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Vitale F, Zileri Dal Verme L, Paratore M, Negri M, Nista EC, Ainora ME, Esposto G, Mignini I, Borriello R, Galasso L, Alfieri S, Gasbarrini A, Zocco MA, Nicoletti A. The Past, Present, and Future of Biomarkers for the Early Diagnosis of Pancreatic Cancer. Biomedicines 2024; 12:2840. [PMID: 39767746 PMCID: PMC11673965 DOI: 10.3390/biomedicines12122840] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/01/2024] [Revised: 11/30/2024] [Accepted: 12/11/2024] [Indexed: 01/04/2025] Open
Abstract
Pancreatic cancer is one of the most aggressive cancers with a very poor 5-year survival rate and reduced therapeutic options when diagnosed in an advanced stage. The dismal prognosis of pancreatic cancer has guided significant efforts to discover novel biomarkers in order to anticipate diagnosis, increasing the population of patients who can benefit from curative surgical treatment. CA 19-9 is the reference biomarker that supports the diagnosis and guides the response to treatments. However, it has significant limitations, a low specificity, and is inefficient as a screening tool. Several potential biomarkers have been discovered in the serum, urine, feces, and pancreatic juice of patients. However, most of this evidence needs further validation in larger cohorts. The advent of advanced omics sciences and liquid biopsy techniques has further enhanced this field of research. The aim of this review is to analyze the historical evolution of the research on novel biomarkers for the early diagnosis of pancreatic cancer, focusing on the current evidence for the most promising biomarkers from different body fluids and the novel trends in research, such as omics sciences and liquid biopsy, in order to favor the application of modern personalized medicine.
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Affiliation(s)
- Federica Vitale
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Lorenzo Zileri Dal Verme
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Mattia Paratore
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Marcantonio Negri
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Enrico Celestino Nista
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Maria Elena Ainora
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Giorgio Esposto
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Irene Mignini
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Raffaele Borriello
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Linda Galasso
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Sergio Alfieri
- Centro Pancreas, Chirurgia Digestiva, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy;
| | - Antonio Gasbarrini
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Maria Assunta Zocco
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
| | - Alberto Nicoletti
- CEMAD Centro Malattie dell’Apparato Digerente, Medicina Interna e Gastroenterologia, Dipartimento di Medicina e Chirurgia Traslazionale, Università Cattolica del Sacro Cuore, Fondazione Policlinico Universitario “A. Gemelli” IRCCS, 00168 Rome, Italy; (F.V.); (L.Z.D.V.); (M.P.); (M.N.); (E.C.N.); (M.E.A.); (G.E.); (I.M.); (R.B.); (L.G.); (A.G.); (A.N.)
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Comparison between Clinical Utility of CXCL-8 and Clinical Practice Tumor Markers for Colorectal Cancer Diagnosis. BIOMED RESEARCH INTERNATIONAL 2022; 2022:1213968. [PMID: 36567905 PMCID: PMC9788896 DOI: 10.1155/2022/1213968] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 03/02/2022] [Revised: 06/28/2022] [Accepted: 10/15/2022] [Indexed: 12/23/2022]
Abstract
Owing to the high incidence and mortality rates of colorectal cancer (CRC), novel biomarkers for CRC diagnosis are critically needed. Therefore, this study is aimed at exploring the clinical utility of serum C-X-C motif chemokine 8 (CXCL-8) for CRC diagnosis and progression compared to the routinely used biomarkers, carcinoembryonic antigen (CEA), and carbohydrate antigen-19-9 (CA19-9). This study included 227 patients with CRC, 110 patients with colorectal adenoma (CA), and 123 healthy participants, who were recruited from the Fujian Medical University Union Hospital from July 1, 2019 to October 31, 2020. Serum concentrations of CXCL-8, CEA, and CA19-9 were detected using enzyme-linked immunosorbent assay and chemiluminescent microparticle immunoassay. Clinicopathological features of patients with CRC were collected and analyzed. The diagnostic efficacy of CXCL-8, CEA, and CA19-9 for CRC was evaluated using receiver operating characteristic (ROC) curves. We found that the serum concentrations of CXCL-8, CEA, and CA19-9 were significantly higher in patients with CRC than those in patients with CA and healthy controls. The diagnostic sensitivity of CXCL-8 alone was higher than those of CEA and CA19-9 both and when combined; thus, CXCL-8 may be better at discriminating patients with CRC from healthy controls and patients with CA. Moreover, combining CXCL-8 with CEA or CA19-9 improved their respective diagnostic performances in distinguishing patients with CRC from CA patients and healthy participants. Notably, we also found that serum concentrations of CXCL-8 were positively correlated with metastases and tumor size. Therefore, our study suggests that serum CXCL-8 may serve as an improved biomarker for CRC diagnosis compared to the traditional tumor markers CEA and CA19-9. Moreover, our findings indicate the potential efficacy of serum CXCL-8 levels as a CRC prognostic biomarker.
