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Sharma R, Komal K, Kumar S, Ghosh R, Pandey P, Gupta GD, Kumar M. Advances in pancreatic cancer diagnosis: from DNA methylation to AI-assisted imaging. Expert Rev Mol Diagn 2025:1-13. [PMID: 40388321 DOI: 10.1080/14737159.2025.2509022] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2025] [Revised: 04/22/2025] [Accepted: 05/16/2025] [Indexed: 05/21/2025]
Abstract
INTRODUCTION Pancreatic Cancer (PC) is a highly aggressive tumor that is mainly diagnosed at later stages. Various imaging technologies, such as CT, MRI, and EUS, possess limitations in early PC diagnosis. Therefore, this review article explores the various innovative biomarkers for PC detection, such as DNA methylation, Noncoding RNAs, and proteomic biomarkers, and the role of AI in PC detection at early stages. AREA COVERED Innovative biomarkers, such as DNA methylation genes, show higher specificity and sensitivity in PC diagnosis. Additionally, various non-coding RNAs, such as long non-coding RNAs (lncRNAs) and microRNAs, show high diagnostic accuracy and serve as diagnostic and prognostic biomarkers. Additionally, proteomic biomarkers retain higher diagnostic accuracy in different body fluids. Apart from this, the utilization of AI showed that AI surpassed the radiologist's diagnostic performance in PC detection. EXPERT OPINION The combination of AI and advanced biomarkers can revolutionize early PC detection. However, large-scale, prospective studies are needed to validate its clinical utility. Further. standardization of biomarker panels and AI algorithms is a vital step toward their reliable applications in early PC detection, ultimately improving patient outcomes. [Figure: see text].
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Affiliation(s)
- Rohit Sharma
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Kumari Komal
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Sourabh Kumar
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Rashmi Ghosh
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
| | - Prachi Pandey
- Department of Quality Assurance, ISF College Pharmacy, Moga, India
| | | | - Manish Kumar
- Department of Pharmaceutics, ISF College Pharmacy, Moga, India
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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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Reese KL, Pantel K, Smit DJ. Multibiomarker panels in liquid biopsy for early detection of pancreatic cancer - a comprehensive review. J Exp Clin Cancer Res 2024; 43:250. [PMID: 39218911 PMCID: PMC11367781 DOI: 10.1186/s13046-024-03166-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/18/2024] [Accepted: 08/16/2024] [Indexed: 09/04/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is frequently detected in late stages, which leads to limited therapeutic options and a dismal overall survival rate. To date, no robust method for the detection of early-stage PDAC that can be used for targeted screening approaches is available. Liquid biopsy allows the minimally invasive collection of body fluids (typically peripheral blood) and the subsequent analysis of circulating tumor cells or tumor-associated molecules such as nucleic acids, proteins, or metabolites that may be useful for the early diagnosis of PDAC. Single biomarkers may lack sensitivity and/or specificity to reliably detect PDAC, while combinations of these circulating biomarkers in multimarker panels may improve the sensitivity and specificity of blood test-based diagnosis. In this narrative review, we present an overview of different liquid biopsy biomarkers for the early diagnosis of PDAC and discuss the validity of multimarker panels.
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Affiliation(s)
- Kim-Lea Reese
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany
| | - Klaus Pantel
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany.
| | - Daniel J Smit
- Institute of Tumor Biology, University Medical Center Hamburg-Eppendorf, Martinistraße 52, Hamburg, 20246, Germany.
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Sakamoto S, Hiraide H, Minoda M, Iwakura N, Suzuki M, Ando J, Takahashi C, Takahashi I, Murai K, Kagami Y, Mizuno T, Koike T, Nara S, Morizane C, Hijioka S, Kashiro A, Honda K, Watanabe R, Urano Y, Komatsu T. Identification of activity-based biomarkers for early-stage pancreatic tumors in blood using single-molecule enzyme activity screening. CELL REPORTS METHODS 2024; 4:100688. [PMID: 38218189 PMCID: PMC10831938 DOI: 10.1016/j.crmeth.2023.100688] [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: 01/23/2023] [Revised: 06/30/2023] [Accepted: 12/15/2023] [Indexed: 01/15/2024]
Abstract
Single-molecule enzyme activity-based enzyme profiling (SEAP) is a methodology to globally analyze protein functions in living samples at the single-molecule level. It has been previously applied to detect functional alterations in phosphatases and glycosidases. Here, we expand the potential for activity-based biomarker discovery by developing a semi-automated synthesis platform for fluorogenic probes that can detect various peptidases and protease activities at the single-molecule level. The peptidase/protease probes were prepared on the basis of a 7-amino-4-methylcoumarin fluorophore. The introduction of a phosphonic acid to the core scaffold made the probe suitable for use in a microdevice-based assay, while phosphonic acid served as the handle for the affinity separation of the probe using Phos-tag. Using this semi-automated scheme, 48 fluorogenic probes for the single-molecule peptidase/protease activity analysis were prepared. Activity-based screening using blood samples revealed altered single-molecule activity profiles of CD13 and DPP4 in blood samples of patients with early-stage pancreatic tumors. The study shows the power of single-molecule enzyme activity screening to discover biomarkers on the basis of the functional alterations of proteins.
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Affiliation(s)
- Shingo Sakamoto
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Hideto Hiraide
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Mayano Minoda
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Nozomi Iwakura
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Misa Suzuki
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Jun Ando
- Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Chiharu Takahashi
- Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Ikuko Takahashi
- Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Kazue Murai
- Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Yu Kagami
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Tadahaya Mizuno
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
| | - Tohru Koike
- Graduate School of Biomedical and Health Sciences, Hiroshima University, 1-2-3, Kasumi, Minami-ku, Hiroshima 734-8553, Japan
| | - Satoshi Nara
- Department of Hepatobiliary and Pancreatic Surgery, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Chigusa Morizane
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Susumu Hijioka
- Department of Hepatobiliary and Pancreatic Oncology, National Cancer Center Hospital, 5-1-1, Tsukiji, Chuo-ku, Tokyo 104-0045, Japan
| | - Ayumi Kashiro
- Institute for Advanced Medical Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Kazufumi Honda
- Institute for Advanced Medical Science, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan; Graduate School of Medicine, Nippon Medical School, 1-1-5 Sendagi, Bunkyo-ku, Tokyo 113-8602, Japan
| | - Rikiya Watanabe
- Cluster for Pioneering Research, Riken, 2-1 Hirosawa, Wako, Saitama 351-0198, Japan
| | - Yasuteru Urano
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan; Graduate School of Medicine, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
| | - Toru Komatsu
- Graduate School of Pharmaceutical Sciences, The University of Tokyo, 7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan.
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Boisteau E, Posseme C, Di Modugno F, Edeline J, Coulouarn C, Hrstka R, Martisova A, Delom F, Treton X, Eriksson LA, Chevet E, Lièvre A, Ogier-Denis E. Anterior gradient proteins in gastrointestinal cancers: from cell biology to pathophysiology. Oncogene 2022; 41:4673-4685. [PMID: 36068336 DOI: 10.1038/s41388-022-02452-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 08/03/2022] [Accepted: 08/23/2022] [Indexed: 11/09/2022]
Abstract
Most of the organs of the digestive tract comprise secretory epithelia that require specialized molecular machines to achieve their functions. As such anterior gradient (AGR) proteins, which comprise AGR1, AGR2, and AGR3, belong to the protein disulfide isomerase family, and are involved in secretory and transmembrane protein biogenesis in the endoplasmic reticulum. They are generally expressed in epithelial cells with high levels in most of the digestive tract epithelia. To date, the vast majority of the reports concern AGR2, which has been shown to exhibit various subcellular localizations and exert pro-oncogenic functions. AGR2 overexpression has recently been associated with a poor prognosis in digestive cancers. AGR2 is also involved in epithelial homeostasis. Its deletion in mice results in severe diffuse gut inflammation, whereas in inflammatory bowel diseases, the secretion of AGR2 in the extracellular milieu participates in the reshaping of the cellular microenvironment. AGR2 thus plays a key role in inflammation and oncogenesis and may represent a therapeutic target of interest. In this review, we summarize the already known roles and mechanisms of action of the AGR family proteins in digestive diseases, their expression in the healthy digestive tract, and in digestive oncology. At last, we discuss the potential diagnostic and therapeutic implications underlying the biology of AGR proteins.
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Affiliation(s)
- Emeric Boisteau
- INSERM U1242, University of Rennes, Rennes, France
- Department of Gastroenterology, University Hospital Pontchaillou, University of Rennes, Rennes, France
| | - Céline Posseme
- INSERM U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Federico Di Modugno
- INSERM U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | - Julien Edeline
- INSERM U1242, University of Rennes, Rennes, France
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France
| | | | - Roman Hrstka
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
| | - Andrea Martisova
- Regional Centre for Applied Molecular Oncology, Masaryk Memorial Cancer Institute, Brno, Czech Republic
- National Centre for Biomolecular Research, Faculty of Science, Masaryk University, Brno, Czech Republic
| | | | - Xavier Treton
- Assistance Publique-Hôpitaux de Paris, University of Paris, Clichy, France
| | - Leif A Eriksson
- Department of Chemistry and Molecular Biology, University of Gothenburg, Göteborg, Sweden
| | - Eric Chevet
- INSERM U1242, University of Rennes, Rennes, France.
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
| | - Astrid Lièvre
- INSERM U1242, University of Rennes, Rennes, France.
- Department of Gastroenterology, University Hospital Pontchaillou, University of Rennes, Rennes, France.
| | - Eric Ogier-Denis
- INSERM U1242, University of Rennes, Rennes, France.
- Centre de Lutte Contre le Cancer Eugène Marquis, Rennes, France.
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Vellan CJ, Jayapalan JJ, Yoong BK, Abdul-Aziz A, Mat-Junit S, Subramanian P. Application of Proteomics in Pancreatic Ductal Adenocarcinoma Biomarker Investigations: A Review. Int J Mol Sci 2022; 23:2093. [PMID: 35216204 PMCID: PMC8879036 DOI: 10.3390/ijms23042093] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/16/2021] [Revised: 01/07/2022] [Accepted: 01/09/2022] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC), a highly aggressive malignancy with a poor prognosis is usually detected at the advanced stage of the disease. The only US Food and Drug Administration-approved biomarker that is available for PDAC, CA 19-9, is most useful in monitoring treatment response among PDAC patients rather than for early detection. Moreover, when CA 19-9 is solely used for diagnostic purposes, it has only a recorded sensitivity of 79% and specificity of 82% in symptomatic individuals. Therefore, there is an urgent need to identify reliable biomarkers for diagnosis (specifically for the early diagnosis), ascertain prognosis as well as to monitor treatment response and tumour recurrence of PDAC. In recent years, proteomic technologies are growing exponentially at an accelerated rate for a wide range of applications in cancer research. In this review, we discussed the current status of biomarker research for PDAC using various proteomic technologies. This review will explore the potential perspective for understanding and identifying the unique alterations in protein expressions that could prove beneficial in discovering new robust biomarkers to detect PDAC at an early stage, ascertain prognosis of patients with the disease in addition to monitoring treatment response and tumour recurrence of patients.
