigate the clinical significance of dysfunctional TECs in pancreatic ductal adenocarcinoma (PDAC) and identify chemical compounds that boost tumor-infiltrating lymphocyte (TIL) numbers. We performed immunohistochemical detection and clinicopathological analysis of VCAM-1 on TECs, which is essential for lymphocyte trafficking. We characterized the gene expression profiles of TECs from fresh PDAC tissues. We isolated compounds that upregulated VCAM-1 and E-selectin expression in TECs and examined their biological activities. Compared to endothelial cells from chronic pancreatitis tissue, TECs showed significantly lower VCAM-1 and E-selectin expression and significant weaknesses in lymphocyte adhesion and transmigration, resulting in decreased T cell infiltration around vessels. Patients with a relatively high percentage of VCAM-1+ vessels among all vessels in PDAC tissue had an improved prognosis. A bioinformatics survey demonstrated that TNFR1 signaling was involved in abnormal VCAM-1 and E-selectin expression in TECs. We screened compounds affecting TNFR1 signaling, and the IAP inhibitor, Embelin, induced these molecules on TECs and enhanced T cell adhesion to TECs and transmigration. Furthermore, in vivo, Embelin enhanced tumor-infiltrating T cell numbers, leading to an antitumor immune response. Embelin accelerates TIL infiltration and the antitumor immune response by recovering VCAM-1 expression in TECs. Our strategy may be a therapeutic approach for accelerating the immunotherapeutic response in immune-quiescent tumors, leading to clinical trials’ success.
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Affiliation(s)
- Kosei Nakajima
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Yoshinori Ino
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.,Department of Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Rie Yamazaki-Itoh
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Chie Naito
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Mari Shimasaki
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan
| | - Mami Takahashi
- Central Animal Division, National Cancer Center Research Institute, Tokyo, Japan
| | - Minoru Esaki
- Hepato-Biliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Satoshi Nara
- Hepato-Biliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Yoji Kishi
- Hepato-Biliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Kazuaki Shimada
- Hepato-Biliary and Pancreatic Surgery Division, National Cancer Center Hospital, Tokyo, Japan
| | - Nobuyoshi Hiraoka
- Division of Molecular Pathology, National Cancer Center Research Institute, Tokyo, Japan.,Department of Analytical Pathology, National Cancer Center Research Institute, Tokyo, Japan.,Division of Pathology and Clinical Laboratories, National Cancer Center Hospital, Tokyo, Japan
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22
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Huang BZ, Binder AM, Sugar CA, Chao CR, Setiawan VW, Zhang ZF. Methylation of immune-regulatory cytokine genes and pancreatic cancer outcomes. Epigenomics 2020; 12:1273-1285. [PMID: 32867538 DOI: 10.2217/epi-2019-0335] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Aim: Given the immunosuppressive nature of pancreatic cancer, we investigated the relationship between epigenetic modification of immune-regulatory cytokine genes and pancreatic cancer outcomes. Materials & methods: We evaluated DNA methylation of 184 pancreatic tumor samples from The Cancer Genome Atlas for 111 CpG loci in seven cytokine genes: IL10, IL6, IL8, TGFβ1, TGFβ2, TGFβ3 and TNF. We used Cox regression to evaluate the associations between methylation and overall survival, disease-specific survival and disease progression (α = 0.05). Results: Poorer survival was associated with increased methylation in fifteen CpG probes in TGFβ1, TGFβ2, TGFβ3 and TNF. We also detected improved outcomes for three loci in IL10, IL8 and IL6. Conclusion: Epigenetic regulation of cytokine-related gene expression may be associated with pancreatic cancer outcomes.
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Affiliation(s)
- Brian Z Huang
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.,Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA.,Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA
| | - Alexandra M Binder
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.,Department of Cancer Epidemiology, University of Hawaii Cancer Center, Honolulu, HI 96813, USA
| | - Catherine A Sugar
- Department of Biostatistics, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA.,Department of Psychiatry & Biobehavioral Sciences, David Geffen School of Medicine at UCLA, Los Angeles, CA 90095, USA
| | - Chun R Chao
- Department of Research & Evaluation, Kaiser Permanente Southern California, Pasadena, CA 91101, USA
| | - Veronica Wendy Setiawan
- Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles, CA 90033, USA.,Norris Comprehensive Cancer Center, Los Angeles, CA 90033, USA
| | - Zuo-Feng Zhang
- Department of Epidemiology, UCLA Fielding School of Public Health, Los Angeles, CA 90095, USA
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23
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PD-L1 engagement on T cells promotes self-tolerance and suppression of neighboring macrophages and effector T cells in cancer. Nat Immunol 2020; 21:442-454. [PMID: 32152508 DOI: 10.1038/s41590-020-0620-x] [Citation(s) in RCA: 271] [Impact Index Per Article: 54.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 01/24/2020] [Indexed: 12/13/2022]
Abstract
Programmed cell death protein 1 (PD-1) ligation delimits immunogenic responses in T cells. However, the consequences of programmed cell death 1 ligand 1 (PD-L1) ligation in T cells are uncertain. We found that T cell expression of PD-L1 in cancer was regulated by tumor antigen and sterile inflammatory cues. PD-L1+ T cells exerted tumor-promoting tolerance via three distinct mechanisms: (1) binding of PD-L1 induced STAT3-dependent 'back-signaling' in CD4+ T cells, which prevented activation, reduced TH1-polarization and directed TH17-differentiation. PD-L1 signaling also induced an anergic T-bet-IFN-γ- phenotype in CD8+ T cells and was equally suppressive compared to PD-1 signaling; (2) PD-L1+ T cells restrained effector T cells via the canonical PD-L1-PD-1 axis and were sufficient to accelerate tumorigenesis, even in the absence of endogenous PD-L1; (3) PD-L1+ T cells engaged PD-1+ macrophages, inducing an alternative M2-like program, which had crippling effects on adaptive antitumor immunity. Collectively, we demonstrate that PD-L1+ T cells have diverse tolerogenic effects on tumor immunity.
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24
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Debreli Coskun M, Sudha T, Bharali DJ, Celikler S, Davis PJ, Mousa SA. αvβ3 Integrin Antagonists Enhance Chemotherapy Response in an Orthotopic Pancreatic Cancer Model. Front Pharmacol 2020; 11:95. [PMID: 32174830 PMCID: PMC7056702 DOI: 10.3389/fphar.2020.00095] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2019] [Accepted: 01/27/2020] [Indexed: 12/19/2022] Open
Abstract
Pancreatic cancer decreases survival time and quality of life because of drug resistance and peripheral neuropathy during conventional treatment. This study was undertaken to investigate whether αvβ3 integrin receptor antagonist compounds NDAT and XT199 can suppress the development of cisplatin resistance and cisplatin-induced peripheral neuropathy in an orthotopic pancreatic SUIT2-luc cancer cell mouse model. Anticancer effects of these compounds and their combination with cisplatin were assessed in this tumor mouse model with bioluminescent signaling and histopathology, and a cytokine assay was used to examine expression of inflammatory cytokines IL-1β, IL-6, IL-10, and TNF-α from plasma samples. To determine the neuroprotective effects of the compounds on cisplatin-induced peripheral neuropathy, behavioral hind-limb posture of the mice was evaluated. The combination therapy of NDAT or XT199 with cisplatin elicited greater inhibition of tumor growth and increased tumor necrosis compared to cisplatin alone. NDAT and XT199 in combination with cisplatin significantly decreased expression of pro-inflammatory cytokines IL-1β, IL-6, and TNF-α and significantly increased expression of anti-inflammatory cytokine IL-10 in comparison to cisplatin alone. Cisplatin-treated groups showed stocking-glove hind-limb posture, whereas NDAT and XT199 with cisplatin-treated groups displayed normal hind-limb posture. Results clearly suggest that NDAT and XT199 treatment with cisplatin that inactivates NF-κB may contribute to increased antitumor and anti-inflammatory efficacy as well as alleviate cisplatin-mediated loss of motor function in this pancreatic tumor mouse model.