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Chen H, Sun G, Han Z, Wang H, Li J, Ye H, Song C, Zhang J, Wang P. Anti-CXCL8 Autoantibody: A Potential Diagnostic Biomarker for Esophageal Squamous Cell Carcinoma. MEDICINA (KAUNAS, LITHUANIA) 2022; 58:medicina58101480. [PMID: 36295640 PMCID: PMC9607113 DOI: 10.3390/medicina58101480] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/23/2022] [Revised: 09/15/2022] [Accepted: 10/13/2022] [Indexed: 11/07/2022]
Abstract
Background and Objectives: Esophageal squamous cell carcinoma (ESCC) is one of the most common malignancies. Anti-tumor associated antigen autoantibodies (TAAbs) can be used as biomarkers for tumor detection. The aim of this study was to identify a reliable TAAb as the diagnostic marker for ESCC. Materials and Methods: The Cancer Genome Atlas (TCGA) database was used to screen candidate genes. The mRNA expression of the key gene was then verified by micro array dataset GSE44021 from the Gene Expression Omnibus (GEO) database and the diag nostic value of the corresponding autoantibody to the key gene in ESCC was detected by enzyme-linked im muno sorbent assay (ELISA). Results: CXCL8 was identified as the key gene. The dataset GSE44021 showed that CXCL8 mRNA expression was prominently over-expressed in ESCC tissues compared with normal tissues. ELISA results showed that the level of anti-CXCL8 autoantibody in ESCC patients was significantly higher than in normal controls and the receiver operating char ac teristic (ROC) curve indicated that anti-CXCL8 autoantibody could discriminate ESCC patients from normal controls, with the area under the ROC curve (AUC) for the verification cohort, and the validation cohort were 0.713 and 0.751, respectively. Conclusions: Our study illustrated that anti-CXCL8 autoantibody had good diagnostic value, and may become a candidate biomarker for ESCC.
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Affiliation(s)
- Huili Chen
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Guiying Sun
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Zhuo Han
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Huimin Wang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Jiaxin Li
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Hua Ye
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Chunhua Song
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
| | - Jianying Zhang
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
- Henan Institute of Medical and Pharmaceutical Sciences, Zhengzhou University, Zhengzhou 450052, China
| | - Peng Wang
- Department of Epidemiology and Statistics, College of Public Health, Zhengzhou University, Zhengzhou 450001, China
- State Key Laboratory of Esophageal Cancer Prevention & Treatment, Zhengzhou University, Zhengzhou 450052, China
- Correspondence: ; Tel.: +86-0371-67781453
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Jing Y, Wang F, Zhang K, Chen Z. Comprehensive analysis of prognostic value and immune infiltration of CXC chemokines in pancreatic cancer. BMC Med Genomics 2022; 15:96. [PMID: 35468838 PMCID: PMC9040222 DOI: 10.1186/s12920-022-01246-4] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/08/2021] [Accepted: 04/18/2022] [Indexed: 11/21/2022] Open
Abstract
BACKGROUND The prognosis of pancreatic cancer is poor, with a 5-year survival rate of less than 10%. Studies have shown that chemokines in the tumour microenvironment are often altered, which is associated with immune infiltration and the prognosis and survival of pancreatic cancer patients. METHODS Multiomics and bioinformatics tools were used to clarify CXC chemokine expression and its role in the pancreatic ductal adenocarcinoma (PDAC) immune microenvironment. RESULTS Most CXC chemokines were upregulated in pancreatic cancer and correlated with patient prognosis. CXC chemokines can activate cancer-related signalling pathways and affect immune infiltration. Furthermore, most CXC chemokines were significantly correlated with the abundance of macrophages, neutrophils and dendritic cells. CXCL5 was selected as a hub gene, and a variety of immune checkpoints, including PD-1/PD-L1 and CTLA-4, were identified. CONCLUSION Our study provides novel insights into CXC chemokine expression and its role in the PDAC immune microenvironment. These results can provide more data about prognostic biomarkers and therapeutic targets of PDAC.