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Affiliation(s)
- Christina Jane Vellan
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
| | - Jaime Jacqueline Jayapalan
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
- University of Malaya Centre for Proteomics Research (UMCPR), Universiti Malaya, Kuala Lumpur 50603, Malaysia
| | - Boon-Koon Yoong
- Department of Surgery, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia;
| | - Azlina Abdul-Aziz
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
| | - Sarni Mat-Junit
- Department of Molecular Medicine, Faculty of Medicine, Universiti Malaya, Kuala Lumpur 50603, Malaysia; (C.J.V.); (A.A.-A.); (S.M.-J.)
| | - Perumal Subramanian
- Department of Biochemistry and Biotechnology, Annamalai University, Chidambaram 608002, Tamil Nadu, India;
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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: 52] [Impact Index Per Article: 13.0] [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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8
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Waters RA, Robinson J, Edwardson JM. Syncollin is an antibacterial polypeptide. Cell Microbiol 2021; 23:e13372. [PMID: 34152077 DOI: 10.1111/cmi.13372] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/20/2021] [Revised: 06/15/2021] [Accepted: 06/17/2021] [Indexed: 11/29/2022]
Abstract
Syncollin is a 16-kDa protein found predominantly in the zymogen granules of pancreatic acinar cells, with expression at lower levels in intestinal epithelial cells and neutrophils. Here, we used Strep-tagged syncollin isolated from the supernatant of transiently transfected mammalian cells to test the hypothesis that syncollin has antibacterial properties, which might enable it to play a role in host defence in the gut and possibly elsewhere. We show that syncollin is an exceptionally thermostable protein with a circular dichroism spectrum consistent with a predominantly beta-sheet structure. Syncollin binds to bacterial peptidoglycan and restricts the growth of representative Gram-positive (Lactococcus lactis) and Gram-negative (Escherichia coli) bacteria. Syncollin induces propidium iodide uptake into E. coli (but not L. lactis), indicating permeabilisation of the bacterial membrane. It also causes surface structural damage in both L. lactis and E. coli, as visualised by scanning electron microscopy. We propose that syncollin is a previously unidentified member of a large group of antimicrobial polypeptides that control the gut microbiome. TAKE AWAYS: Syncollin is a 16-kDa protein found in pancreatic zymogen granules. Syncollin is highly thermostable and has a predominantly beta-sheet structure. Syncollin binds peptidoglycan and restricts the growth of L. lactis and E. coli. Syncollin causes propidium iodide uptake into E. coli (but not L. lactis). Syncollin causes surface structural damage in both L. lactis and E. coli.
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Affiliation(s)
- Rosie A Waters
- Department of Pharmacology, University of Cambridge, Cambridge, UK
| | - James Robinson
- Mechanistic Biology and Profiling, Discovery Sciences, R&D, AstraZeneca, Cambridge, UK
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Sohrabi E, Rezaie E, Heiat M, Sefidi-Heris Y. An Integrated Data Analysis of mRNA, miRNA and Signaling Pathways in Pancreatic Cancer. Biochem Genet 2021; 59:1326-1358. [PMID: 33813720 DOI: 10.1007/s10528-021-10062-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/04/2020] [Accepted: 03/16/2021] [Indexed: 02/06/2023]
Abstract
Although many genes and miRNAs have been reported for various cancers, pancreatic cancer's specific genes or miRNAs have not been studied precisely yet. Therefore, we have analyzed the gene and miRNA expression profile of pancreatic cancer data in the gene expression omnibus (GEO) database. The microarray-derived miRNAs and mRNAs were annotated by gene ontology (GO) and signaling pathway analysis. We also recognized mRNAs that were targeted by miRNA through the mirDIP database. An integrated analysis of the microarray revealed that only 6 out of 43 common miRNAs had significant differences in their expression profiles between the tumor and normal groups (P value < 0.05 and |log Fold Changes (logFC)|> 1). The hsa-miR-210 had upregulation, whereas hsa-miR-375, hsa-miR-216a, hsa-miR-217, hsa-miR-216b and hsa-miR-634 had downregulation in pancreatic cancer (PC). The analysis results also revealed 109 common mRNAs by microarray and mirDIP 4.1 databases. Pathway analysis showed that amoebiasis, axon guidance, PI3K-Akt signaling pathway, absorption and focal adhesion, adherens junction, platelet activation, protein digestion, human papillomavirus infection, extracellular matrix (ECM) receptor interaction, and riboflavin metabolism played important roles in pancreatic cancer. GO analysis revealed the significant enrichment in the three terms of biological process, cellular component, and molecular function, which were identified as the most important processes associated strongly with pancreatic cancer. In conclusion, DTL, CDH11, COL5A1, ITGA2, KIF14, SMC4, VCAN, hsa-mir-210, hsa-mir-217, hsa-mir-216a, hsa-mir-216b, hsa-mir-375 and hsa-mir-634 can be reported as the novel diagnostic or even therapeutic markers for the future studies. Also, the hsa-mir-107 and hsa-mir-125a-5p with COL5A1, CDH11 and TGFBR1 genes can be introduced as major miRNA and genes on the miRNA-drug-mRNA network. The new regulatory network created in our study could give a deeper knowledge of the pancreatic cancer.
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Affiliation(s)
- Ehsan Sohrabi
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Science, Tehran, Iran
| | - Ehsan Rezaie
- Molecular Biology Research Center, Systems Biology and Poisonings Institute, Baqiyatallah University of Medical Science, P.O. Box 19395-5487, Tehran, Iran.
| | - Mohammad Heiat
- Baqiyatallah Research Center for Gastroenterology and Liver Diseases, Baqiyatallah University of Medical Science, Tehran, Iran
| | - Yousef Sefidi-Heris
- Division of Molecular Cell Biology, Department of Biology, Shiraz University, Shiraz, Iran
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10
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The Case for GNMT as a Biomarker and a Therapeutic Target in Pancreatic Cancer. Pharmaceuticals (Basel) 2021; 14:ph14030209. [PMID: 33802396 PMCID: PMC7998508 DOI: 10.3390/ph14030209] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/28/2020] [Revised: 02/26/2021] [Accepted: 03/01/2021] [Indexed: 12/03/2022] Open
Abstract
The high mortality rate for pancreatic cancer (PC) is due to the lack of specific symptoms at early tumor stages and a high biological aggressiveness. Reliable biomarkers and new therapeutic targets would help to improve outlook in PC. In this study, we analyzed the expression of GNMT in a panel of pancreatic cancer cell lines and in early-stage paired patient tissue samples (normal and diseased) by quantitative reverse transcription-PCR (qRT-PCR). We also investigated the effect of 1,2,3,4,6-penta-O-galloyl-β-d-glucopyranoside (PGG) as a therapeutic agent for PC. We find that GNMT is markedly downregulated (p < 0.05), in a majority of PC cell lines. Similar results are observed in early-stage patient tissue samples, where GNMT expression can be reduced by a 100-fold or more. We also show that PGG is a strong inhibitor of PC cell proliferation, with an IC50 value of 12 ng/mL, and PGG upregulates GNMT expression in a dose-dependent manner. In conclusion, our data show that GNMT has promise as a biomarker and as a therapeutic target for PC.
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11
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Turanli B, Yildirim E, Gulfidan G, Arga KY, Sinha R. Current State of "Omics" Biomarkers in Pancreatic Cancer. J Pers Med 2021; 11:127. [PMID: 33672926 PMCID: PMC7918884 DOI: 10.3390/jpm11020127] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/22/2021] [Revised: 02/08/2021] [Accepted: 02/11/2021] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer is one of the most fatal malignancies and the seventh leading cause of cancer-related deaths related to late diagnosis, poor survival rates, and high incidence of metastasis. Unfortunately, pancreatic cancer is predicted to become the third leading cause of cancer deaths in the future. Therefore, diagnosis at the early stages of pancreatic cancer for initial diagnosis or postoperative recurrence is a great challenge, as well as predicting prognosis precisely in the context of biomarker discovery. From the personalized medicine perspective, the lack of molecular biomarkers for patient selection confines tailored therapy options, including selecting drugs and their doses or even diet. Currently, there is no standardized pancreatic cancer screening strategy using molecular biomarkers, but CA19-9 is the most well known marker for the detection of pancreatic cancer. In contrast, recent innovations in high-throughput techniques have enabled the discovery of specific biomarkers of cancers using genomics, transcriptomics, proteomics, metabolomics, glycomics, and metagenomics. Panels combining CA19-9 with other novel biomarkers from different "omics" levels might represent an ideal strategy for the early detection of pancreatic cancer. The systems biology approach may shed a light on biomarker identification of pancreatic cancer by integrating multi-omics approaches. In this review, we provide background information on the current state of pancreatic cancer biomarkers from multi-omics stages. Furthermore, we conclude this review on how multi-omics data may reveal new biomarkers to be used for personalized medicine in the future.
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Affiliation(s)
- Beste Turanli
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Esra Yildirim
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Gizem Gulfidan
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
| | - Kazim Yalcin Arga
- Department of Bioengineering, Marmara University, 34722 Istanbul, Turkey; (B.T.); (E.Y.); (G.G.)
- Turkish Institute of Public Health and Chronic Diseases, 34718 Istanbul, Turkey
| | - Raghu Sinha
- Department of Biochemistry and Molecular Biology, Penn State College of Medicine, Hershey, PA 17033, USA
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12
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Debernardi S, O’Brien H, Algahmdi AS, Malats N, Stewart GD, Plješa-Ercegovac M, Costello E, Greenhalf W, Saad A, Roberts R, Ney A, Pereira SP, Kocher HM, Duffy S, Blyuss O, Crnogorac-Jurcevic T. A combination of urinary biomarker panel and PancRISK score for earlier detection of pancreatic cancer: A case-control study. PLoS Med 2020; 17:e1003489. [PMID: 33301466 PMCID: PMC7758047 DOI: 10.1371/journal.pmed.1003489] [Citation(s) in RCA: 37] [Impact Index Per Article: 7.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 12/23/2020] [Accepted: 11/19/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest cancers, with around 9% of patients surviving >5 years. Asymptomatic in its initial stages, PDAC is mostly diagnosed late, when already a locally advanced or metastatic disease, as there are no useful biomarkers for detection in its early stages, when surgery can be curative. We have previously described a promising biomarker panel (LYVE1, REG1A, and TFF1) for earlier detection of PDAC in urine. Here, we aimed to establish the accuracy of an improved panel, including REG1B instead of REG1A, and an algorithm for data interpretation, the PancRISK score, in additional retrospectively collected urine specimens. We also assessed the complementarity of this panel with CA19-9 and explored the daily variation and stability of the biomarkers and their performance in common urinary tract cancers. METHODS AND FINDINGS Clinical specimens were obtained from multiple centres: Barts Pancreas Tissue Bank, University College London, University of Liverpool, Spanish National Cancer Research Center, Cambridge University Hospital, and University of Belgrade. The biomarker panel was assayed on 590 urine specimens: 183 control samples, 208 benign hepatobiliary disease samples (of which 119 were chronic pancreatitis), and 199 PDAC samples (102 stage I-II and 97 stage III-IV); 50.7% were from female individuals. PDAC samples were collected from patients before treatment. The samples were assayed using commercially available ELISAs. Statistical analyses were performed using non-parametric Kruskal-Wallis tests adjusted for multiple comparisons, and multiple logistic regression. Training and validation datasets for controls and PDAC samples were obtained after random division of the whole available dataset in a 1:1 ratio. The substitution of REG1A with REG1B enhanced the performance of the panel to detect resectable PDAC. In a comparison of controls and PDAC stage I-II samples, the areas under the receiver operating characteristic curve (AUCs) increased from 0.900 (95% CI 0.843-0.957) and 0.926 (95% CI 0.843-1.000) in the training (50% of the dataset) and validation sets, respectively, to 0.936 in both the training (95% CI 0.903-0.969) and the validation (95% CI 0.888-0.984) datasets for the new panel including REG1B. This improved panel showed both sensitivity (SN) and specificity (SP) to be >85%. Plasma CA19-9 enhanced the performance of this panel in discriminating PDAC I-II patients from controls, with AUC = 0.992 (95% CI 0.983-1.000), SN = 0.963 (95% CI 0.913-1.000), and SP = 0.967 (95% CI 0.924-1.000). We demonstrate that the biomarkers do not show significant daily variation, and that they are stable for up to 5 days at room temperature. The main limitation of our study is the low number of stage I-IIA PDAC samples (n = 27) and lack of samples from individuals with hereditary predisposition to PDAC, for which specimens collected from control individuals were used as a proxy. CONCLUSIONS We have successfully validated our urinary biomarker panel, which was improved by substituting REG1A with REG1B. At a pre-selected cutoff of >80% SN and SP for the affiliated PancRISK score, we demonstrate a clinically applicable risk stratification tool with a binary output for risk of developing PDAC ('elevated' or 'normal'). PancRISK provides a step towards precision surveillance for PDAC patients, which we will test in a prospective clinical study, UroPanc.