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Affiliation(s)
- Melis Debreli Coskun
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States.,Department of Biology, Faculty of Arts and Sciences, Uludag University, Bursa, Turkey
| | - Thangirala Sudha
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States
| | - Dhruba J Bharali
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States
| | - Serap Celikler
- Department of Biology, Faculty of Arts and Sciences, Uludag University, Bursa, Turkey
| | - Paul J Davis
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States.,Department of Medicine, Albany Medical College, Albany, NY, United States
| | - Shaker A Mousa
- Pharmaceutical Research Institute, Albany College of Pharmacy and Health Sciences, Rensselaer, NY, United States
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25
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Kim JH. Interleukin-8 in the Tumor Immune Niche: Lessons from Comparative Oncology. ADVANCES IN EXPERIMENTAL MEDICINE AND BIOLOGY 2020; 1240:25-33. [PMID: 32060885 DOI: 10.1007/978-3-030-38315-2_2] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/12/2022]
Abstract
Interleukin (IL)-8 is a chemokine that is essential for inflammation and angiogenesis. IL-8 expression is elevated in tumor cell lines and tissues, as well as in peripheral blood obtained from cancer patients. Primary works have attempted to determine the biological effect of IL-8 on tumor cells, including cell proliferation, survival, and migration. More recently, IL-8 has acquired considerable attention as an immune modulator in the context of certain tumor microenvironments (TME); specifically, it can support a niche that favors tumor progression and metastasis. Tumor-derived IL-8 stimulates inflammation by interacting with the microenvironmental constituents, including fibroblasts, endothelial cells, and immune cells. However, the tumor immune system is complex, and mechanisms that construct the immune phenotype remain incompletely characterized. Herein, we will (1) address a potential role of IL-8 in regulating gene expression to establish immune landscape in tumor. Then, we will (2) review IL-8 signaling in the maintenance of stem cells and regulation of hematopoietic progenitors. Finally, (3) IL-8 functions will be discussed in naturally occurring animal cancers that offer a clinically realistic model for translational research. This chapter will provide a new insight into the tumor immune niche and help us develop immunotherapies for cancers.
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Affiliation(s)
- Jong-Hyuk Kim
- Animal Cancer Care and Research Program, University of Minnesota, St Paul, MN, USA. .,Department of Veterinary Clinical Sciences, College of Veterinary Medicine, University of Minnesota, St Paul, MN, USA. .,Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
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26
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Kruger D, Yako YY, Devar J, Lahoud N, Smith M. Inflammatory cytokines and combined biomarker panels in pancreatic ductal adenocarcinoma: Enhancing diagnostic accuracy. PLoS One 2019; 14:e0221169. [PMID: 31415645 PMCID: PMC6695103 DOI: 10.1371/journal.pone.0221169] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/08/2019] [Accepted: 07/31/2019] [Indexed: 12/11/2022] Open
Abstract
Background Early diagnosis of pancreatic ductal adenocarcinoma (PDAC) is challenged by the absence of accurate early diagnostic and prognostic biomarkers. CA19-9 is the established, diagnostic tumour marker in PDAC, despite its limitations. Effective primary screening using circulating biomarker panels have only been considered in a handful of studies and we investigated whether combinations of inflammatory cytokines and angiogenic factors in multivariate logistic models could facilitate earlier diagnosis in our South African setting. Methods Plasma levels of 38 cytokines and angiogenic factors were measured in 131 Black South African patients, 85 with PDAC, 25 with benign biliary pathology (BBP) and 21 benign non-HPB controls (BC), by use of human magnetic multiplex screening assays. Multivariate biomarker panels were developed by identifying the top performing biomolecules from univariate logistic regression. Receiver-operator characteristic (ROC) curves and area under the ROC curve (AUC) are reported. Results Classification modelling to distinguish PDAC patients from BC showed that a panel of CA19-9 and CXCL10 (IP-10) demonstrated improved diagnostic power over CA19-9 alone (AUC = 0.977 vs. AUC = 0.807, p-value = 0.001). A combined panel including age, BMI and IL-15 showed significant diagnostic power in discriminating PDAC from BBP (AUC = 0.952, p < 0.0001). Finally, a combined panel of IL-8, IL-15 and gender demonstrated diagnostic accuracy (AUC = 0.830, p < 0.0001) in distinguishing PDAC in the presence of jaundice from benign controls with either jaundice, choledocholithiasis or common bile duct injury. Conclusions Combined biomarker panels improve diagnostic accuracy in PDAC. In addition to CA19-9, cytokines CXCL10, IL-8 and IL-15 are strong additions to diagnostic biomarker panels in PDAC in Black South Africans.
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Affiliation(s)
- Deirdré Kruger
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- * E-mail:
| | - Yandiswa Y. Yako
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - John Devar
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Hepato-Pancreatico-Biliary Unit, Department of General Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
| | - Nicola Lahoud
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
| | - Martin Smith
- Department of Surgery, School of Clinical Medicine, Faculty of Health Sciences, University of the Witwatersrand, Johannesburg, South Africa
- Hepato-Pancreatico-Biliary Unit, Department of General Surgery, Chris Hani Baragwanath Academic Hospital, Johannesburg, South Africa
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27
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Mirandola M, Sabogal Rueda MD, Andreis F, Meriggi F, Codignola C, Gadaldi E, Prochilo T, Libertini M, Di Biasi B, Abeni C, Noventa S, Rota L, Ogliosi C, Zaniboni A. Yoga Protocol for Cancer Patients: A Systematic Exploration of Psychophysiological Benefits. Rev Recent Clin Trials 2019; 14:261-268. [PMID: 31362680 DOI: 10.2174/1574887114666190729143742] [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: 03/26/2019] [Revised: 04/24/2019] [Accepted: 07/19/2019] [Indexed: 11/22/2022]
Abstract
BACKGROUND Several studies report that practicing Yoga may lead to numerous psychophysiological benefits in patients undergoing treatment for cancer. Moreover, it may result in an effective alternative for coping with sleep disturbances, anxiety, depression and fatigue symptoms. A study based on the "Yoga in Oncology" project of the Foundation Poliambulanza was carried out, and it was designed to explore the benefits of Yoga, therefore corroborating Yoga as a therapeutic activity that can have a beneficial impact on patients diagnosed with cancer. METHODS Seventy patients were recruited, of whom 20% were males and 80% were females 18 years of age and older. All patients were being treated at the oncology department for gastrointestinal, mammary or genital carcinoma, and the disease was metastatic in 80% of patients. Data were collected between April 2013 and May 2017. The protocol consisted of a weekly 90-minute Yoga lesson for 8 consecutive weeks, and the data collection was carried out in 2 phases: (T0) preprotocol assessment and (T1) postprotocol assessment. Psychophysiological assessment was carried out with the following scales: the (BFI) Brief Fatigue Inventory, (HADS) Hospital Anxiety and Depression Scale and (PSQI) Pittsburgh Sleep Quality Index. RESULTS Data analysis showed a significant difference between the (T0) and (T1) HADS (Hospital Anxiety and Depression Scale) scores. The constructs of this scale consist of psychological variables for the assessment of anxiety and depression. In contrast, scores from the (BFI) Brief Fatigue Inventory and (PSQI) Pittsburgh Sleep Quality Index did not show significant differences between (T0) and (T1): such scales are relative to psychophysiological variables for an assessment of the perception of fatigue and quality of sleep. CONCLUSION It is noteworthy that the data, once analyzed, showed a significant difference between preprotocol and postprotocol levels of anxiety and depression but not for the perception of fatigue or the quality of sleep. In accordance with the scientific literature, data from this study highlight that practicing Yoga may promote changes in the levels of perceived anxiety and depression in patients undergoing treatment for cancer, thus positively affecting their (QoL). It is clear that the difference in significance between the psychological and physiological variables considered here and the statistical significance found only in levels of anxiety and depression encourage further studies to account for the nature of fatigue and sleep disturbances and how to address these symptoms in oncological patients. Moreover, other points of interest for future clinical research regard the evaluation of the reason for the possible denial to participate to this kind of study, as well as the social-cultural differences in patients' behavior.