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Affiliation(s)
- Yanhua Jing
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Fengjiao Wang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Ke Zhang
- Department of Integrative Oncology, Fudan University Shanghai Cancer Center, Shanghai, 200032 China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
| | - Zhen Chen
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, 200032 China
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Dielectrophoresis-Based Biosensor for Detection of the Cancer Biomarkers CEA and CA 242 in Serum. CHEMOSENSORS 2022. [DOI: 10.3390/chemosensors10030104] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
We show that dielectrophoresis (DEP) spectroscopy is an effective transduction mechanism for detection of the concentration levels of the pancreatic cancer biomarkers cancer antigen (CA) 242 and carcinoembryonic antigen (CEA) in serum. We noticed a frequency dependence of the negative DEP force applied by interdigitated electrodes on functionalized polystyrene microspheres (PM) with respect to changes in the number of these cancer antigens bound to the PM. An electrode array with a well-defined gradient of the electric field was designed and used, which enabled the automation of the signal processing and reproducibility of the signal acquired by the biosensor.
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Pawluczuk E, Łukaszewicz-Zając M, Gryko M, Kulczyńska-Przybik A, Mroczko B. Serum CXCL8 and Its Specific Receptor (CXCR2) in Gastric Cancer. Cancers (Basel) 2021; 13:cancers13205186. [PMID: 34680333 PMCID: PMC8534112 DOI: 10.3390/cancers13205186] [Citation(s) in RCA: 12] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Revised: 10/05/2021] [Accepted: 10/13/2021] [Indexed: 12/30/2022] Open
Abstract
Gastric cancer (GC) is the second leading cause of cancer-related deaths worldwide. This malignancy is usually diagnosed at an advanced stage. Therefore, novel biomarkers useful in the early detection of GC are sorely needed. Some authors suggest the role of chemokines and their specific receptors in GC pathogenesis. The aim of the study was to investigate whether serum CXCL8 and its receptor (CXCR2) might be considered as potential candidates for biomarkers in the diagnosis and prognosis of GC. The study included 98 subjects: 64 GC patients and 34 healthy volunteers. CXCL8 and CXCR2 concentrations were assessed by the enzyme-linked immunosorbent assay (ELISA) method. Serum CXCL8 and CXCR2 concentrations were significantly higher in GC patients than in healthy controls, similar to the well-established tumor marker (CA19-9) and marker of inflammation (CRP). Diagnostic sensitivity of CXCL8 was the highest among all proteins tested and increased for the combined assessment with CA19-9. The area under the ROC curve for CXCL8 was higher than those for CXCR2 and classical tumor markers. Serum CXCL8 levels were indicated as a significant risk factor of GC occurrence. Our findings suggest that serum CXCL8 is a promising candidate for a biomarker in GC diagnosis and might be used as a significant predictor of GC risk.