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Affiliation(s)
- Silvana Debernardi
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Harrison O’Brien
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Asma S. Algahmdi
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Nuria Malats
- Centro Nacional de Investigaciones Oncológicas, Madrid, Spain
- Centro de Investigación Biomédica en Red de Cáncer, Madrid Spain
| | - Grant D. Stewart
- Department of Surgery, University of Cambridge, Cambridge, United Kingdom
| | - Marija Plješa-Ercegovac
- Institute of Medical and Clinical Biochemistry, Faculty of Medicine, University of Belgrade, Belgrade, Serbia
| | - Eithne Costello
- Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - William Greenhalf
- Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool, United Kingdom
| | - Amina Saad
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Rhiannon Roberts
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Alexander Ney
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Stephen P. Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | - Hemant M. Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stephen Duffy
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
| | - Oleg Blyuss
- School of Physics, Astronomy and Mathematics, University of Hertfordshire, Hatfield, United Kingdom
- Department of Paediatrics and Paediatric Infectious Diseases, Institute of Child Health, Sechenov First Moscow State Medical University, Moscow, Russia
- Department of Applied Mathematics, Lobachevsky State University of Nizhny Novgorod, Nizhny Novgorod, Russia
| | - Tatjana Crnogorac-Jurcevic
- Centre for Cancer Biomarkers and Biotherapeutics, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
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13
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Zhang WH, Wang WQ, Han X, Gao HL, Li TJ, Xu SS, Li S, Xu HX, Li H, Ye LY, Lin X, Wu CT, Long J, Yu XJ, Liu L. Advances on diagnostic biomarkers of pancreatic ductal adenocarcinoma: A systems biology perspective. Comput Struct Biotechnol J 2020; 18:3606-3614. [PMID: 33304458 PMCID: PMC7710502 DOI: 10.1016/j.csbj.2020.11.018] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2020] [Revised: 11/08/2020] [Accepted: 11/10/2020] [Indexed: 12/26/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a lethal malignancy that is usually diagnosed at an advanced stage when curative surgery is no longer an option. Robust diagnostic biomarkers with high sensitivity and specificity for early detection are urgently needed. Systems biology provides a powerful tool for understanding diseases and solving challenging biological problems, allowing biomarkers to be identified and quantified with increasing accuracy, sensitivity, and comprehensiveness. Here, we present a comprehensive overview of efforts to identify biomarkers of PDAC using genomics, transcriptomics, proteomics, metabonomics, and bioinformatics. Systems biology perspective provides a crucial "network" to integrate multi-omics approaches to biomarker identification, shedding additional light on early PDAC detection.
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Affiliation(s)
- Wu-Hu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wen-Quan Wang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Han
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - He-Li Gao
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Tian-Jiao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuai-Shuai Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shuo Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hua-Xiang Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Hao Li
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Long-Yun Ye
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xuan Lin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Chun-Tao Wu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Long
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xian-Jun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Liang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Shanghai Pancreatic Cancer Institute, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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14
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Pancreatic duct ligation reduces premalignant pancreatic lesions in a Kras model of pancreatic adenocarcinoma in mice. Sci Rep 2020; 10:18344. [PMID: 33110094 PMCID: PMC7591874 DOI: 10.1038/s41598-020-74947-4] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Accepted: 09/22/2020] [Indexed: 02/07/2023] Open
Abstract
Pancreatic duct ligation (PDL) in the murine model has been described as an exocrine pancreatic atrophy-inducing procedure. However, its influence has scarcely been described on premalignant lesions. This study describes the histological changes of premalignant lesions and the gene expression in a well-defined model of pancreatic ductal adenocarcinoma by PDL. Selective ligation of the splenic lobe of the pancreas was performed in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice (PDL-Kras mice). Three experimental groups were evaluated: PDL group, controls and shams. The presence and number of premalignant lesions (PanIN 1–3 and Atypical Flat Lesions—AFL) in proximal (PP) and distal (DP) pancreas were studied for each group over time. Microarray analysis was performed to find differentially expressed genes (DEG) between PP and PD. Clinical human specimens after pancreaticoduodenectomy with ductal occlusion were also evaluated. PDL-Kras mice showed an intense pattern of atrophy in DP which was shrunk to a minimal portion of tissue. Mice in control and sham groups had a 7 and 10-time increase respectively of risk of high-grade PanIN 2 and 3 and AFL in their DP than PDL-Kras mice. Furthermore, PDL-Kras mice had significantly less PanIN 1 and 2 and AFL lesions in DP compared to PP. We identified 38 DEGs comparing PP and PD. Among them, several mapped to protein secretion and digestion while others such as Nupr1 have been previously associated with PanIN and PDAC. PDL in Ptf1a-Cre(+/ki); K-ras LSLG12Vgeo(+/ki) mice induces a decrease in the presence of premalignant lesions in the ligated DP. This could be a potential line of research of interest in some cancerous risk patients.
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15
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Moidu NA, A Rahman NS, Syafruddin SE, Low TY, Mohtar MA. Secretion of pro-oncogenic AGR2 protein in cancer. Heliyon 2020; 6:e05000. [PMID: 33005802 PMCID: PMC7519367 DOI: 10.1016/j.heliyon.2020.e05000] [Citation(s) in RCA: 33] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/21/2020] [Revised: 08/25/2020] [Accepted: 09/17/2020] [Indexed: 12/12/2022] Open
Abstract
Anterior gradient-2 (AGR2) protein mediates the formation, breakage and isomerization of disulphide bonds during protein maturation in the endoplasmic reticulum (ER) and contributes to the homoeostasis of the secretory pathway. AGR2 promotes tumour development and metastasis and its elevated expression is almost completely restricted to malignant tumours. Interestingly, this supposedly ER-resident protein can be localised to other compartments of cancer cells and can also be secreted into the extracellular milieu. There are emerging evidences that describe the gain-of-function activities of the extracellular AGR2, particularly in cancer development. Here, we reviewed studies detailing the expression, pathological and physiological roles associated with AGR2 and compared the duality of localization, intracellular and extracellular, with special emphasis on the later. We also discussed the possible mechanisms of AGR2 secretion as well as deliberating the functional impacts of AGR2 in cancer settings. Last, we deliberate the current therapeutic strategies and posit the potential use AGR2, as a prognosis and diagnosis marker in cancer.
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Affiliation(s)
- Nurshahirah Ashikin Moidu
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras 56000 Kuala Lumpur, Malaysia
| | - Nisa Syakila A Rahman
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras 56000 Kuala Lumpur, Malaysia
| | - Saiful Effendi Syafruddin
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras 56000 Kuala Lumpur, Malaysia
| | - Teck Yew Low
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras 56000 Kuala Lumpur, Malaysia
| | - M Aiman Mohtar
- UKM Medical Molecular Biology Institute (UMBI), Universiti Kebangsaan Malaysia, Cheras 56000 Kuala Lumpur, Malaysia
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16
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Yang C, Liu Z, Zeng X, Wu Q, Liao X, Wang X, Han C, Yu T, Zhu G, Qin W, Peng T. Evaluation of the diagnostic ability of laminin gene family for pancreatic ductal adenocarcinoma. Aging (Albany NY) 2020; 11:3679-3703. [PMID: 31182680 PMCID: PMC6594799 DOI: 10.18632/aging.102007] [Citation(s) in RCA: 27] [Impact Index Per Article: 5.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/25/2019] [Accepted: 05/29/2019] [Indexed: 12/21/2022]
Abstract
A poor outcome for pancreatic ductal adenocarcinoma (PDAC) patients is still a challenge worldwide. The aim of our study is to investigate the potential of key laminin subunits for being used both as a diagnostic and prognostic biomarker for PDAC patients. We evaluated the mRNA expression and prognostic value of laminin gene family in PDAC tissues using online public databases. Moreover, the relationship between key laminin subunits in PDAC blood cells and circulating tumor cells (CTCs) and the distinguishing ability of joint serum levels with carbohydrate antigen 19-9 (CA19-9) was analyzed. Two key differentially expressed subunits (LAMA3 and LAMC2) that are associated with prognosis of PDAC patients were found to show a potential for distinguishing between PDAC and non-tumor tissues. LAMA3 and LAMC2 expression were found to be positively related with CTC quantity in PDAC blood (R=0.628, p=0.029; R=0.776, p=0.003, respectively) using IgG chips. Furthermore, serum LAMC2 levels offered significant improvement over using CA19-9 alone for the discrimination of PDAC. Joint serum LAMC2 and CA19-9 levels increased the net benefit proportion in early stage/operational PDAC patients. Using integrated profiling, we identified LAMA3 and LAMC2 as potential therapeutic targets and prognostic markers for PDAC, for which further validation is warranted.