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Affiliation(s)
- Mara Mirandola
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | | | - Federica Andreis
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Fausto Meriggi
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Claudio Codignola
- General Surgery Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Elena Gadaldi
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Tiziana Prochilo
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Michela Libertini
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Brunella Di Biasi
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Chiara Abeni
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Silvia Noventa
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Luigina Rota
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Chiara Ogliosi
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
| | - Alberto Zaniboni
- Oncology Department, Poliambulanza Foundation, via Leonida Bissolati 57, 25124 Brescia, Italy
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28
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Ramsey ML, Talbert E, Ahn D, Bekaii-Saab T, Badi N, Bloomston PM, Conwell DL, Cruz-Monserrate Z, Dillhoff M, Farren MR, Hinton A, Krishna SG, Lesinski GB, Mace T, Manilchuk A, Noonan A, Pawlik TM, Rajasekera PV, Schmidt C, Guttridge D, Hart PA. Circulating interleukin-6 is associated with disease progression, but not cachexia in pancreatic cancer. Pancreatology 2019; 19:80-87. [PMID: 30497874 PMCID: PMC6613190 DOI: 10.1016/j.pan.2018.11.002] [Citation(s) in RCA: 31] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/12/2018] [Revised: 09/09/2018] [Accepted: 11/09/2018] [Indexed: 12/11/2022]
Abstract
BACKGROUND Cachexia is a wasting syndrome characterized by involuntary loss of >5% body weight due to depletion of adipose and skeletal muscle mass. In cancer, the pro-inflammatory cytokine interleukin-6 (IL-6) is considered a mediator of cachexia and a potential biomarker, but the relationship between IL-6, weight loss, and cancer stage is unknown. In this study we sought to evaluate IL-6 as a biomarker of cancer cachexia while accounting for disease progression. METHODS We retrospectively studied 136 subjects with biopsy-proven pancreatic ductal adenocarcinoma (PDAC), considering the high prevalence of cachexia is this population. Clinical data were abstracted from subjects in all cancer stages, and plasma IL-6 levels were measured using a multiplex array and a more sensitive ELISA. Data were evaluated with univariate comparisons, including Kaplan-Meier survival curves, and multivariate Cox survival models. RESULTS On multiplex, a total of 43 (31.4%) subjects had detectable levels of plasma IL-6, while by ELISA all subjects had detectable IL-6 levels. We found that increased plasma IL-6 levels, defined as detectable for multiplex and greater than median for ELISA, were not associated with weight loss at diagnosis, but rather with the presence of metastasis (p < 0.001 for multiplex and p = 0.007 for ELISA). Further, while >5% weight loss was not associated with worse survival, increased plasma IL-6 by either methodology was. CONCLUSION Circulating IL-6 levels do not correlate with cachexia (when defined by weight loss), but rather with advanced cancer stage. This suggests that IL-6 may mediate wasting, but should not be considered a diagnostic biomarker for PDAC-induced cachexia.
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Affiliation(s)
- Mitchell L Ramsey
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Erin Talbert
- Department of Cancer Biology and Genetics and The Ohio State University Comprehensive Cancer Center Cachexia Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Daniel Ahn
- Division of Hematology/Medical Oncology, Mayo Clinic, Phoenix, AZ, USA
| | | | - Niharika Badi
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | | | - Darwin L Conwell
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Zobeida Cruz-Monserrate
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Mary Dillhoff
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Matthew R Farren
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Alice Hinton
- Division of Biostatistics, The Ohio State University, Columbus, OH, USA
| | - Somashekar G Krishna
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Gregory B Lesinski
- Department of Hematology and Medical Oncology, Winship Cancer Institute of Emory University, Atlanta, GA, USA
| | - Thomas Mace
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA; Comprehensive Cancer Center, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Andrei Manilchuk
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Anne Noonan
- Division of Medical Oncology, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Timothy M Pawlik
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Priyani V Rajasekera
- Department of Cancer Biology and Genetics and The Ohio State University Comprehensive Cancer Center Cachexia Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Carl Schmidt
- Department of Surgery, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Denis Guttridge
- Department of Cancer Biology and Genetics and The Ohio State University Comprehensive Cancer Center Cachexia Program, The Ohio State University Wexner Medical Center, Columbus, OH, USA
| | - Phil A Hart
- Division of Gastroenterology, Hepatology, and Nutrition, The Ohio State University Wexner Medical Center, Columbus, OH, USA.
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Casadonte R, Kriegsmann M, Perren A, Baretton G, Deininger S, Kriegsmann K, Welsch T, Pilarsky C, Kriegsmann J. Development of a Class Prediction Model to Discriminate Pancreatic Ductal Adenocarcinoma from Pancreatic Neuroendocrine Tumor by MALDI Mass Spectrometry Imaging. Proteomics Clin Appl 2018; 13:e1800046. [DOI: 10.1002/prca.201800046] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/05/2018] [Revised: 11/05/2018] [Indexed: 12/13/2022]
Affiliation(s)
| | - Mark Kriegsmann
- Institute of PathologyUniversity of Heidelberg Heidelberg 69120 Germany
| | - Aurel Perren
- Institute of PathologyUniversity of Bern Bern 3012 Switzerland
| | - Gustavo Baretton
- Institute of PathologyUniversity Hospital Carl Gustav Carus at the Technical University of Dresden Dresden 01307 Germany
| | | | - Katharina Kriegsmann
- Department of HematologyOncology and RheumatologyUniversity of Heidelberg Heidelberg 69120 Germany
| | - Thilo Welsch
- Institute of PathologyUniversity Hospital Carl Gustav Carus at the Technical University of Dresden Dresden 01307 Germany
| | - Christian Pilarsky
- Institute of PathologyUniversity Hospital Carl Gustav Carus at the Technical University of Dresden Dresden 01307 Germany
| | - Jörg Kriegsmann
- Proteopath GmbH Trier 54296 Germany
- MVZ for HistologyCytology and Molecular Diagnostics Trier 54296 Germany
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30
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Kim M, Park JM, Lee SJ, Kang CD, Kang M, Kim JH, Lee S, Cho SW. [Pancreatic Neuroendocrine Tumor Presenting as Acute Pancreatitis]. THE KOREAN JOURNAL OF GASTROENTEROLOGY 2018; 71:98-102. [PMID: 29471608 DOI: 10.4166/kjg.2018.71.2.98] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 11/03/2022]
Abstract
We report a case of acute pancreatitis secondary to pancreatic neuroendocrine tumor. A 46-year old man presented with upper abdominal pain. The serum amylase and lipase were elevated. Abdominal computed tomography (CT) and magnetic resonance cholangiopancreatography revealed a 1.7 cm sized mass at the pancreas body with a dilatation of the upstream pancreatic duct and mild infiltrations of peripancreatic fat. An endoscopic ultrasound-guided fine needle biopsy was performed for the pancreatic mass, but only necrotic tissue was observed on the pathologic examination. A chest and neck CT scan revealed anterior mediastinal, paratracheal, and cervical lymph node enlargement, which were indicative of metastasis. An ultrasound-guided core needle biopsy was performed for the enlarged neck lymph node, and pathologic examination revealed a metastatic poorly differentiated carcinoma. Immunohistochemical analysis showed positive staining for synaptophysin, chromogranin A, and CD 56, indicative of a neuroendocrine carcinoma.
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Affiliation(s)
- Minjeong Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Jin Myung Park
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Sung Joon Lee
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Chang Don Kang
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - MyungHo Kang
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Ji Hyun Kim
- Department of Internal Medicine, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Seungkoo Lee
- Department of Anatomic Pathology, Kangwon National University School of Medicine, Chuncheon, Korea
| | - Seong Whi Cho
- Department of Radiology, Kangwon National University School of Medicine, Chuncheon, Korea
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31
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Abstract
Pancreatic cancer is characterized by an extensive fibroinflammatory reaction that includes immune cells, fibroblasts, extracellular matrix, vascular and lymphatic vessels, and nerves. Overwhelming evidence indicates that the pancreatic cancer microenvironment regulates cancer initiation, progression, and maintenance. Pancreatic cancer treatment has progressed little over the past several decades, and the prognosis remains one of the worst for any cancer. The contribution of the microenvironment to carcinogenesis is a key area of research, offering new potential targets for treating the disease. Here, we explore the composition of the pancreatic cancer stroma, discuss the network of interactions between different components, and describe recent attempts to target the stroma therapeutically. We also discuss current areas of active research related to the tumor microenvironment.