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Affiliation(s)
- Elżbieta Pawluczuk
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (E.P.); (A.K.-P.)
| | - Marta Łukaszewicz-Zając
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
| | - Mariusz Gryko
- Second Department of General Surgery, Medical University of Bialystok, 15-274 Bialystok, Poland;
| | - Agnieszka Kulczyńska-Przybik
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (E.P.); (A.K.-P.)
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (E.P.); (A.K.-P.)
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
- Correspondence:
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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: 40] [Impact Index Per Article: 10.0] [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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Zhang M, Huang L, Ding G, Huang H, Cao G, Sun X, Lou N, Wei Q, Shen T, Xu X, Cao L, Yan Q. Interferon gamma inhibits CXCL8-CXCR2 axis mediated tumor-associated macrophages tumor trafficking and enhances anti-PD1 efficacy in pancreatic cancer. J Immunother Cancer 2021; 8:jitc-2019-000308. [PMID: 32051287 PMCID: PMC7057481 DOI: 10.1136/jitc-2019-000308] [Citation(s) in RCA: 120] [Impact Index Per Article: 30.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 01/09/2020] [Indexed: 12/14/2022] Open
Abstract
Background Pancreatic cancer (PC) is a common malignancy of the digestive system and is characterized by poor prognosis and early metastasis. Tumor immune escape plays an important role in PC progression. Programmed death 1 (PD1) blockade therapy is a promising treatment for patients with PC, but is yet to achieve significant clinical effects so far. Interferon gamma (IFN-γ) is a soluble dimeric cytokine that is closely associated with tumor immune surveillance and cytotoxicity. IFN-γ suppresses a variety of tumor-derived cytokines in PC, such as CXCL8. In the present study, we investigated the therapeutic efficacy of combined anti-PD1 and IFN-γ treatment in PC. Methods BxPC-3 and Panc-1 human PC cell lines were used to construct a murine PC model. Blood samples (n=44) and surgical resection specimens (n=36) from human patients with PC were also collected. χ2 test, two-tailed unpaired t-test or Kaplan-Meier survival analysis was used to calculate p values. Results PD1/PD-L1 signaling was overexpressed in PC tumor-bearing mice. Anti-PD1 prevented tumor growth if initiated early after tumor inoculation; however, delayed anti-PD1 treatment showed limited benefit. Murine PC model had a preferential expansion of CXCR2+CD68+ macrophages, and these cells showed an immunosuppressive nature (M2 polarization). PC tumors overexpressed CXCL8 and tumor-derived CXCL8 deficiency prohibited the trafficking of CXCR2+CD68+ macrophages. IFN-γ suppressed the expression of tumor-derived CXCL8, and combined with IFN-γ treatment, delayed anti-PD1 treatment showed significant antitumor effects. Thus, we conclude that murine CXCR2+CD68+ macrophages traffic to PC tumors by tumor-derived CXCL8 and mediate local immunosuppression, which limits the efficacy of PD1 blockade therapy. IFN-γ suppresses tumor-derived CXCL8 and inhibits the tumor trafficking of CXCR2+CD68+ macrophages by blocking the CXCL8–CXCR2 axis to enhance anti-PD1 efficacy. Human PC also produces high levels of CXCL8. Patients with PC present elevated CXCR2 expression on peripheral and tumor-infiltrating CD68+ macrophages, which are associated with advanced tumor stage and poor prognosis. Conclusion Our findings suggest that IFN-γ is a translatable, therapeutic option to improve the efficacy of PD1 blockade therapy by preventing trafficking of CXCR2+CD68+ macrophages via blocking the CXCL8–CXCR2 axis.