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Affiliation(s)
- Chengkun Yang
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Zhengqian Liu
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xianmin Zeng
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Qiongyuan Wu
- Department of Tuina, The First Affiliated Hospital of Guangxi University of Chinese Medicine, Nanning, Guangxi Province, China
| | - Xiwen Liao
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Xiangkun Wang
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Chuangye Han
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tingdong Yu
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Guangzhi Zhu
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Wei Qin
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
| | - Tao Peng
- Department of Hepatobiliary Surgery, The first Affiliated Hospital of Guangxi Medical University, Nanning, Guangxi Province, China
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17
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Peng H, Pan S, Yan Y, Brand RE, Petersen GM, Chari ST, Lai LA, Eng JK, Brentnall TA, Chen R. Systemic Proteome Alterations Linked to Early Stage Pancreatic Cancer in Diabetic Patients. Cancers (Basel) 2020; 12:cancers12061534. [PMID: 32545216 PMCID: PMC7352938 DOI: 10.3390/cancers12061534] [Citation(s) in RCA: 25] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2020] [Revised: 06/05/2020] [Accepted: 06/07/2020] [Indexed: 02/07/2023] Open
Abstract
BACKGROUND Diabetes is a risk factor associated with pancreatic ductal adenocarcinoma (PDAC), and new adult-onset diabetes can be an early sign of pancreatic malignancy. Development of blood-based biomarkers to identify diabetic patients who warrant imaging tests for cancer detection may represent a realistic approach to facilitate earlier diagnosis of PDAC in a risk population. METHODS A spectral library-based proteomic platform was applied to interrogate biomarker candidates in plasma samples from clinically well-defined diabetic cohorts with and without PDAC. Random forest algorithm was used for prediction model building and receiver operating characteristic (ROC) curve analysis was applied to evaluate the prediction probability of potential biomarker panels. RESULTS Several biomarker panels were cross-validated in the context of detection of PDAC within a diabetic background. In combination with carbohydrate antigen 19-9 (CA19-9), the panel, which consisted of apolipoprotein A-IV (APOA4), monocyte differentiation antigen CD14 (CD14), tetranectin (CLEC3B), gelsolin (GSN), histidine-rich glycoprotein (HRG), inter-alpha-trypsin inhibitor heavy chain H3 (ITIH3), plasma kallikrein (KLKB1), leucine-rich alpha-2-glycoprotein (LRG1), pigment epithelium-derived factor (SERPINF1), plasma protease C1 inhibitor (SERPING1), and metalloproteinase inhibitor 1 (TIMP1), demonstrated an area under curve (AUC) of 0.85 and a two-fold increase in detection accuracy compared to CA19-9 alone. The study further evaluated the correlations of protein candidates and their influences on the performance of biomarker panels. CONCLUSIONS Proteomics-based multiplex biomarker panels improved the detection accuracy for diagnosis of early stage PDAC in diabetic patients.
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Affiliation(s)
- Hong Peng
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (H.P.); (S.P.)
| | - Sheng Pan
- The Brown Foundation Institute of Molecular Medicine, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA; (H.P.); (S.P.)
- Department of Integrative Biology and Pharmacology, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA
| | - Yuanqing Yan
- Department of Neurosurgery, McGovern Medical School, University of Texas Health Science Center at Houston, Houston, TX 77030, USA;
| | - Randall E. Brand
- Department of Medicine, University of Pittsburgh, Pittsburgh, PA 15261, USA;
| | - Gloria M. Petersen
- Department of Medicine, Mayo Clinic, Rochester, MN 55902, USA; (G.M.P.); (S.T.C.)
| | - Suresh T. Chari
- Department of Medicine, Mayo Clinic, Rochester, MN 55902, USA; (G.M.P.); (S.T.C.)
| | - Lisa A. Lai
- Division of Gastroenterology, Department of Medicine, the University of Washington, Seattle, WA 98195, USA; (L.A.L.); (T.A.B.)
| | - Jimmy K. Eng
- Proteomics Resource, The University of Washington, Seattle, WA 98109, USA;
| | - Teresa A. Brentnall
- Division of Gastroenterology, Department of Medicine, the University of Washington, Seattle, WA 98195, USA; (L.A.L.); (T.A.B.)
| | - Ru Chen
- Section of Gastroenterology and Hepatology, Department of Medicine, Baylor College of Medicine, Houston, TX 77030, USA
- Correspondence:
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18
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Whitwell HJ, Worthington J, Blyuss O, Gentry-Maharaj A, Ryan A, Gunu R, Kalsi J, Menon U, Jacobs I, Zaikin A, Timms JF. Improved early detection of ovarian cancer using longitudinal multimarker models. Br J Cancer 2020; 122:847-856. [PMID: 31937926 PMCID: PMC7078315 DOI: 10.1038/s41416-019-0718-9] [Citation(s) in RCA: 56] [Impact Index Per Article: 11.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/28/2019] [Revised: 12/06/2019] [Accepted: 12/16/2019] [Indexed: 12/20/2022] Open
Abstract
BACKGROUND Ovarian cancer has a poor survival rate due to late diagnosis and improved methods are needed for its early detection. Our primary objective was to identify and incorporate additional biomarkers into longitudinal models to improve on the performance of CA125 as a first-line screening test for ovarian cancer. METHODS This case-control study nested within UKCTOCS used 490 serial serum samples from 49 women later diagnosed with ovarian cancer and 31 control women who were cancer-free. Proteomics-based biomarker discovery was carried out using pooled samples and selected candidates, including those from the literature, assayed in all serial samples. Multimarker longitudinal models were derived and tested against CA125 for early detection of ovarian cancer. RESULTS The best performing models, incorporating CA125, HE4, CHI3L1, PEBP4 and/or AGR2, provided 85.7% sensitivity at 95.4% specificity up to 1 year before diagnosis, significantly improving on CA125 alone. For Type II cases (mostly high-grade serous), models achieved 95.5% sensitivity at 95.4% specificity. Predictive values were elevated earlier than CA125, showing the potential of models to improve lead time. CONCLUSIONS We have identified candidate biomarkers and tested longitudinal multimarker models that significantly improve on CA125 for early detection of ovarian cancer. These models now warrant independent validation.
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Affiliation(s)
- Harry J Whitwell
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
| | - Jenny Worthington
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
| | - Oleg Blyuss
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
- Department of Paediatrics, Sechenov University, Moscow, 119146, Russia
- School of Physics, Astronomy and Mathematics, University of Hertfordshire, College Lane, Hatfield, UK
| | | | - Andy Ryan
- MRC Clinical Trials Unit at UCL, 90 High Holborn, London, WC1V 6LJ, UK
| | - Richard Gunu
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
| | - Jatinderpal Kalsi
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
- MRC Clinical Trials Unit at UCL, 90 High Holborn, London, WC1V 6LJ, UK
| | - Usha Menon
- MRC Clinical Trials Unit at UCL, 90 High Holborn, London, WC1V 6LJ, UK
| | - Ian Jacobs
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
- President and Vice-Chancellor's Office, University of New South Wales, Sydney, NSW, 2052, Australia
| | - Alexey Zaikin
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK
- Department of Paediatrics, Sechenov University, Moscow, 119146, Russia
- Department of Mathematics, University College London, London, W1T 7DN, UK
- Department of Applied Mathematics, Lobachevsky State University of Nizhniy Novgorod, Nizhniy Novgorod, 603022, Russia
| | - John F Timms
- Department of Women's Cancer, Institute for Women's Health, University College London, Gower Street, London, WC1E 6BT, UK.
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Zhou YY, Chen LP, Zhang Y, Hu SK, Dong ZJ, Wu M, Chen QX, Zhuang ZZ, Du XJ. Integrated transcriptomic analysis reveals hub genes involved in diagnosis and prognosis of pancreatic cancer. Mol Med 2019; 25:47. [PMID: 31706267 PMCID: PMC6842480 DOI: 10.1186/s10020-019-0113-2] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2019] [Accepted: 09/20/2019] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND The hunt for the molecular markers with specificity and sensitivity has been a hot area for the tumor treatment. Due to the poor diagnosis and prognosis of pancreatic cancer (PC), the excision rate is often low, which makes it more urgent to find the ideal tumor markers. METHODS Robust Rank Aggreg (RRA) methods was firstly applied to identify the differentially expressed genes (DEGs) between PC tissues and normal tissues from GSE28735, GSE15471, GSE16515, and GSE101448. Among these DEGs, the highly correlated genes were clustered using WGCNA analysis. The co-expression networks and molecular complex detection (MCODE) Cytoscape app were then performed to find the sub-clusters and confirm 35 candidate genes. For these genes, least absolute shrinkage and selection operator (lasso) regression model was applied and validated to build a diagnostic risk score model. Cox proportional hazard regression analysis was used and validated to build a prognostic model. RESULTS Based on integrated transcriptomic analysis, we identified a 19 gene module (SYCN, PNLIPRP1, CAP2, GNMT, MAT1A, ABAT, GPT2, ADHFE1, PHGDH, PSAT1, ERP27, PDIA2, MT1H, COMP, COL5A2, FN1, COL1A2, FAP and POSTN) as a specific predictive signature for the diagnosis of PC. Based on the two consideration, accuracy and feasibility, we simplified the diagnostic risk model as a four-gene model: 0.3034*log2(MAT1A)-0.1526*log2(MT1H) + 0.4645*log2(FN1) -0.2244*log2(FAP), log2(gene count). Besides, a four-hub gene module was also identified as prognostic model = - 1.400*log2(CEL) + 1.321*log2(CPA1) + 0.454*log2(POSTN) + 1.011*log2(PM20D1), log2(gene count). CONCLUSION Integrated transcriptomic analysis identifies two four-hub gene modules as specific predictive signatures for the diagnosis and prognosis of PC, which may bring new sight for the clinical practice of PC.
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Affiliation(s)
- Yang-Yang Zhou
- Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Li-Ping Chen
- Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
- Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000 Zhejiang China
| | - Yi Zhang
- Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000 Zhejiang China
| | - Sun-Kuan Hu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Zhao-Jun Dong
- Chemical Biology Research Center, College of Pharmaceutical Sciences, Wenzhou Medical University, Wenzhou, 325000 Zhejiang China
| | - Ming Wu
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Qiu-Xiang Chen
- Department of Ultrasound, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Zhi-Zhi Zhuang
- Department of Rheumatology and Immunology, The Second Affiliated Hospital and Yuying Children’s Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
| | - Xiao-Jing Du
- Department of Gastroenterology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325000 Zhejiang Province China
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20
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Qian L, Li Q, Baryeh K, Qiu W, Li K, Zhang J, Yu Q, Xu D, Liu W, Brand RE, Zhang X, Chen W, Liu G. Biosensors for early diagnosis of pancreatic cancer: a review. Transl Res 2019; 213:67-89. [PMID: 31442419 DOI: 10.1016/j.trsl.2019.08.002] [Citation(s) in RCA: 44] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/11/2019] [Revised: 08/06/2019] [Accepted: 08/06/2019] [Indexed: 12/21/2022]
Abstract
Pancreatic cancer is characterized by extremely high mortality and poor prognosis and is projected to be the leading cause of cancer deaths by 2030. Due to the lack of early symptoms and appropriate methods to detect pancreatic carcinoma at an early stage as well as its aggressive progression, the disease is often quite advanced by the time a definite diagnosis is established. The 5-year relative survival rate for all stages is approximately 8%. Therefore, detection of pancreatic cancer at an early surgically resectable stage is the key to decrease mortality and to improve survival. The traditional methods for diagnosing pancreatic cancer involve an imaging test, such as ultrasound or magnetic resonance imaging, paired with a biopsy of the mass in question. These methods are often expensive, time consuming, and require trained professionals to use the instruments and analyze the imaging. To overcome these issues, biosensors have been proposed as a promising tool for the early diagnosis of pancreatic cancer. The present review critically discusses the latest developments in biosensors for the early diagnosis of pancreatic cancer. Protein and microRNA biomarkers of pancreatic cancer and corresponding biosensors for pancreatic cancer diagnosis have been reviewed, and all these cases demonstrate that the emerging biosensors are becoming an increasingly relevant alternative to traditional techniques. In addition, we discuss the existing problems in biosensors and future challenges.