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Affiliation(s)
- Yaqing Zhang
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA;
| | - Howard C Crawford
- Department of Molecular and Integrative Physiology, University of Michigan, Ann Arbor, Michigan 48109, USA.,Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA
| | - Marina Pasca di Magliano
- Department of Surgery, University of Michigan, Ann Arbor, Michigan 48109, USA; .,Rogel Cancer Center, University of Michigan, Ann Arbor, Michigan 48109, USA.,Department of Cell and Developmental Biology, University of Michigan, Ann Arbor, Michigan 48109, USA
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32
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Immune dysregulation in cancer patients developing immune-related adverse events. Br J Cancer 2018; 120:63-68. [PMID: 30377338 PMCID: PMC6325132 DOI: 10.1038/s41416-018-0155-1] [Citation(s) in RCA: 131] [Impact Index Per Article: 18.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/09/2018] [Revised: 05/24/2018] [Accepted: 06/01/2018] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Up to 40% of cancer patients on immune checkpoint inhibitors develop clinically significant immune-related adverse events (irAEs). The role of host immune status and function in predisposing patients to the development of irAEs remains unknown. METHODS Sera from 65 patients receiving immune checkpoint inhibitors and 13 healthy controls were evaluated for 40 cytokines at pre-treatment, after 2-3 weeks and after 6 weeks and analysed for correlation with the development of irAEs. RESULTS Of the 65 cancer patients enrolled, 55% were women; the mean age was 65 years and 98% received anti-PD1/PDL1 therapy. irAEs occurred in 35% of cases. Among healthy controls, cytokine levels were stable over time and lower than those in cancer patients at baseline. Significant increases in CXCL9, CXCL10, CXCL11 and CXCL13 occurred 2 weeks post treatment, and in CXCL9, CXCL10, CXCL11, CXCL13, IL-10 and CCL26 at 6 weeks post treatment. Patients who developed irAEs had lower levels of CXCL9, CXCL10, CXCL11 and CXCL19 at baseline and exhibited greater increases in CXCL9 and CXCL10 levels at post treatment compared to patients without irAEs. CONCLUSIONS Patients who developed irAEs have lower baseline levels and greater post-treatment increases in multiple cytokine levels, suggesting that underlying immune dysregulation may be associated with heightened risk for irAEs.
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Shen L, Li J, Liu Q, Song W, Zhang X, Tiruthani K, Hu H, Das M, Goodwin TJ, Liu R, Huang L. Local Blockade of Interleukin 10 and C-X-C Motif Chemokine Ligand 12 with Nano-Delivery Promotes Antitumor Response in Murine Cancers. ACS NANO 2018; 12:9830-9841. [PMID: 30253648 DOI: 10.1021/acsnano.8b00967] [Citation(s) in RCA: 95] [Impact Index Per Article: 13.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 06/08/2023]
Abstract
In many cancers, the tumor microenvironment (TME) is largely immune suppressive, blocking the antitumor immunity and resulting in immunotherapy resistance. Interleukin 10 (IL-10) is a major player controlling the immunosuppressive TME in different murine tumor models. Increased IL-10 production suppresses intratumoral dendritic cell production of interleukin 12, thereby limiting antitumor cytotoxic T-cell responses and activation of NK cells during therapy. We engineered, formulated, and delivered genes encoding an IL-10 protein trap to change immunosuppressive TME, which could enhance antitumor immunity. Additionally, to achieve stronger and long-term therapeutic efficacy in a pancreatic cancer model, we targeted C-X-C motif chemokine ligand 12 (CXCL12), a key factor for inhibiting T-cell tumor infiltration, and simultaneously delivered an IL-10 trap. Following three injections of the lipid-protamine-DNA (LPD) nanoparticles loaded with trap genes (IL-10 trap and CXCL12 trap), we found tumor growth reduction and significantly prolonged survival of the host compared to control groups. Furthermore, the combination trap gene treatment significantly reduced immunosuppressive cells, such as M2 macrophages, MDSCs, and PD-L1+ cells, and activated immunosuppressive tolerogenic dendritic cells, NK cells, and macrophages intratumorally. We have also shown that, when effectively delivered to the tumor, the IL-10 trap gene alone can inhibit triple-negative breast cancer growth. This strategy may allow clinicians and researchers to change the immunosuppressive microenvironment in the tumor with either a single therapeutic agent or in combination with other immunotherapies to prime the immune system, preventing cancer invasion and prolonging patient survival.
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34
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Bodnarczuk T, Deskur A, Dolegowska K, Dolegowska B, Starzynska T, Blogowski W. Hydroxyeicosatetraenoic acids in patients with pancreatic cancer: a preliminary report. Am J Cancer Res 2018; 8:1865-1872. [PMID: 30323978 PMCID: PMC6176181] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2018] [Accepted: 08/23/2018] [Indexed: 06/08/2023] Open
Abstract
Previous experimental reports have demonstrated that lipoxygenase (LOX) derivatives of arachidonic acid (AA), such as hydroxyeicosatetraenoic acids (HETEs), may be of significance in the pathogenesis of pancreatic cancer. However, these observations have not been confirmed in clinical studies. In the current study, we comprehensively evaluated the systemic levels of selected LOX-derived HETEs such as 5-, 12- and 15-HETE in patients with pancreatic adenocarcinoma (n=36), chronic pancreatitis (n=39), and in healthy individuals (n=35). Compared to healthy individuals, patients with pancreatic adenocarcinoma showed 3-8-fold higher levels of 5-, 12- and 15-HETE (at least P<0.003). Similar results were observed in patients with chronic pancreatitis, who had elevated concentrations of all examined HETE acids compared to healthy volunteers (in all cases at least P<0.03). Interestingly, the levels of the examined HETEs were not significantly associated with the TNM stage of pancreatic cancer in our patients. Finally, analyses of receiver operating characteristic curves demonstrated that all HETEs examined had relatively low area under the curve values for discriminating pancreatic adenocarcinoma from non-cancerous conditions (0.49-0.61; P>0.05 in each case). Our study provides first preliminary clinical evidence for the significance of the examined HETEs in the clinical pathogenesis of pancreatic cancer and other pancreatic diseases in humans. Moreover, our data demonstrate that the HETEs examined here do not show sufficient clinical potential to be used as independent (bio)markers for differentiating pancreatic adenocarcinoma from other non-cancerous conditions in humans.