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Affiliation(s)
- Mingjie Zhang
- Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China
| | - Lifeng Huang
- Key Laboratory of Biomedicine and Health, Hangzhou Normal University Hangzhou School of Medicine, Hangzhou, China
| | - Guoping Ding
- Department of Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China
| | - Huilian Huang
- Key Laboratory of Molecular Medicine, Huzhou Central Hospital, Huzhou, China
| | - Guoliang Cao
- Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China
| | - Xu Sun
- Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China
| | - Neng Lou
- Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China
| | - Qiang Wei
- Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China
| | - Tao Shen
- Department of Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China
| | - Xiaodong Xu
- Department of Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China
| | - Liping Cao
- Department of Surgery, Zhejiang University School of Medicine Sir Run Run Shaw Hospital, Hangzhou, China
| | - Qiang Yan
- Department of Hepatobiliary and Pancreatic Surgery, Huzhou Central Hospital, Huzhou, China
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Procoagulant Disorders in Patients with Newly Diagnosed Pancreatic Adenocarcinoma. ACTA ACUST UNITED AC 2020; 56:medicina56120677. [PMID: 33316933 PMCID: PMC7763230 DOI: 10.3390/medicina56120677] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/12/2020] [Revised: 12/02/2020] [Accepted: 12/04/2020] [Indexed: 11/17/2022]
Abstract
Background and objectives: Cancer coagulopathy is thought to be partially due to the up-regulation of tissue factor (TF), thrombin-antithrombin complex (TAT) and soluble P-selectin (sP-selectin). The purpose of this study was to evaluate the clinical significance of TF, TAT and sP-selectin in patients with pancreatic cancer. Materials and methods: The study included 93 subjects: 73 newly diagnosed patients with pancreatic adenocarcinoma (42 with stage I-III and 31 with metastatic cancer (stage IV)) and a control group of 20 healthy subjects. Analyzed patients were hospitalized in the Department of Digestive Tract Diseases, Medical University of Lodz or in the Department of Digestive Tract Surgery, Silesian University, Katowice, Poland. All laboratory parameters were measured using ELISA procedures. Results: TF plasma levels were detectable in all patients and were significantly higher in metastatic cancer compared to stage I-III patients and the control group (p < 0.05). In patients with pancreatic adenocarcinoma, the median levels of TAT were also elevated compared to the control group. Moreover, patients with metastases had significantly higher TAT concentration compared to the I-III cancer group. On the other hand, only the metastatic patients group showed significantly higher plasma sP-selectin levels compared to the controls (p = 0.009), whereas there was no difference between localized and metastatic cancer patients. Conclusions: The coagulation disorders are present in the majority of patients with pancreatic adenocarcinoma already at the diagnosis stage and reflect cancer progression and spread.
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Łukaszewicz-Zając M, Pączek S, Mroczko P, Kulczyńska-Przybik A. The Significance of CXCL1 and CXCL8 as Well as Their Specific Receptors in Colorectal Cancer. Cancer Manag Res 2020; 12:8435-8443. [PMID: 32982437 PMCID: PMC7501593 DOI: 10.2147/cmar.s267176] [Citation(s) in RCA: 18] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/10/2020] [Accepted: 08/14/2020] [Indexed: 12/17/2022] Open
Abstract
Every year, almost 2 million people develop colorectal cancer (CRC), which makes it the fourth most common malignancy worldwide. It is also estimated that approximately 48% of CRC patients will die from the disease. Thus, noninvasive and accurate methods for early detection and prevention of CRC are sorely needed. It is suggested that C-X-C motif ligand 1 (CXCL1) and C-X-C motif ligand 8 (CXCL8) as well as their cognate receptors can mediate tumor growth, proliferation, survival, neoangiogenesis and metastasis of malignant cells, including CRC. However, little is known about the clinical significance of these proteins as potential biomarkers for CRC. Therefore, in our review, we performed a comprehensive literature search using the PubMed database to identify original articles that investigated whether CXCL1 and CXCL8 and their receptors play a role in CRC pathogenesis. In summary, our review highlighted the potential significance of CXCL1/CXCR2 and CXCL8/CXCR1,-2 in the diagnosis and progression of CRC as well as indicated their potential therapeutic significance. However, given the non-specific nature of analyzed chemokines and a small number of studies concerning the assessment of blood concentration of these proteins in CRC patients, investigations need to be continued in the future before selected chemokines could be established as biomarkers for CRC.