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Affiliation(s)
- Lisheng Qian
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Qiaobin Li
- Department of Chemistry & Biochemistry, North Dakota State University, Fargo, North Dakota
| | - Kwaku Baryeh
- Department of Chemistry & Biochemistry, North Dakota State University, Fargo, North Dakota
| | - Wanwei Qiu
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Kun Li
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Jing Zhang
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Qingcai Yu
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Dongqin Xu
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Wenju Liu
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China
| | - Randall E Brand
- Division of Gastroenterology, Hepatology and Nutrition, University of Pittsburgh Medical Center, Hillman Cancer Center, University of Pittsburgh, Pittsburgh, Pennsylvania
| | - Xueji Zhang
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China; School of Biomedical Engineering, Shenzhen University Health Science Center, Shenzhen, Guangdong, PR China.
| | - Wei Chen
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China; School of Food Science & Engineering, Hefei University of Technology, Hefei, Anhui, PR China.
| | - Guodong Liu
- Institute of Biomedical and Health, School of Life and Health Science, Anhui Science and Technology University, Fengyang, Anhui, PR China; Department of Chemistry & Biochemistry, North Dakota State University, Fargo, North Dakota.
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21
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Vandenbrouck Y, Christiany D, Combes F, Loux V, Brun V. Bioinformatics Tools and Workflow to Select Blood Biomarkers for Early Cancer Diagnosis: An Application to Pancreatic Cancer. Proteomics 2019; 19:e1800489. [DOI: 10.1002/pmic.201800489] [Citation(s) in RCA: 16] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/03/2019] [Revised: 08/11/2019] [Indexed: 12/28/2022]
Affiliation(s)
- Yves Vandenbrouck
- University of Grenoble Alpes, INSERM, CEA, IRIG‐BGE, U1038 Grenoble 38000 France
| | - David Christiany
- University of Grenoble Alpes, INSERM, CEA, IRIG‐BGE, U1038 Grenoble 38000 France
- MaIAGE, INRA, Université Paris‐Saclay Jouy‐en‐Josas 78350 France
| | - Florence Combes
- University of Grenoble Alpes, INSERM, CEA, IRIG‐BGE, U1038 Grenoble 38000 France
| | - Valentin Loux
- MaIAGE, INRA, Université Paris‐Saclay Jouy‐en‐Josas 78350 France
| | - Virginie Brun
- University of Grenoble Alpes, INSERM, CEA, IRIG‐BGE, U1038 Grenoble 38000 France
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22
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Downing S, Zhang F, Chen Z, Tzanakakis ES. MicroRNA-7 directly targets Reg1 in pancreatic cells. Am J Physiol Cell Physiol 2019; 317:C366-C374. [PMID: 31166710 DOI: 10.1152/ajpcell.00013.2019] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Regenerating islet-derived (Reg) proteins, which were first discovered in the pancreas, are associated with increased proliferation, prevention of apoptosis, and enhanced differentiation in normal and disease states, but very little is known about the regulation of their expression. We hypothesized that Reg expression is influenced by microRNAs. Bioinformatic analysis predicted Reg1 to be a target of microRNA-7 (miR-7), which influences pancreatic β-cell function. To this end, we investigated the effects of miR-7 on Reg1 expression in pancreatic acinar and islet β-cells. High levels of Reg1 were noted by immunostaining and Western blotting in acinar cells in contrast to islet cells. A reciprocal expression pattern was observed for miR-7. Overexpression of miR-7 resulted in Reg1 mRNA suppression and reduction of secreted Reg1 protein. Conversely, miR-7 knockdown led to increases in Reg1. Targeting of Reg1 by miR-7 was confirmed via luciferase activity assays. In contrast, miR-7 did not directly repress the human ortholog of Reg1 REG1A as well as REG1B indicating species differences in the regulation of Reg expression. This is the first account of microRNA modulation of any Reg member warranting studies to fill gaps in our knowledge of Reg protein biology, particularly in disease contexts.
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Affiliation(s)
- Shawna Downing
- Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts
| | - Fan Zhang
- Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts
| | - Zijing Chen
- Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts
| | - Emmanuel S Tzanakakis
- Department of Chemical and Biological Engineering, Tufts University, Medford, Massachusetts.,Clinical and Translational Science Institute, Tufts Medical Center, Boston, Massachusetts
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23
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Yun JW, Zhao Z, Yan X, Vatamaniuk MZ, Lei XG. Glutathione peroxidase-1 inhibits transcription of regenerating islet-derived protein-2 in pancreatic islets. Free Radic Biol Med 2019; 134:385-393. [PMID: 30703484 PMCID: PMC6588445 DOI: 10.1016/j.freeradbiomed.2019.01.024] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/21/2018] [Revised: 01/06/2019] [Accepted: 01/20/2019] [Indexed: 12/22/2022]
Abstract
Our group previously demonstrated that overexpression of selenium-dependent glutathione peroxidase-1 (GPX1) in mice (OE) led to escalated glucose-stimulated insulin secretion and hyperinsulinemia. Because we found a strong correlation of this phenotype with a diminished expression of regenerating islet-derived protein 2 (REG2) in the OE pancreatic islets, the present study was to reveal underlying mechanisms for that down-regulation of REG2 by GPX1 as a major scavenger of reactive oxygen species. We first treated the OE and wild-type (WT) mice and their islets with ROS-generating diquat, streptozotocin, and H2O2 and ROS-scavenging ebselen and N-acetylcysteine (NAC). Their effects on pancreatic and islet REG2 protein and(or) secretion were opposite (P < 0.05). Thereafter, we identified 13 transcriptional factors with putative binding sites in the Reg2 proximate promoter, and found that only activator protein-1 (AP-1) and albumin D box-binding protein (DBP) mRNA and protein levels were affected (elevated) (P < 0.05) by the GPX1 overproduction in the OE pancreatic islets compared with the WT islets. Contrary to that of Reg2 expression, their mRNA abundances in the cultured islets were elevated (P < 0.05) by ebselen and NAC, but decreased (P < 0.05) by H2O2. Both AP-1 and DBP could bind to the Reg2 promoter at the location of -168 to 0 base pair (bp) in the OE islets. Deleting the AP-1 (-143/-137 and -60/-57 bp) and(or) DBP (-35/-29 bp) binding domains in the Reg2 promoter attenuated and(or) abolished the inhibition of Reg2 promoter activation by ebselen as the GPX1 mimic in βTC-3 cells. In conclusion, the down-regulation of Reg2 expression in the GPX1-overproducing pancreatic islets was mediated by a transcriptional inhibition of the gene through two ROS responsive transcription factors AP-1 and DBP. Our findings reveal GPX1 as a novel regulator of Reg2 expression, and linking these two previously-unrelated proteins will have broad biomedical implications.
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Affiliation(s)
- Jun-Won Yun
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA; Department of Biotechnology, The Catholic University of Korea, Bucheon 14662, Republic of Korea
| | - Zeping Zhao
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
| | - Xi Yan
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA
| | | | - Xin Gen Lei
- Department of Animal Science, Cornell University, Ithaca, NY 14853, USA.
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24
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Zhou Y, Zang Y, Yang Y, Xiang J, Chen Z. Candidate genes involved in metastasis of colon cancer identified by integrated analysis. Cancer Med 2019; 8:2338-2347. [PMID: 30884206 PMCID: PMC6536975 DOI: 10.1002/cam4.2071] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2018] [Revised: 01/29/2019] [Accepted: 02/07/2019] [Indexed: 12/12/2022] Open
Abstract
Colon cancer is one of the most malignant cancers worldwide. Nearly 20% of all colon cancer patients are diagnosed at stage IV (metastasis). However, further study of colon cancer is difficult due to a lack of understanding of its pathogenesis. In this study, we acquired high–throughput sequence data from TCGA datasets and performed integrated bioinformatic analysis including differential gene expression analysis, gene ontology and KEGG pathways analysis, protein–protein analysis, survival analysis, and multivariate Cox proportional hazards regression analysis in order to identify a panel of key candidate genes involved in the metastasis of colon cancer. We then constructed a prognostic signature based on the expression of REG1B, TGM6, NTF4, PNMA5, and HOXC13 which could provide significant prognostic value for colon cancer.
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Affiliation(s)
- Yiming Zhou
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yiwen Zang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Yi Yang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Jianbin Xiang
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
| | - Zongyou Chen
- Department of General Surgery, Huashan Hospital, Fudan University, Shanghai, China
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25
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Satyananda V, Gupta R, Hari DM, Yeh J, Chen KT. Advances in Translational Research and Clinical Care in Pancreatic Cancer: Where Are We Headed? Gastroenterol Res Pract 2019; 2019:7690528. [PMID: 30863442 PMCID: PMC6378762 DOI: 10.1155/2019/7690528] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/30/2018] [Accepted: 01/08/2019] [Indexed: 02/06/2023] Open
Abstract
While significant advances have been made in the treatment of many different solid tumors, pancreatic cancer remains a glaring exception. Overall 5-year survival rates for pancreatic cancer remain in the single digits. While newer chemotherapy regimens such as FOLFIRINOX and nab-paclitaxel/gemcitabine have demonstrated modest improvement in survival benefit for metastatic disease and have improved the resectability rates of previously borderline or locally advanced tumors, clinically significant improvements from immunotherapy and targeted therapy remain to be demonstrated. Regardless, a wealth of basic science research in pancreatic cancer has been directed at understanding its aggressive biology and its resistance to therapy. We present a brief summary of key areas of laboratory research and its translation to clinical care.
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Affiliation(s)
- Vikas Satyananda
- Division of Surgical Oncology, Department of Surgery, Harbor-UCLA Medical Center, USA
| | - Rohan Gupta
- Division of Medical Oncology, Department of Medicine, Harbor-UCLA Medical Center, USA
| | - Danielle M. Hari
- Division of Surgical Oncology, Department of Surgery, Harbor-UCLA Medical Center, USA
| | - James Yeh
- Division of Medical Oncology, Department of Medicine, Harbor-UCLA Medical Center, USA
| | - Kathryn T. Chen
- Division of Surgical Oncology, Department of Surgery, Harbor-UCLA Medical Center, USA
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26
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Igbinigie E, Guo F, Jiang SW, Kelley C, Li J. Dkk1 involvement and its potential as a biomarker in pancreatic ductal adenocarcinoma. Clin Chim Acta 2019; 488:226-234. [PMID: 30452897 DOI: 10.1016/j.cca.2018.11.023] [Citation(s) in RCA: 37] [Impact Index Per Article: 6.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/07/2018] [Revised: 11/12/2018] [Accepted: 11/14/2018] [Indexed: 02/05/2023]
Abstract
Dickkopf-1 (Dkk1)'s dysregulation has been implicated in the pathogenesis of a variety of cancers. It is part of the Dkk family of proteins that includes Dkk2, Dkk3 and Dkk4. This family of secreted proteins shares similar conserved cysteine domains and inhibits the Wnt/b-catenin pathway by causing proteasomal B-catenin degradation, inducing apoptosis, and preventing cell proliferation. Pancreatic ductal adenocarcinoma (PDAC) is the 4th leading cause of cancer mortality in the United States due to the late stage of diagnosis and the limited effectiveness of current therapy. Dkk1 is found increased in PADC patients' specimens and serum. Dkk1 can be a promising biomarker specific to PDAC, which has the potential to increase PDAC survival rates through improving early stage detection and monitoring progression compared to current biomarker gold standards. In addition, recent studies suggest that Dkk1 could be an excellent target for cancer immunotherapy. Interestingly, Dkk1-CKAP4-PI3K/AKT signal pathway also plays role in pancreatic cancer cell proliferation. In this review, we present the multiple mechanisms of Dkk1 in PDAC studied thus far and explore its function, regulation, and clinical applications in gynecological cancers including pancreatic ductal adenocarcinoma (PDAC), breast, ovarian, cervical, and endometrial cancer. Further research into Dkk1's mechanism and use as a diagnostic tool, alone or in combination with other biomarkers, could prove clinically useful for better understanding the pathology of PDAC and improving its early detection and treatment.