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Affiliation(s)
- Tomasz Bodnarczuk
- Department of Gastroenterology, Pomeranian Medical UniversitySzczecin, Poland
| | - Anna Deskur
- Department of Gastroenterology, Pomeranian Medical UniversitySzczecin, Poland
| | - Katarzyna Dolegowska
- Department of Microbiology, Immunology and Laboratory Medicine, Pomeranian Medical UniversitySzczecin, Poland
| | - Barbara Dolegowska
- Department of Microbiology, Immunology and Laboratory Medicine, Pomeranian Medical UniversitySzczecin, Poland
| | - Teresa Starzynska
- Department of Gastroenterology, Pomeranian Medical UniversitySzczecin, Poland
| | - Wojciech Blogowski
- Department of Internal Medicine, University of Zielona GoraZielona Gora, Poland
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35
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Zhang L, Tao L, Guo L, Zhan J, Yuan C, Ma Z, Jiang B, Xiu D. G-CSF associates with neurogenesis and predicts prognosis and sensitivity to chemotherapy in pancreatic ductal adenocarcinoma. Cancer Manag Res 2018; 10:2767-2775. [PMID: 30147373 PMCID: PMC6103318 DOI: 10.2147/cmar.s165226] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/28/2022] Open
Abstract
Background Recent studies demonstrated that granulocyte colony-stimulating factor (G-CSF), regularly used for the prevention of neutropenia, is engaged in cancer progression. However, the role of G-CSF in pancreatic ductal adenocarcinoma (PDAC) is not clear. The aim of the present study was to investigate the expression and prognostic value of G-CSF in patients with PDAC. Materials and methods The localization and expression of G-CSF in PDAC were examined by immunohistochemistry (IHC). The analysis of the levels of G-CSF in plasma was evaluated using ELISA kit. The correlation between G-CSF expression and patients’ survival was assessed by Kaplan–Meier analysis. Results In IHC specimens, G-CSF was discovered predominantly in the cell cytoplasm and expressed in most of PDAC, while in plasma, the systemic level of G-CSF is no different between normal patients and pancreatic cancer patients. In 100 PDAC cases with IHC, patients with grades 2 and 3 were defined as the high expression group (41 patients, 41%), and those with grades 0 and 1 as the low expression group (59 patients, 59%). Significant correlation was noted between high G-CSF expression and neural invasion (P = 0.042) or early recurrence (P < 0.001). G-CSF appeared to be an independent adverse prognostic factor (hazard ratio = 1.774, 95% confidence interval 1.150–2.737, P = 0.010) in addition to N stage (P = 0.002). Specifically, adjuvant chemotherapy consisting of gemcitabine prolongs survival of patients with high G-CSF expression (median survival time 14 months vs 7.5 months). Morphologically, high G-CSF expression cells demonstrate the association with neurogenesis. Conclusion High expression of G-CSF is a prognostic marker and an indicator to chemotherapy response in PDAC.
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Affiliation(s)
- Lingfu Zhang
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China,
| | - Lianyuan Tao
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China,
| | - Limei Guo
- Department of Pathology, Peking University Third Hospital, Beijing, People's Republic of China
| | - Jun Zhan
- Laboratory of Molecular Cell Biology and Tumor Biology, Department of Anatomy, Histology and Embryology, Peking University Health Science Center, Beijing, People's Republic of China
| | - Chunhui Yuan
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China,
| | - Zhaolai Ma
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China,
| | - Bin Jiang
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China,
| | - Dianrong Xiu
- Department of General Surgery, Peking University Third Hospital, Beijing, People's Republic of China,
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36
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Lewis HL, Chakedis JM, Talbert E, Haverick E, Rajasekera P, Hart P, Bloomston M, Dillhoff M, Pawlik TM, Guttridge D, Schmidt CR. Perioperative cytokine levels portend early death after pancreatectomy for ductal adenocarcinoma. J Surg Oncol 2018; 117:1260-1266. [PMID: 29205349 DOI: 10.1002/jso.24940] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2017] [Accepted: 11/05/2017] [Indexed: 02/06/2023]
Abstract
BACKGROUND Soluble signaling molecules may play an important role in malignant pathogenesis. We hypothesize that perioperative cytokine levels are associated with outcomes in patients with pancreatic adenocarcinoma (PDAC) undergoing surgical resection. METHODS One hundered and eighteen patients with benign or malignant pancreatic disease were enrolled in a prospective study through a protocol for banking biologic samples. Peripheral blood was drawn at time of operation, and a multiplex cytokine assay was performed. Statistical analysis was via χ2 and Kaplan Meier methods. RESULTS Of 118 patients enrolled, 85 (72%) had a diagnosis of PDAC, and 60 (70%) ultimately underwent partial pancreatectomy. Cytokine levels were not associated with postoperative complications in this initial cohort. A plasma level of monocyte chemoattractant protein-1 (MCP-1) pg/mL ≤118 was associated with better overall survival (OS) (median survival 21 months vs 12.8 months, P = 0.023), as was non-detectable interleukin-8 (IL-8) (19 months) versus detectable IL-8 (12.8 months, P = 0.05). Patients with both MCP-1 >118 pg/mL and detectable IL-8 had a median survival of 10.6 months (P = 0.028). CONCLUSIONS MCP-1 and IL-8 cytokine levels are associated with decreased survival following pancreatectomy for PDAC, and may be useful biomarkers. Measurement of these cytokine levels at different time points in future investigations will be important to validate these findings.
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Affiliation(s)
- Heather L Lewis
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Jeff M Chakedis
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Erin Talbert
- Center for Regenerative Medicine and Cell Based Therapies, College of Medicine, Ohio State University, Columbus, Ohio
| | - Ericka Haverick
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Priyani Rajasekera
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Philip Hart
- Department of Gastroenterology, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | | | - Mary Dillhoff
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Timothy M Pawlik
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
| | - Denis Guttridge
- Center for Regenerative Medicine and Cell Based Therapies, College of Medicine, Ohio State University, Columbus, Ohio
| | - Carl R Schmidt
- Division of Surgical Oncology, Department of Surgery, Wexner Medical Center, Ohio State University, Columbus, Ohio
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37
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Maddaly R, Subramaniyan A, Balasubramanian H. Cancer Cytokines and the Relevance of 3D Cultures for Studying Those Implicated in Human Cancers. J Cell Biochem 2017; 118:2544-2558. [PMID: 28262975 DOI: 10.1002/jcb.25970] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/11/2017] [Accepted: 03/02/2017] [Indexed: 01/29/2023]
Abstract
Cancers are complex conditions and involve several factors for oncogenesis and progression. Of the various factors influencing the physiology of cancers, cytokines are known to play significant roles as mediators of functions. Intricate cytokine networks have been identified in cancers and interest in cytokines associated with cancers has been gaining ground. Of late, some of these cytokines are even identified as potential targets for cancer therapy apart from a few others such as IL-6 being identified as markers for disease prognosis. Of the major contributors to cancer research, cancer cell lines occupy the top slot as the most widely used material in vitro. In vitro cell cultures have seen significant evolution by the introduction of 3-dimensional (3D) culture systems. 3D cell cultures are now widely accepted as excellent material for cancer research which surpass the traditional monolayer cultures. Cancer research has benefited from 3D cell cultures for understanding the various hallmarks of cancers. However, the potential of these culture systems are still unexploited for cancer cytokine research compared to the other aspects of cancers such as gene expression changes, drug-induced toxicity, morphology, angiogenesis, and invasion. Considering the importance of cancer cytokines, 3D cell cultures can be better utilized in understanding their roles and functions. Some of the possibilities where 3D cell cultures can contribute to cancer cytokine research arise from the distinct morphology of the tumor spheroids, the extracellular matrix (ECM), and the spontaneous occurrence of nutrient and oxygen gradients. Also, the 3D culture models enable one to co-culture different types of cells as a simulation of in vivo conditions, enhancing their utility to study cancer cytokines. We review here the cancer associated cytokines and the contributions of 3D cancer cell cultures for studying cancer cytokines. J. Cell. Biochem. 118: 2544-2558, 2017. © 2017 Wiley Periodicals, Inc.