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Affiliation(s)
| | - Sara Pączek
- Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | - Piotr Mroczko
- Department of Criminal Law and Criminology, Faculty of Law, University of Bialystok, Bialystok, Poland
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Litman-Zawadzka A, Łukaszewicz-Zając M, Gryko M, Kulczyńska-Przybik A, Kędra B, Mroczko B. Specific Receptors for the Chemokines CXCR2 and CXCR4 in Pancreatic Cancer. Int J Mol Sci 2020; 21:ijms21176193. [PMID: 32867211 PMCID: PMC7504436 DOI: 10.3390/ijms21176193] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 08/25/2020] [Indexed: 12/16/2022] Open
Abstract
Background: The mortality rate of pancreatic cancer (PC) is equal to its incidence and the majority of PC patients die within a few months of diagnosis. Therefore, a search for new biomarkers useful in the diagnosis and prognosis of PC is ongoing. Objectives: The aim of our study was to compare the utility of CXCR2 and CXCR4 in the diagnosis and prediction of PC with classical tumor marker (carcinoembryonic antigen, CEA) and marker of inflammation–C-reactive protein (CRP). Patients and Methods: The study comprised 64 subjects — 32 PC patients and 32 healthy volunteers. Serum concentrations of tested proteins were analysed using immunological methods. Results: Serum CXCR2 and CXCR4 concentrations, similarly to those of CEA and CRP, were significantly elevated in PC patients compared to healthy controls. Moreover, concentrations of CXCR4 were significantly correlated with CXCR2 and CRP levels, while CRP concentrations were correlated with CXCR2 and CEA levels. The diagnostic sensitivity and the predictive value for negative (PV−ve) results for CXCR4 were similar to those of CEA and higher than those of CXCR2 and CRP, while the area under the ROC curve (AUC) for CXCR4 was the highest among all tested proteins (CXCR2, CEA, CRP). Moreover, serum CXCR2 was found to be a significant predictor of PC risk. Conclusions: CXCR4 is a better candidate for a tumor marker than CXCR2 in the diagnosis of PC, while serum CXCR2 is a significant predictor of PC risk.
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Affiliation(s)
- Ala Litman-Zawadzka
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (B.M.)
- Correspondence: ; Tel.: +48-85-8318785; Fax: +48-85-8318585
| | - Marta Łukaszewicz-Zając
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
| | - Mariusz Gryko
- Second Department of General Surgery, Medical University of Bialystok, 15-276 Bialystok, Poland; (M.G.); (B.K.)
| | - Agnieszka Kulczyńska-Przybik
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (B.M.)
| | - Bogusław Kędra
- Second Department of General Surgery, Medical University of Bialystok, 15-276 Bialystok, Poland; (M.G.); (B.K.)
| | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland; (A.K.-P.); (B.M.)