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Affiliation(s)
- Eseosaserea Igbinigie
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Fengbiao Guo
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA; Department of Histology and Embryology, Shantou University Medical College, Shantou 515000, China.
| | - Shi-Wen Jiang
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Cullen Kelley
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA.
| | - Jinping Li
- Department of Biomedical Sciences, Mercer University School of Medicine, Savannah, GA 31404, USA; Department of Biochemistry and Molecular Biology, Mayo Clinic, Florida Campus, Jacksonville, FL 32224, USA.
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27
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Llop E, Guerrero PE, Duran A, Barrabés S, Massaguer A, Ferri MJ, Albiol-Quer M, de Llorens R, Peracaula R. Glycoprotein biomarkers for the detection of pancreatic ductal adenocarcinoma. World J Gastroenterol 2018; 24:2537-2554. [PMID: 29962812 PMCID: PMC6021768 DOI: 10.3748/wjg.v24.i24.2537] [Citation(s) in RCA: 29] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/23/2018] [Revised: 05/04/2018] [Accepted: 06/09/2018] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaC) shows a clear tendency to increase in the next years and therefore represents an important health and social challenge. Currently, there is an important need to find biomarkers for PaC early detection because the existing ones are not useful for that purpose. Recent studies have indicated that there is a large window of time for PaC early detection, which opens the possibility to find early biomarkers that could greatly improve the dismal prognosis of this tumor. The present manuscript reviews the state of the art of the existing PaC biomarkers. It focuses on the anomalous glycosylation process and its role in PaC. Glycan structures of glycoconjugates such as glycoproteins are modified in tumors and these modifications can be detected in biological fluids of the cancer patients. Several studies have found serum glycoproteins with altered glycan chains in PaC patients, but they have not shown enough specificity for PaC. To find more specific cancer glycoproteins we propose to analyze the glycan moieties of a battery of glycoproteins that have been reported to increase in PaC tissues and that can also be found in serum. The combination of these new candidate glycoproteins with their aberrant glycosylation together with the existing biomarkers could result in a panel, which would expect to give better results as a new tool for early diagnosis of PaC and to monitor the disease.
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Affiliation(s)
- Esther Llop
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Pedro E Guerrero
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Adrià Duran
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Sílvia Barrabés
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Anna Massaguer
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - María José Ferri
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
- Clinic Laboratory, University Hospital Dr Josep Trueta, Girona 17007, Spain
| | - Maite Albiol-Quer
- Department of Surgery, Hepato-biliary and Pancreatic Surgery Unit, University Hospital Dr Josep Trueta, Girona 17007, Spain
| | - Rafael de Llorens
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
| | - Rosa Peracaula
- Department of Biology, Biochemistry and Molecular Biology Unit, University of Girona, Girona 17003, Spain
- Biomedical Research Institute of Girona (IdIBGi). Parc Hospitalari Martí i Julià-Edifici M2, Salt 17190, Spain
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Kim J, Bamlet WR, Oberg AL, Chaffee KG, Donahue G, Cao XJ, Chari S, Garcia BA, Petersen GM, Zaret KS. Detection of early pancreatic ductal adenocarcinoma with thrombospondin-2 and CA19-9 blood markers. Sci Transl Med 2018; 9:9/398/eaah5583. [PMID: 28701476 DOI: 10.1126/scitranslmed.aah5583] [Citation(s) in RCA: 184] [Impact Index Per Article: 26.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/13/2016] [Revised: 12/16/2016] [Accepted: 04/27/2017] [Indexed: 12/15/2022]
Abstract
Markers are needed to facilitate early detection of pancreatic ductal adenocarcinoma (PDAC), which is often diagnosed too late for effective therapy. Starting with a PDAC cell reprogramming model that recapitulated the progression of human PDAC, we identified secreted proteins and tested a subset as potential markers of PDAC. We optimized an enzyme-linked immunosorbent assay (ELISA) using plasma samples from patients with various stages of PDAC, from individuals with benign pancreatic disease, and from healthy controls. A phase 1 discovery study (n = 20), a phase 2a validation study (n = 189), and a second phase 2b validation study (n = 537) revealed that concentrations of plasma thrombospondin-2 (THBS2) discriminated among all stages of PDAC consistently. The receiver operating characteristic (ROC) c-statistic was 0.76 in the phase 1 study, 0.84 in the phase 2a study, and 0.87 in the phase 2b study. The plasma concentration of THBS2 was able to discriminate resectable stage I cancer as readily as stage III/IV PDAC tumors. THBS2 plasma concentrations combined with those for CA19-9, a previously identified PDAC marker, yielded a c-statistic of 0.96 in the phase 2a study and 0.97 in the phase 2b study. THBS2 data improved the ability of CA19-9 to distinguish PDAC from pancreatitis. With a specificity of 98%, the combination of THBS2 and CA19-9 yielded a sensitivity of 87% for PDAC in the phase 2b study. A THBS2 and CA19-9 blood marker panel measured with a conventional ELISA may improve the detection of patients at high risk for PDAC.
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Affiliation(s)
- Jungsun Kim
- Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), Perelman School of Medicine, University of Pennsylvania, 9-131 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA
| | - William R Bamlet
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Ann L Oberg
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Kari G Chaffee
- Division of Biomedical Statistics and Informatics, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Greg Donahue
- Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), Perelman School of Medicine, University of Pennsylvania, 9-131 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA
| | - Xing-Jun Cao
- Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Suresh Chari
- Division of Gastroenterology and Hepatology, Department of Medicine, Mayo Clinic, Rochester, MN 55905, USA
| | - Benjamin A Garcia
- Epigenetics Program, Department of Biochemistry and Biophysics, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Gloria M Petersen
- Division of Epidemiology, Department of Health Sciences Research, Mayo Clinic, Rochester, MN 55905, USA
| | - Kenneth S Zaret
- Institute for Regenerative Medicine, Department of Cell and Developmental Biology, Abramson Cancer Center (Tumor Biology Program), Perelman School of Medicine, University of Pennsylvania, 9-131 Smilow Center for Translational Research, 3400 Civic Center Boulevard, Philadelphia, PA 19104-5157, USA.
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Zhang X, Shi S, Zhang B, Ni Q, Yu X, Xu J. Circulating biomarkers for early diagnosis of pancreatic cancer: facts and hopes. Am J Cancer Res 2018; 8:332-353. [PMID: 29636993 PMCID: PMC5883088] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2018] [Accepted: 02/25/2018] [Indexed: 06/08/2023] Open
Abstract
Pancreatic cancer (PC) is characterized by extremely high mortality and poor prognosis, which are largely ascribed to difficulties in early diagnosis and limited therapeutics. Although there is a sufficient window for intervention before preneoplastic lesions progress to invasive disease, effective early detection of PC remains difficult using current biomarkers and imaging techniques. Biomarkers with satisfactory diagnostic efficacy and convenient analysis methods are urgently required. In this review, we summarized recent advances in the identification of biomarkers in circulation for early detection of PC. A number of novel circulating biomarkers, such as metabolites, cell-free DNA (cfDNA), noncoding RNA, and exosomes, that show promising diagnostic value have been discovered using advances in sequencing techniques and "omics" analyses. Panels comprising several biomarkers may also exhibit better diagnostic performance. In the future, we need more efficient circulating biomarkers for the identification of noninvasive precursor lesions and early disease. Collaborative large-scale studies are also required to show the clinical validity and applicability of potential biomarkers.
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Affiliation(s)
- Xu Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer CenterShanghai 200032, China
- Department of Oncology, Shanghai Medical College, Fudan UniversityShanghai 200032, China
- Pancreatic Cancer Institute, Fudan UniversityShanghai 200032, China
- Shanghai Pancreatic Cancer InstituteShanghai, China
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30
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Park J, Han D, Do M, Woo J, Wang JI, Han Y, Kwon W, Kim SW, Jang JY, Kim Y. Proteome characterization of human pancreatic cyst fluid from intraductal papillary mucinous neoplasm by liquid chromatography/tandem mass spectrometry. RAPID COMMUNICATIONS IN MASS SPECTROMETRY : RCM 2017; 31:1761-1772. [PMID: 28815810 DOI: 10.1002/rcm.7959] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/12/2017] [Revised: 07/12/2017] [Accepted: 08/11/2017] [Indexed: 06/07/2023]
Abstract
RATIONALE In recent years, the molecular components of pancreatic cyst fluid have been used for diagnosis and prognosis. Because the protein markers that are currently used in clinical tests are unreliable, proteomic studies to find new protein markers are being conducted. However, such researches have been limited due to the complexity of pancreatic cyst fluid and the immaturity of proteomic techniques. METHODS To overcome these limitations and provide a pancreatic cyst proteome dataset, we examined cyst fluid proteome with tandem mass spectrometry. The proteomic analysis was performed using a Orbitrap-based mass spectrometer (Q-Exactive) coupled with a 50-cm-long nano-liquid chromatography column. Protein mutations were identified using mutation sequence database search. RESULTS A total of 5850 protein groups were identified from microliters of cyst fluid. Among those, 3934 protein groups were reported for the first time in pancreatic cyst fluid. Although high-abundance proteins were not depleted in the experiment, our dataset detected almost all pancreatic tumor markers such as mucin family members, S100 proteins, and CEA-related proteins. In addition, 590 protein mutation marker candidates were discovered. CONCLUSIONS We provide a comprehensive cyst proteome dataset that includes cystic cellular proteins and mutated proteins. Our findings would serve as a rich resource for further IPMN studies and clinical applications. The MS data have been deposited in the ProteomeXchange with identifier PXD005671 (http://proteomecentral.proteomexchange.org/dataset/PXD005671).
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MESH Headings
- Amino Acid Sequence
- Biomarkers, Tumor/analysis
- Carcinoma, Pancreatic Ductal/chemistry
- Carcinoma, Pancreatic Ductal/pathology
- Chromatography, Liquid/methods
- Cyst Fluid/chemistry
- Humans
- Neoplasms, Cystic, Mucinous, and Serous/chemistry
- Neoplasms, Cystic, Mucinous, and Serous/pathology
- Pancreas/chemistry
- Pancreas/pathology
- Pancreatic Cyst/chemistry
- Pancreatic Cyst/pathology
- Pancreatic Neoplasms/chemistry
- Pancreatic Neoplasms/pathology
- Proteome/analysis
- Proteomics/methods
- Tandem Mass Spectrometry/methods
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Affiliation(s)
- Joonho Park
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Dohyun Han
- Biomedical Research Institute, Seoul National University Hospital, 101 Daehak-ro, Seoul, Korea
| | - Misol Do
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Jongmin Woo
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Joseph I Wang
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Youngmin Han
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Wooil Kwon
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Sun-Whe Kim
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
| | - Youngsoo Kim
- Department of Biomedical Engineering, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
- Department of Biomedical Sciences, Seoul National University College of Medicine, 103 Daehak-ro, Seoul, Korea
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31
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Keane MG, Shah A, Pereira SP, Joshi D. Novel biomarkers and endoscopic techniques for diagnosing pancreaticobiliary malignancy. F1000Res 2017; 6:1643. [PMID: 28944047 PMCID: PMC5585877 DOI: 10.12688/f1000research.11371.1] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 09/06/2017] [Indexed: 12/12/2022] Open
Abstract
The UK incidence of pancreatic ductal adenocarcinoma is 9 per 100,000 population, and biliary tract cancer occurs at a rate of 1–2 per 100,000. The incidence of both cancers is increasing annually and these tumours continue to be diagnosed late and at an advanced stage, limiting options for curative treatment. Population-based screening programmes do not exist for these cancers, and diagnosis currently is dependent on symptom recognition, but often symptoms are not present until the disease is advanced. Recently, a number of promising blood and urine biomarkers have been described for pancreaticobiliary malignancy and are summarised in this review. Novel endoscopic techniques such as single-operator cholangioscopy and confocal endomicroscopy have been used in some centres to enhance standard endoscopic diagnostic techniques and are also evaluated in this review.