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Affiliation(s)
- Ravi Maddaly
- Faculty of Biomedical Sciences, Technology, and Research, Department of Human Genetics, Sri Ramachandra University, Porur, Chennai 600116, India
| | - Aishwarya Subramaniyan
- Faculty of Biomedical Sciences, Technology, and Research, Department of Human Genetics, Sri Ramachandra University, Porur, Chennai 600116, India
| | - Harini Balasubramanian
- Faculty of Biomedical Sciences, Technology, and Research, Department of Human Genetics, Sri Ramachandra University, Porur, Chennai 600116, India
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38
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Salmiheimo A, Mustonen H, Vainionpää S, Shen Z, Kemppainen E, Puolakkainen P, Seppänen H. Tumour-associated macrophages activate migration and STAT3 in pancreatic ductal adenocarcinoma cells in co-cultures. Pancreatology 2017; 17:635-641. [PMID: 28476581 DOI: 10.1016/j.pan.2017.04.013] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/18/2016] [Revised: 03/29/2017] [Accepted: 04/24/2017] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Tumour-associated macrophages participate in tumour development and progression. The aim of this study was to assess the interactions of pancreatic cancer cells and pro-inflammatory M1 and anti-inflammatory M2 macrophages, specifically their effect on pancreatic cancer cell migration and the changes in STAT-signalling. METHODS Monocytes were isolated from healthy subjects and differentiated into macrophages with M-CSF. The macrophages were polarized towards M1 by IL-12 and towards M2 by IL-10. We studied also the effect of pan-JAK/STAT-inhibitor P6. Macrophage polarization and STAT and NFkB-activation in both MiaPaCa-2 and macrophages were assessed by flow cytometry. We recorded the effect of co-culture on migration rate of pancreatic cancer cells MiaPaCa-2. RESULTS Macrophages increased the migration rate of pancreatic cancer cells. Co-culture activated STAT1, STAT3, STAT5, AKT, and NFkB in macrophages and STAT3 in MiaPaCa-2 cells. IL-12 polarized macrophages towards M1 and decreased the migration rate of pancreatic cancer cells in co-cultures as well as P6. IL-10 skewed macrophage polarization towards M2 and induced increase of pancreatic cancer cells in co-cultures. CONCLUSION Co-culture with macrophages increased pancreatic cancer cell migration and activated STAT3. It is possible to activate and deactivate migration of pancreatic cancer cells trough macrophage polarization.
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Affiliation(s)
- Aino Salmiheimo
- Department of Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Harri Mustonen
- Department of Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Sanna Vainionpää
- Department of Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Zhanlong Shen
- Department of Gastroenterological Surgery, Peking University People's Hospital, Beijing, China
| | - Esko Kemppainen
- Department of Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
| | - Pauli Puolakkainen
- Department of Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland.
| | - Hanna Seppänen
- Department of Surgery, University of Helsinki, Helsinki University Hospital, Helsinki, Finland
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39
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Kumari N, Agrawal U, Mishra AK, Kumar A, Vasudeva P, Mohanty NK, Saxena S. Predictive role of serum and urinary cytokines in invasion and recurrence of bladder cancer. Tumour Biol 2017; 39:1010428317697552. [PMID: 28378639 DOI: 10.1177/1010428317697552] [Citation(s) in RCA: 33] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/15/2022] Open
Abstract
Urothelial cancer patients are prone to recurrence, and there is no marker to predict which cases become refractory to the immunotherapy given to these patients. Tumour behaviour is decided by the dynamics between the pro- and anti-tumorigenic cytokines. In this study, 27 cytokines were estimated in serum and urine of 72 urothelial cancer patients and 42 healthy volunteer controls. Serum cytokines IL-1RA, IL-4 and RANTES were in significantly higher concentration in serum of patients compared to controls, while IL-2 was significantly less in concentration. Patients were found to have significantly high concentrations of 12 urinary cytokines (IL-2, IL-4, IL-8, IL-10, GM-CSF, IFN-γ, IP-10, MIP-1a, PDGF, MIP-1b, RANTES and VEGF) in comparison to healthy controls. Serum VEGF and urinary IL-1ra, IL-4, IL-10, GM-CSF, IP-10, MIP-1a and MIP-1b concentrations were found significantly higher in concentration in high-grade tumours compared to low-grade tumours. There was no difference in either the serum or urinary cytokines between non-invasive and muscle-invasive cases. Serum IL-1ra, IL-6, IL-10, TNF-α and VEGF and urinary IL-1ra, IL-4, IL-8, IL-10, GM-CSF, IP-10, MIP-1a, PDGF, MIP-1b and VEGF were found to be significantly higher in recurrent patients compared to non-recurrent patients. Of these, high concentrations of urinary IL-1RA, IL-4, IL-10, IP-10, PDGF and VEGF and serum IL-1ra, IL-6, IL-10, VEGF and TNF-α were associated with poor recurrence-free survival. Poor recurrence-free survival was also seen with increasing number of cytokines showing high concentrations. The study shows that the estimation of a combination of these cytokines in minimally or non-invasive samples may act as a prognostic indicator.
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Affiliation(s)
- Nitu Kumari
- 1 National Institute of Pathology (Indian Council of Medical Research), New Delhi, India.,2 BITS Pilani, Pilani, India
| | - Usha Agrawal
- 1 National Institute of Pathology (Indian Council of Medical Research), New Delhi, India.,3 Faculty of Health and Biomedical Sciences, Symbiosis International University, Pune, India
| | | | - Anup Kumar
- 5 Department of Urology, Safdarjung Hospital, New Delhi, India
| | - Pawan Vasudeva
- 5 Department of Urology, Safdarjung Hospital, New Delhi, India
| | | | - Sunita Saxena
- 1 National Institute of Pathology (Indian Council of Medical Research), New Delhi, India
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40
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Khan MAA, Azim S, Zubair H, Bhardwaj A, Patel GK, Khushman M, Singh S, Singh AP. Molecular Drivers of Pancreatic Cancer Pathogenesis: Looking Inward to Move Forward. Int J Mol Sci 2017; 18:ijms18040779. [PMID: 28383487 PMCID: PMC5412363 DOI: 10.3390/ijms18040779] [Citation(s) in RCA: 45] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/02/2017] [Revised: 03/28/2017] [Accepted: 03/30/2017] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PC) continues to rank among the most lethal cancers. The consistent increase in incidence and mortality has made it the seventh leading cause of cancer-associated deaths globally and the third in the United States. The biggest challenge in combating PC is our insufficient understanding of the molecular mechanism(s) underlying its complex biology. Studies during the last several years have helped identify several putative factors and events, both genetic and epigenetic, as well as some deregulated signaling pathways, with implications in PC onset and progression. In this review article, we make an effort to summarize our current understanding of molecular and cellular events involved in the pathogenesis of pancreatic malignancy. Specifically, we provide up-to-date information on the genetic and epigenetic changes that occur during the initiation and progression of PC and their functional involvement in the pathogenic processes. We also discuss the impact of the tumor microenvironment on the molecular landscape of PC and its role in aggressive disease progression. It is envisioned that a better understanding of these molecular factors and the mechanisms of their actions can help unravel novel diagnostic and prognostic biomarkers and can also be exploited for future targeted therapies.
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Affiliation(s)
- Mohammad Aslam Aslam Khan
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Shafquat Azim
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Haseeb Zubair
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Arun Bhardwaj
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Girijesh Kumar Patel
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Moh'd Khushman
- Departments of Interdisciplinary Clinical Oncology, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
| | - Seema Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
| | - Ajay Pratap Singh
- Department of Oncologic Sciences, Mitchell Cancer Institute, University of South Alabama, Mobile, AL 36604, USA.
- Department of Biochemistry and Molecular Biology, College of Medicine, University of South Alabama, Mobile, AL 36604, USA.
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Serum Cytokinome Profile Evaluation: A Tool to Define New Diagnostic and Prognostic Markers of Cancer Using Multiplexed Bead-Based Immunoassays. Mediators Inflamm 2016; 2016:3064643. [PMID: 28050120 PMCID: PMC5168457 DOI: 10.1155/2016/3064643] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/12/2016] [Revised: 09/19/2016] [Accepted: 10/27/2016] [Indexed: 12/15/2022] Open
Abstract
In recent years, many researchers are focusing their attention on the link between inflammation and cancer. The inflammation is involved in the tumor development and suppression, by stimulating the immune response. In particular, the transition from chronic inflammation to cancer produces angiogenic and growth factors able to repair the tissue and to promote cancer cell survival, implantation, and growth. In this contest, the cytokines contribute to the development of these processes becoming active before and during the inflammatory process and playing an important function at the various disease levels. Thus, these proteins can represent specific markers of tumor development and progression. Therefore the "cytokinome" term is used to indicate the evaluation of cytokine pattern by using an "omics" approach. Newly, specific protein chips of considerable and improved sensitivity are being developed to determine simultaneously several and different cytokines. This can be achieved by a multiplex technology that, through the use of small amounts of serum or other fluids, is used to determine the presence and the levels of underrepresented cytokines. Since this method is an accurate, sensitive, and reproducible cytokine assay, it is already used in many different studies. Thus, this review focuses on the more latest aspects related to cytokinome profile evaluation in different cancers.