- Department of Biochemical Diagnostics, Medical University of Bialystok, 15-269 Bialystok, Poland;
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CXCL-8 in Preoperative Colorectal Cancer Patients: Significance for Diagnosis and Cancer Progression. Int J Mol Sci 2020; 21:ijms21062040. [PMID: 32192002 PMCID: PMC7139325 DOI: 10.3390/ijms21062040] [Citation(s) in RCA: 26] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2020] [Revised: 03/14/2020] [Accepted: 03/15/2020] [Indexed: 12/11/2022] Open
Abstract
Introduction. Since colorectal cancer (CRC) is the second most commonly diagnosed malignancy in Europe and third worldwide, novel biomarkers for diagnosing the disease are critically needed. Objectives. According to our knowledge, the present study is the first to evaluate the clinical usefulness of serum CXCL-8 (C-X-C motif chemokine 8) in the diagnosis and progression of CRC compared to classical tumor marker CEA (carcinoembryonic antigen) and marker of inflammation CRP (C-reactive protein). Patients and Methods. The study included 59 CRC patients and 46 healthy volunteers. Serum levels of selected proteins were measured using ELISA (enzyme-linked immunosorbent assay), CMIA (chemiluminescent microparticle immunoassay), and immunoturbidimetric methods. Results. Serum concentrations of CXCL-8, similarly to those of the classical tumor marker CEA and inflammatory state marker CRP, were significantly higher in CRC patients than in healthy controls. There were statistically significant differences in CXCL-8 concentrations between tumor stages, as established by the Kruskal–Wallis test and confirmed by the post hoc Dwass–Steele–Critchlow–Fligner test. CXCL-8 levels were also significantly elevated in CRC patients with distant metastases compared to patients in the subgroup without metastases. Diagnostic sensitivity, predictive values for negative results (NPV), and AUC (area under the Receiver Operating Characteristic Curve—ROC curve) of CXCL-8 were higher than those of CEA, while diagnostic specificity and predictive values for positive results (PPV) of CXCL-8 were higher than those of CRP. Conclusions. Our findings indicate greater utility of CXCL-8 in comparison to the classical tumor marker CEA in the diagnosis of CRC. Moreover, serum CXCL-8 might be a potential biomarker of colorectal cancer progression.
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Yang HJ, Xue JM, Li J, Wan LH, Zhu YX. Identification of key genes and pathways of diagnosis and prognosis in cervical cancer by bioinformatics analysis. Mol Genet Genomic Med 2020; 8:e1200. [PMID: 32181600 PMCID: PMC7284022 DOI: 10.1002/mgg3.1200] [Citation(s) in RCA: 21] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2019] [Revised: 02/09/2020] [Accepted: 02/21/2020] [Indexed: 12/24/2022] Open
Abstract
Background Cervical cancer as one of the most common malignant tumors lead to bad prognosis among women. Some researches already focus on the carcinogenesis and pathogenesis of cervical cancer, but it is still necessary to identify more key genes and pathways. Methods Differentially expressed genes were identified by GEO2R from the gene expression omnibus (GEO) website, then gene ontology (GO) and Kyoto Encyclopedia of Genes and Genomes (KEGG) enrichment analyzed by DAVID. Meanwhile, protein–protein interaction network was constructed by STRING, and both key genes and modules were found in visualizing network through Cytoscape. Besides, GEPIA did the differential expression of key genes and survival analysis. Finally, the expression of genes related to prognosis was further explored by UNLCAN, oncomine, and the human protein atlas. Results Totally 57 differentially expressed genes were founded, not only enriched in G1/S transition of mitotic cell cycle, mitotic nuclear division, and cell division but also participated in cytokine–cytokine receptor interaction, toll‐like receptor signaling pathway, and amoebiasis. Additionally, 12 hub genes and 3 key modules were screened in the Cytoscape visualization network. Further survival analysis showed that TYMS (OMIM accession number 188350), MCM2 (OMIM accession number 116945), HELLS (OMIM accession number 603946), TOP2A (OMIM accession number 126430), and CXCL8 (OMIM accession number 146930) were associated with the prognosis of cervical cancer. Conclusion This study aim to better understand the characteristics of some genes and signaling pathways about cervical cancer by bioinformatics, and could provide further research ideas to find new mechanism, more prognostic factors, and potential therapeutic targets for cervical cancer.
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Affiliation(s)
- Hua-Ju Yang
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Jinshan Hospital of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Clinical Cancer Research Center, Chongqing, China
| | - Jin-Min Xue
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Jinshan Hospital of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Clinical Cancer Research Center, Chongqing, China
| | - Jie Li
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Jinshan Hospital of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Clinical Cancer Research Center, Chongqing, China
| | - Ling-Hong Wan
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Jinshan Hospital of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Clinical Cancer Research Center, Chongqing, China
| | - Yu-Xi Zhu
- Department of Oncology, The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Department of Oncology, Jinshan Hospital of The First Affiliated Hospital of Chongqing Medical University, Chongqing, China.,Chongqing Clinical Cancer Research Center, Chongqing, China
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