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Affiliation(s)
| | - Amar Shah
- Institute of Liver Studies, King's College Hospital, London, UK
| | - Stephen P Pereira
- UCL Institute for Liver and Digestive Health, Royal Free Campus, London, UK
| | - Deepak Joshi
- Institute of Liver Studies, King's College Hospital, London, UK
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32
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Seang S, Somasunderam A, Nigalye M, Somsouk M, Schacker TW, Sanchez JL, Hunt PW, Utay NS, Lake JE. Circulating LOXL 2 Levels Reflect Severity of Intestinal Fibrosis and GALT CD4 + T Lymphocyte Depletion in Treated HIV Infection. Pathog Immun 2017; 2:239-252. [PMID: 28782046 PMCID: PMC5542020 DOI: 10.20411/pai.v2i2.180] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND Incomplete immune reconstitution may occur despite successful antiretroviral therapy (ART). Gut-associated lymphoid tissue (GALT) fibrosis may contribute via local CD4+ T lymphocyte depletion, intestinal barrier disruption, microbial translocation, and immune activation. METHODS In a cross-sectional analysis, we measured circulating fibrosis biomarker levels on cryopreserved plasma from adult HIV-infected (HIV+) SCOPE study participants on suppressive ART who also had fibrosis quantification on recto-sigmoid biopsies. Relationships among biomarker levels, clinical and demographic variables, GALT lymphoid aggregate (LA) collagen deposition, and LA CD4+ T lymphocyte density were analyzed using simple regression. Biomarker levels were also compared to levels in HIV+ viremic SCOPE participants and a convenience sample of HIV-uninfected (HIV-) samples. RESULTS HIV+ aviremic participants (n = 39) were 92% male and 41% non-white, with median age 48 years, CD4+ T lymphocyte count 277 cells/mm3, and 17 years since HIV diagnosis. Most biomarkers were lower in HIV- (n = 36) vs HIV+ aviremic individuals, although CXCL4 levels were higher. HIV+ viremic individuals (N = 18) had higher median TGF-β3, CIC-C1Q, and TIMP-1 (P < 0.05) and lower LOXL2 levels (P = 0.08) than HIV+ aviremic individuals. Only higher LOXL2 levels correlated with more GALT collagen deposition (R = 0.44, P= 0.008) and lower LA CD4+ T lymphocyte density (R = -0.32, P = 0.05) among aviremic individuals. CONCLUSIONS Circulating LOXL2 levels may be a noninvasive measure of intestinal fibrosis and GALT CD4+ T lymphocyte depletion in treated HIV infection. LOXL2 crosslinks elastin and collagen, and elevated LOXL2 levels occur in pathologic states, making LOXL2 inhibition a potential interventional target for intestinal fibrosis and its sequelae.
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Affiliation(s)
- Sophie Seang
- Pitie Salpetrière Hospital, University Pierre et Marie Curie, Paris, FRANCE and INSERM UMR-S943
| | | | | | - Ma Somsouk
- University of California, San Francisco, California
| | | | | | | | | | - Jordan E. Lake
- University of Texas Health Science Center at Houston, Houston, Texas
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Liang C, Qin Y, Zhang B, Ji S, Shi S, Xu W, Liu J, Xiang J, Liang D, Hu Q, Ni Q, Xu J, Yu X. Oncogenic KRAS Targets MUC16/CA125 in Pancreatic Ductal Adenocarcinoma. Mol Cancer Res 2017; 15:201-212. [PMID: 28108627 DOI: 10.1158/1541-7786.mcr-16-0296] [Citation(s) in RCA: 40] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/01/2016] [Revised: 10/10/2016] [Accepted: 10/31/2016] [Indexed: 11/16/2022]
Abstract
UNLABELLED Pancreatic ductal adenocarcinoma (PDAC) is a devastating disease with the 5-year survival rate less than 6%. Previous results indicated that serum levels of CA125 (encoded by MUC16) could be used to predict which groups of pancreatic cancer patients may benefit from surgery. However, the underlying mechanism remains elusive. Herein, using the Cancer Genome Atlas and clinicopathologic data obtained from our center, we demonstrate that high CA125 serum levels and expression levels of MUC16 are predictive of poor prognosis. MUC16 is also validated as a downstream target of KRAS, and their expression strongly correlated with each other in vitro and in vivo Mechanistically, the KRAS/ERK axis induced upregulation of MUC16 and shedding of CA125 via its effector c-Myc in SW1990 and PANC-1 pancreatic cancer cells. Notably, proto-oncogene c-Myc could bind to the promoter of MUC16 and transcriptionally activate its expression. Taken together, these data establish CA125 as a prognostic marker for pancreatic cancer, and mechanistic studies uncovered the KRAS/c-Myc axis as a driving factor for upregulation of MUC16. IMPLICATIONS The current study uncovers the contribution of oncogenic KRAS to serum marker CA125 production through a mechanism that involves the ERK/c-Myc axis. Mol Cancer Res; 15(2); 201-12. ©2016 AACR.
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Affiliation(s)
- Chen Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Yi Qin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Bo Zhang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Shunrong Ji
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Si Shi
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Wenyan Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jiang Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jinfeng Xiang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Dingkong Liang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Qiangsheng Hu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Jin Xu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, Shanghai, China.
- Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
- Pancreatic Cancer Institute, Fudan University, Shanghai, China
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Zhang Q, Chen S, Zeng L, Chen Y, Lian G, Qian C, Li J, Xie R, Huang KH. New developments in the early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2017; 11:149-156. [PMID: 27937041 DOI: 10.1080/17474124.2017.1271323] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Pancreatic cancer is an aggressive carcinoma of the digestive system and radical resection, which is available to very few patients, is the only possibility for cure. Since therapeutic choices are limited at the advanced stage, screening and early diagnostic tools are indispensable for a better prognosis. Areas covered: This review illustrates serologic and imaging examinations, and carbohydrate antigens, microRNAs, methylation biomarkers, molecules in exosomes, ultrasound, computed tomography, magnetic resonance imaging, positron emission tomography and endoscopic retrograde cholangiopancreatography, among other topics. No matter which approach is used, the accuracy of early diagnosis is extremely low. Combining different methods greatly improves the accuracy of early diagnosis. This review was conducted utilizing PubMed with key search words pancreatic cancer, early diagnosis, biomarkers and imaging. Expert commentary: Appropriate combination of biomarkers and imaging technologies will become standard practice in the future. Because the incidence of and mortality from pancreatic cancer is rising, further study of new approaches for the early detection of pancreatic tumors is essential.
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Affiliation(s)
- QiuBo Zhang
- a Department of Gastroenterology , Lihuili Hospital of Ningbo Medical Center , Ningbo , China
| | - ShaoJie Chen
- b Department of Oncology , the Fifth Affiliated Hospital of Sun Yat-Sen University , Zhuhai , China
| | - LinJuan Zeng
- b Department of Oncology , the Fifth Affiliated Hospital of Sun Yat-Sen University , Zhuhai , China
| | - YinTing Chen
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - GuoDa Lian
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - ChenChen Qian
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - JiaJia Li
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - RuiJie Xie
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
| | - Kai-Hong Huang
- c Department of Gastroenterology , Sun Yat-Sen Memorial Hospital of Sun Yat-Sen University , Guangzhou , China
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Heiler S, Wang Z, Zöller M. Pancreatic cancer stem cell markers and exosomes - the incentive push. World J Gastroenterol 2016; 22:5971-6007. [PMID: 27468191 PMCID: PMC4948278 DOI: 10.3748/wjg.v22.i26.5971] [Citation(s) in RCA: 75] [Impact Index Per Article: 8.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/19/2016] [Revised: 06/03/2016] [Accepted: 06/28/2016] [Indexed: 02/06/2023] Open
Abstract
Pancreatic cancer (PaCa) has the highest death rate and incidence is increasing. Poor prognosis is due to late diagnosis and early metastatic spread, which is ascribed to a minor population of so called cancer stem cells (CSC) within the mass of the primary tumor. CSC are defined by biological features, which they share with adult stem cells like longevity, rare cell division, the capacity for self renewal, differentiation, drug resistance and the requirement for a niche. CSC can also be identified by sets of markers, which for pancreatic CSC (Pa-CSC) include CD44v6, c-Met, Tspan8, alpha6beta4, CXCR4, CD133, EpCAM and claudin7. The functional relevance of CSC markers is still disputed. We hypothesize that Pa-CSC markers play a decisive role in tumor progression. This is fostered by the location in glycolipid-enriched membrane domains, which function as signaling platform and support connectivity of the individual Pa-CSC markers. Outside-in signaling supports apoptosis resistance, stem cell gene expression and tumor suppressor gene repression as well as miRNA transcription and silencing. Pa-CSC markers also contribute to motility and invasiveness. By ligand binding host cells are triggered towards creating a milieu supporting Pa-CSC maintenance. Furthermore, CSC markers contribute to the generation, loading and delivery of exosomes, whereby CSC gain the capacity for a cell-cell contact independent crosstalk with the host and neighboring non-CSC. This allows Pa-CSC exosomes (TEX) to reprogram neighboring non-CSC towards epithelial mesenchymal transition and to stimulate host cells towards preparing a niche for metastasizing tumor cells. Finally, TEX communicate with the matrix to support tumor cell motility, invasion and homing. We will discuss the possibility that CSC markers are the initial trigger for these processes and what is the special contribution of CSC-TEX.