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Interleukins 17 and 23 in patients with gastric neoplasms. Sci Rep 2016; 6:37451. [PMID: 27869179 PMCID: PMC5116626 DOI: 10.1038/srep37451] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/15/2016] [Accepted: 10/25/2016] [Indexed: 12/12/2022] Open
Abstract
Recently there has been heightened interest in the potential significance of interleukin (IL)-17 and IL-23 in the development/progression of human malignancies. Here, we analyzed the systemic levels of these cytokines in 75 patients with different types of gastric neoplasms (carcinoma, gastrointestinal stromal tumors, neuroendocrine neoplasms, and lymphomas) and 42 healthy volunteers. We found that patients with all types of gastric neoplasms have significantly lower IL-23 levels. However, in comparison to the levels in healthy individuals, IL-17 concentrations were lower only in patients with types of gastric neoplasms other than carcinoma. Interestingly, IL-17 levels significantly differed between patients with early and advanced gastric carcinoma. No significant associations were detected between the systemic levels of examined interleukins and TNM staging. However, peripheral levels of IL-23 were correlated with the absolute numbers of circulating populations of bone marrow-derived mesenchymal and very small embryonic/epiblast-like stem cells in patients with gastric carcinoma. ROC curve analyses demonstrated that systemic levels of IL-17 seem to meet basic criteria for consideration as a helpful diagnostic marker in the detection of gastric carcinoma. In conclusion, our study provides translational evidence confirming the clinical significance of IL-17 and IL-23 in the pathogenesis of different types of gastric neoplasms in humans.
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Abstract
OBJECTIVES We aimed to determine the severity and co-occurrence of established and potential paraneoplastic conditions in pancreatic cancer (weight loss, new onset diabetes, fatigue, and depression) and their relation to patient characteristics. METHODS Using information from personal interviews with 510 cases and 463 controls, we obtained adjusted odds ratios for weight loss, long-term and new-onset diabetes, fatigue, and depression before diagnosis. Among cases, we investigated the extent to which these factors occurred together and the characteristics of those reporting them. RESULTS The adjusted odds ratio for weight loss (>3% of usual weight) was 27.0 (95% confidence interval, 17.1-42.6). Severe weight loss was common (21% of cases lost >15%), and was more common in those previously obese. Diabetes was more common in cases and was strongly associated with weight loss (P < 0.0001). Diabetes in cases more often led to prescription of insulin, compared with controls.Fatigue and depression were significantly more common in cases than controls but not related to weight loss or diabetes. These conditions were not related to stage at diagnosis. CONCLUSIONS Weight loss, often severe, and new-onset diabetes frequently occur together before diagnosis of pancreatic cancer. Fatigue and depression are also potential precursors of diagnosis.
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Xun Q, Wang H, He F. Bone marrow mesenchymal stem cells for treatment of pancreatic diseases: Research status and prospects. Shijie Huaren Xiaohua Zazhi 2016; 24:3232-3237. [DOI: 10.11569/wcjd.v24.i21.3232] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
The incidence of pancreatic diseases is increasing year by year. Current treatments for pancreatic diseases are mainly symptomatic, and the research on the repair and restoration of function of the pancreatic cells progresses slowly. Stem cells have been widely used in the treatment of diseases in recent years because of their ability of multi-directional differentiation and repair of cell damage caused by disease and injury. Numerous studies confirm that pancreatic stem cells after transplantation can differentiate into pancreatic cells and play an important role in the recovery of external secretory function and repair of the damaged pancreatic cells. Particularly, both in vivo and in vitro studies show that bone marrow mesenchymal stem cells have achieved remarkable results in the treatment of pancreatic diseases, laying a theoretical and practical basis for clinical treatment of pancreatic diseases with stem cells. This article outlines the progress in treatment of acute pancreatitis, chronic pancreatitis and pancreatic cancer with bone marrow mesenchymal stem cells, demonstrating that stem cells are expected to become one of new methods for the treatment of pancreatic diseases.
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Błogowski W, Bodnarczuk T, Starzyńska T. Concise Review: Pancreatic Cancer and Bone Marrow-Derived Stem Cells. Stem Cells Transl Med 2016; 5:938-45. [PMID: 27217346 PMCID: PMC4922853 DOI: 10.5966/sctm.2015-0291] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/11/2015] [Accepted: 02/15/2016] [Indexed: 12/12/2022] Open
Abstract
UNLABELLED Pancreatic adenocarcinoma remains one of the most challenging diseases of modern gastroenterology, and, even though considerable effort has been put into understanding its pathogenesis, the exact molecular mechanisms underlying the development and/or systemic progression of this malignancy still remain unclear. Recently, much attention has been paid to the potential role of bone marrow-derived stem cells (BMSCs) in this malignancy. Hence, herein, we comprehensively review the most recent discoveries and current achievements and concepts in this field. Specifically, we discuss the significance of identifying pancreatic cancer stem cells and novel therapeutic approaches involving molecular interference of their metabolism. We also describe advances in the current understanding of the biochemical and molecular mechanisms responsible for BMSC mobilization during pancreatic cancer development and systemic spread. Finally, we summarize experimental, translational, and/or clinical evidence regarding the contribution of bone marrow-derived mesenchymal stem cells, endothelial progenitor cells, hematopoietic stem/progenitor cells, and pancreatic stellate cells in pancreatic cancer development/progression. We also present their potential therapeutic value for the treatment of this deadly malignancy in humans. SIGNIFICANCE Different bone marrow-derived stem cell populations contribute to the development and/or progression of pancreatic cancer, and they might also be a promising "weapon" that can be used for anticancer treatments in humans. Even though the exact role of these stem cells in pancreatic cancer development and/or progression in humans still remains unclear, this concept continues to drive a completely novel scientific avenue in pancreatic cancer research and gives rise to innovative ideas regarding novel therapeutic modalities that can be safely offered to patients.
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Affiliation(s)
- Wojciech Błogowski
- Department of Internal Medicine, University of Zielona Góra, Zielona Góra, Poland
| | - Tomasz Bodnarczuk
- Division of Internal Medicine, 109th Military Hospital, Szczecin, Poland
| | - Teresa Starzyńska
- Department of Gastroenterology, Pomeranian Medical University in Szczecin, Szczecin, Poland
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Karakaxas D, Sioziou A, Aravantinos G, Coker A, Papanikolaou IS, Liakakos T, Dervenis C, Gazouli M. Genetic polymorphisms of interleukin 1β gene and sporadic pancreatic neuroendocrine tumors susceptibility. World J Gastrointest Oncol 2016; 8:520-525. [PMID: 27326321 PMCID: PMC4909453 DOI: 10.4251/wjgo.v8.i6.520] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/11/2016] [Revised: 03/01/2016] [Accepted: 03/17/2016] [Indexed: 02/05/2023] Open
Abstract
AIM To evaluate the association between the interleukin 1β (IL-1β) polymorphisms and the pancreatic neuroendocrine tumor (pNET) development. METHODS A case-control study was conducted analyzing IL-1β polymorphisms using germline DNA collected in a population-based case-control study of pancreatic cancer (51 pNET cases, 85 pancreatic ductal adenocarcinoma cases, 19 intraductal papillary mucinous neoplasm and 98 healthy controls). RESULTS The distribution of genotypes for the -511 C/T polymorphism in the pNET patient groups showed significant difference compared to the control group. It is known that the carriers of the IL-1β -511T allele have increased concentrations of IL-1β. The -511 CT and TT high-expression genotypes were over-represented in pNET patients. CONCLUSION The findings of this study suggested a possible role of IL-1β -511 C/T genotypes in the pathogenesis of pNETs since the presence of the IL-1β -511 CT and TT genotypes and the T allele was associated with an increased risk of pNET only.
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47
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Lin WR, Lim SN, Yen TH, Alison MR. The Influence of Bone Marrow-Secreted IL-10 in a Mouse Model of Cerulein-Induced Pancreatic Fibrosis. BIOMED RESEARCH INTERNATIONAL 2016; 2016:4601532. [PMID: 27314021 PMCID: PMC4893579 DOI: 10.1155/2016/4601532] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 02/24/2016] [Accepted: 05/03/2016] [Indexed: 12/11/2022]
Abstract
This study aimed to understand the role of IL-10 secreted from bone marrow (BM) in a mouse model of pancreatic fibrosis. The severity of cerulein-induced inflammation, fibrosis, and the frequency of BM-derived myofibroblasts were evaluated in the pancreas of mice receiving either a wild-type (WT) BM or an IL-10 knockout (KO) BM transplantation. The area of collagen deposition increased significantly in the 3 weeks after cerulein cessation in mice with an IL-10 KO BM transplant (13.7 ± 0.6% and 18.4 ± 1.1%, p < 0.05), but no further increase was seen in WT BM recipients over this time. The percentage of BM-derived myofibroblasts also increased in the pancreas of the IL-10 KO BM recipients after cessation of cerulein (6.7 ± 1.1% and 11.9 ± 1.3%, p < 0.05), while this figure fell in WT BM recipients after cerulein withdrawal. Furthermore, macrophages were more numerous in the IL-10 KO BM recipients than the WT BM recipients after cerulein cessation (23.2 ± 2.3 versus 15.3 ± 1.7 per HPF, p < 0.05). In conclusion, the degree of fibrosis, inflammatory cell infiltration, and the number of BM-derived myofibroblasts were significantly different between IL-10 KO BM and WT BM transplanted mice, highlighting a likely role of IL-10 in pancreatitis.
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Affiliation(s)
- Wey-Ran Lin
- Department of Gastroenterology and Hepatology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Siew-Na Lim
- Department of Neurology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Tzung-Hai Yen
- Department of Nephrology, Chang Gung Memorial Hospital, Chang Gung University College of Medicine, Taoyuan 333, Taiwan
| | - Malcolm R. Alison
- Centre for Tumour Biology, Barts and The London School of Medicine and Dentistry, London EC1M 6BQ, UK
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Yako YY, Kruger D, Smith M, Brand M. Cytokines as Biomarkers of Pancreatic Ductal Adenocarcinoma: A Systematic Review. PLoS One 2016; 11:e0154016. [PMID: 27170998 PMCID: PMC4865360 DOI: 10.1371/journal.pone.0154016] [Citation(s) in RCA: 65] [Impact Index Per Article: 7.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/04/2015] [Accepted: 04/07/2016] [Indexed: 12/24/2022] Open
Abstract
OBJECTIVES A systematic review of the role of cytokines in clinical medicine as diagnostic, prognostic, or predictive biomarkers in pancreatic ductal adenocarcinoma was undertaken. MATERIALS AND METHODS A systematic review was conducted according to the 2009 PRISMA guidelines. PubMed database was searched for all original articles on the topic of interest published until June 2015, and this was supplemented with references cited in relevant articles. Studies were evaluated for risk of bias using the Quality in Prognosis Studies tools. RESULTS Forty one cytokines were investigated with relation to pancreatic ductal adenocarcinoma (PDAC) in 65 studies, ten of which were analyzed by more than three studies. Six cytokines (interleukin[IL]-1β, -6, -8, -10, vascular endothelial growth factor, and transforming growth factor) were consistently reported to be increased in PDAC by more than four studies; irrespective of sample type; method of measurement; or statistical analysis model used. When evaluated as part of distinct panels that included CA19-9, IL-1β, -6 and -8 improved the performance of CA19-9 alone in differentiating PDAC from healthy controls. For example, a panel comprising IL-1β, IL-8, and CA 19-9 had a sensitivity of 94.1% vs 85.9%, specificity of 100% vs 96.3%, and area under the curve of 0.984 vs 0.925. The above-mentioned cytokines were associated with the severity of PDAC. IL-2, -6, -10, VEGF, and TGF levels were reported to be altered after patients received therapy or surgery. However, studies did not show any evidence of their ability to predict treatment response. CONCLUSION Our review demonstrates that there is insufficient evidence to support the role of individual cytokines as diagnostic, predictive or prognostic biomarkers for PDAC. However, emerging evidence indicates that a panel of cytokines may be a better tool for discriminating PDAC from other non-malignant pancreatic diseases or healthy individuals.
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Affiliation(s)
- Yandiswa Yolanda Yako
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Deirdré Kruger
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Martin Smith
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
| | - Martin Brand
- Department of Surgery, Faculty of Health Sciences, University of Witwatersrand, Parktown, Gauteng, South Africa
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Significance of Interleukin-6 in Papillary Thyroid Carcinoma. J Thyroid Res 2016; 2016:6178921. [PMID: 27034885 PMCID: PMC4808558 DOI: 10.1155/2016/6178921] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/29/2015] [Accepted: 02/17/2016] [Indexed: 12/18/2022] Open
Abstract
This study sought to reveal the significance of IL-6 in papillary thyroid carcinoma by determining its circulating levels, tumoral protein, and mRNA expressions. As compared to the healthy individuals, serum IL-6 was significantly higher in patients with benign thyroid diseases and PTC. Further, its level was significantly higher in PTC patients as compared to patients with benign thyroid diseases. ROC curves also confirmed a good discriminatory efficacy of serum IL-6 between healthy individuals and patients with benign thyroid diseases and PTC. The circulating IL-6 was significantly associated with poor overall survival in PTC patients. IL-6 immunoreactivity was significantly high in PTC patients as compared to the benign thyroid disease patients. Significantly higher IL-6 mRNA expression was also observed in the primary tumour tissues of PTC patients than the adjacent normal tissues. The protein expression of IL-6 at both the circulating and tissue level correlated with disease aggressiveness in PTC patients. Moreover, a significant positive correlation was observed between the IL-6 protein and mRNA expression in the primary tumours of PTC patients. Finally in conclusion, IL-6 has an important role in thyroid cancer progression. Thus targeting IL-6 signalling can help in clinical management of thyroid carcinoma patients.
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50
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Xu XD, Hu J, Wang M, Peng F, Tian R, Guo XJ, Xie Y, Qin RY. Circulating myeloid-derived suppressor cells in patients with pancreatic cancer. Hepatobiliary Pancreat Dis Int 2016; 15:99-105. [PMID: 26818550 DOI: 10.1016/s1499-3872(15)60413-1] [Citation(s) in RCA: 35] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
BACKGROUND Myeloid-derived suppressor cells (MDSCs) are heterogeneous cell types that suppress T-cell responses in cancer patients and animal models, some MDSC subpopulations are increased in patients with pancreatic cancer. The present study was to investigate a specific subset of MDSCs in patients with pancreatic cancer and the mechanism of MDSCs increase in these patients. METHODS Myeloid cells from whole blood were collected from 37 patients with pancreatic cancer, 17 with cholangiocarcinoma, and 47 healthy controls. Four pancreatic cancer cell lines were co-cultured with normal peripheral blood mononuclear cells (PBMCs) to test the effect of tumor cells on the conversion of PBMCs to MDSCs. Levels of granulocyte-macrophage colony-stimulating factor (GM-CSF) and arginase activity in the plasma of cancer patients were analyzed by enzyme-linked immunosorbent assay. RESULTS CD14+/CD11b+/HLA-DR- MDSCs were increased in patients with pancreatic or bile duct cancer compared with those in healthy controls, and this increase was correlated with clinical cancer stage. Pancreatic cancer cell lines induced PBMCs to MDSCs in a dose-dependent manner. GM-CSF and arginase activity levels were significantly increased in the serum of patients with pancreatic cancer. CONCLUSIONS MDSCs were tumor related: tumor cells induced PBMCs to MDSCs in a dose-dependent manner and circulating CD14+/CD11b+/HLA-DR- MDSCs in pancreatic cancer patients were positively correlated with tumor burden. MDSCs might be useful markers for pancreatic cancer detection and progression.
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Affiliation(s)
- Xiao-Dong Xu
- Department of Biliary-Pancreatic Surgery, Affiliated Tongji Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan 430030, China.
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