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36
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Radon TP, Massat NJ, Jones R, Alrawashdeh W, Dumartin L, Ennis D, Duffy SW, Kocher HM, Pereira SP, Guarner posthumous L, Murta-Nascimento C, Real FX, Malats N, Neoptolemos J, Costello E, Greenhalf W, Lemoine NR, Crnogorac-Jurcevic T. Identification of a Three-Biomarker Panel in Urine for Early Detection of Pancreatic Adenocarcinoma. Clin Cancer Res 2015; 21:3512-21. [PMID: 26240291 PMCID: PMC4539580 DOI: 10.1158/1078-0432.ccr-14-2467] [Citation(s) in RCA: 140] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/22/2022]
Abstract
PURPOSE Noninvasive biomarkers for early detection of pancreatic ductal adenocarcinoma (PDAC) are currently not available. Here, we aimed to identify a set of urine proteins able to distinguish patients with early-stage PDAC from healthy individuals. EXPERIMENTAL DESIGN Proteomes of 18 urine samples from healthy controls, chronic pancreatitis, and patients with PDAC (six/group) were assayed using GeLC/MS/MS analysis. The selected biomarkers were subsequently validated with ELISA assays using multiple logistic regression applied to a training dataset in a multicenter cohort comprising 488 urine samples. RESULTS LYVE-1, REG1A, and TFF1 were selected as candidate biomarkers. When comparing PDAC (n = 192) with healthy (n = 87) urine specimens, the resulting areas under the receiver-operating characteristic curves (AUC) of the panel were 0.89 [95% confidence interval (CI), 0.84-0.94] in the training (70% of the data) and 0.92 (95% CI, 0.86-0.98) in the validation (30% of the data) datasets. When comparing PDAC stage I-II (n = 71) with healthy urine specimens, the panel achieved AUCs of 0.90 (95% CI, 0.84-0.96) and 0.93 (95% CI, 0.84-1.00) in the training and validation datasets, respectively. In PDAC stage I-II and healthy samples with matching plasma CA19.9, the panel achieved a higher AUC of 0.97 (95% CI, 0.94-0.99) than CA19.9 (AUC = 0.88; 95% CI, 0.81-0.95, P = 0.005). Adding plasma CA19.9 to the panel increased the AUC from 0.97 (95% CI, 0.94-0.99) to 0.99 (95% CI, 0.97-1.00, P = 0.04), but did not improve the comparison of stage I-IIA PDAC (n = 17) with healthy urine. CONCLUSIONS We have established a novel, three-protein biomarker panel that is able to detect patients with early-stage pancreatic cancer in urine specimens.
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Affiliation(s)
- Tomasz P Radon
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Nathalie J Massat
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
| | | | - Wasfi Alrawashdeh
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Laurent Dumartin
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Darren Ennis
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stephen W Duffy
- Centre for Cancer Prevention, Wolfson Institute of Preventive Medicine, Queen Mary University of London, London, United Kingdom
| | - Hemant M Kocher
- Centre for Tumour Biology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Stephen P Pereira
- Institute for Liver and Digestive Health, University College London, London, United Kingdom
| | | | | | - Francisco X Real
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - Núria Malats
- Centro Nacional de Investigaciones Oncológicas (CNIO), Madrid, Spain
| | - John Neoptolemos
- The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom
| | - Eithne Costello
- The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom
| | - William Greenhalf
- The NIHR Liverpool Pancreas Biomedical Research Unit, Liverpool, United Kingdom
| | - Nick R Lemoine
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom
| | - Tatjana Crnogorac-Jurcevic
- Centre for Molecular Oncology, Barts Cancer Institute, Queen Mary University of London, London, United Kingdom.
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37
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Husi H, Skipworth RJE, Cronshaw A, Stephens NA, Wackerhage H, Greig C, Fearon KCH, Ross JA. Programmed cell death 6 interacting protein (PDCD6IP) and Rabenosyn-5 (ZFYVE20) are potential urinary biomarkers for upper gastrointestinal cancer. Proteomics Clin Appl 2015; 9:586-96. [PMID: 25644331 DOI: 10.1002/prca.201400111] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/14/2014] [Revised: 12/02/2014] [Accepted: 01/27/2015] [Indexed: 12/19/2022]
Abstract
PURPOSE Cancer of the upper digestive tract (uGI) is a major contributor to cancer-related death worldwide. Due to a rise in occurrence, together with poor survival rates and a lack of diagnostic or prognostic clinical assays, there is a clear need to establish molecular biomarkers. EXPERIMENTAL DESIGN Initial assessment was performed on urine samples from 60 control and 60 uGI cancer patients using MS to establish a peak pattern or fingerprint model, which was validated by a further set of 59 samples. RESULTS We detected 86 cluster peaks by MS above frequency and detection thresholds. Statistical testing and model building resulted in a peak profiling model of five relevant peaks with 88% overall sensitivity and 91% specificity, and overall correctness of 90%. High-resolution MS of 40 samples in the 2-10 kDa range resulted in 646 identified proteins, and pattern matching identified four of the five model peaks within significant parameters, namely programmed cell death 6 interacting protein (PDCD6IP/Alix/AIP1), Rabenosyn-5 (ZFYVE20), protein S100A8, and protein S100A9, of which the first two were validated by Western blotting. CONCLUSIONS AND CLINICAL RELEVANCE We demonstrate that MS analysis of human urine can identify lead biomarker candidates in uGI cancers, which makes this technique potentially useful in defining and consolidating biomarker patterns for uGI cancer screening.
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Affiliation(s)
- Holger Husi
- Glasgow Cardiovascular Research Centre, University of Glasgow, Glasgow, UK.,School of Clinical Sciences, University of Edinburgh, Edinburgh, UK
| | | | - Andrew Cronshaw
- School of Biological Sciences, University of Edinburgh, Edinburgh, UK
| | | | | | - Carolyn Greig
- School of Clinical Sciences, University of Edinburgh, Edinburgh, UK.,School of Sport, Exercise and Rehabilitation Sciences, University of Birmingham, Birmingham, UK
| | | | - James A Ross
- School of Clinical Sciences, University of Edinburgh, Edinburgh, UK
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38
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Garczyk S, von Stillfried S, Antonopoulos W, Hartmann A, Schrauder MG, Fasching PA, Anzeneder T, Tannapfel A, Ergönenc Y, Knüchel R, Rose M, Dahl E. AGR3 in breast cancer: prognostic impact and suitable serum-based biomarker for early cancer detection. PLoS One 2015; 10:e0122106. [PMID: 25875093 PMCID: PMC4398490 DOI: 10.1371/journal.pone.0122106] [Citation(s) in RCA: 37] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2014] [Accepted: 02/20/2015] [Indexed: 11/19/2022] Open
Abstract
Blood-based early detection of breast cancer has recently gained novel momentum, as liquid biopsy diagnostics is a fast emerging field. In this study, we aimed to identify secreted proteins which are up-regulated both in tumour tissue and serum samples of breast cancer patients compared to normal tissue and sera. Based on two independent tissue cohorts (n = 75 and n = 229) and one serum cohort (n = 80) of human breast cancer and healthy serum samples, we characterised AGR3 as a novel potential biomarker both for breast cancer prognosis and early breast cancer detection from blood. AGR3 expression in breast tumours is significantly associated with oestrogen receptor α (P<0.001) and lower tumour grade (P<0.01). Interestingly, AGR3 protein expression correlates with unfavourable outcome in low (G1) and intermediate (G2) grade breast tumours (multivariate hazard ratio: 2.186, 95% CI: 1.008-4.740, P<0.05) indicating an independent prognostic impact. In sera analysed by ELISA technique, AGR3 protein concentration was significantly (P<0.001) elevated in samples from breast cancer patients (n = 40, mainly low stage tumours) compared to healthy controls (n = 40). To develop a suitable biomarker panel for early breast cancer detection, we measured AGR2 protein in human serum samples in parallel. The combined AGR3/AGR2 biomarker panel achieved a sensitivity of 64.5% and a specificity of 89.5% as shown by receiver operating characteristic (ROC) curve statistics. Thus our data clearly show the potential usability of AGR3 and AGR2 as biomarkers for blood-based early detection of human breast cancer.
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Affiliation(s)
- Stefan Garczyk
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Saskia von Stillfried
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Wiebke Antonopoulos
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Arndt Hartmann
- Institute of Pathology, University Hospital Erlangen, Erlangen, Germany
| | - Michael G. Schrauder
- Department of Gynaecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
| | - Peter A. Fasching
- Department of Gynaecology and Obstetrics, University Hospital Erlangen, Erlangen, Germany
| | - Tobias Anzeneder
- Patients' Tumor Bank of Hope (PATH) Foundation, München, Germany
| | - Andrea Tannapfel
- Institute of Pathology, Ruhr-University Bochum, Bochum, Germany, on behalf of the PATH Biobank group
| | - Yavuz Ergönenc
- Department for Senology, St Anna Hospital, Herne, Germany, on behalf of the PATH Biobank group
| | - Ruth Knüchel
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Michael Rose
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
| | - Edgar Dahl
- Molecular Oncology Group, Institute of Pathology, Medical Faculty of the RWTH Aachen University, Aachen, Germany
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39
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Jenkinson C, Earl J, Ghaneh P, Halloran C, Carrato A, Greenhalf W, Neoptolemos J, Costello E. Biomarkers for early diagnosis of pancreatic cancer. Expert Rev Gastroenterol Hepatol 2015; 9:305-15. [PMID: 25373768 DOI: 10.1586/17474124.2015.965145] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
Pancreatic ductal adenocarcinoma is an aggressive malignancy with a 5-year survival rate of approximately 5%. The lack of established strategies for early detection contributes to this poor prognosis. Although several novel candidate biomarkers have been proposed for earlier diagnosis, none have been adopted into routine clinical use. In this review, the authors examine the challenges associated with finding new pancreatic cancer diagnostic biomarkers and explore why translation of biomarker research for patient benefit has thus far failed. The authors also review recent progress and highlight advances in the understanding of the biology of pancreatic cancer that may lead to improvements in biomarker detection and implementation.
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Affiliation(s)
- Claire Jenkinson
- Department of Molecular and Clinical Cancer Medicine, National Institute for Health Research Liverpool Pancreas Biomedical Research Unit, University of Liverpool, Daulby Street, Liverpool L69 3GA, UK
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40
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Cote GA, Gore AJ, McElyea SD, Heathers LE, Xu H, Sherman S, Korc M. A pilot study to develop a diagnostic test for pancreatic ductal adenocarcinoma based on differential expression of select miRNA in plasma and bile. Am J Gastroenterol 2014; 109:1942-52. [PMID: 25350767 PMCID: PMC4261139 DOI: 10.1038/ajg.2014.331] [Citation(s) in RCA: 86] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/08/2014] [Accepted: 09/01/2014] [Indexed: 01/17/2023]
Abstract
OBJECTIVES Accurate peripheral markers for the diagnosis of pancreatic ductal adenocarcinoma (PDAC) are lacking. We measured the differential expression of select microRNAs (miRNAs) in plasma and bile among patients with PDAC, chronic pancreatitis (CP), and controls. METHODS We identified patients (n=215) with treatment-naive PDAC (n=77), CP with bile/pancreatic duct pathology (n=67), and controls (n=71) who had been prospectively enrolled in a Pancreatobiliary Biorepository at the time of endoscopic retrograde cholangiopancreatography or endoscopic ultrasound. Controls were patients with choledocholithiasis but normal pancreata. The sample was separated into training (n=95) and validation (n=120) cohorts to establish and then test the performance of PDAC Signature Panels in diagnosing PDAC. The training cohort (n=95) included age-matched patients with PDAC, CP, and controls. Panels were derived from the differential expression of 10 candidate miRNAs in plasma or bile. We selected miRNAs having excellent accuracy for inclusion in regression models. RESULTS Using the training cohort, we confirmed the differential expression of 9/10 miRNAs in plasma (miR-10b, -30c, -106b, -132, -155, -181a, -181b, -196a, and -212) and 7/10 in bile (excluding miR-21, -132, and -181b). Of these, five (miR-10b, -155, -106b, -30c, and -212) had excellent accuracy for distinguishing PDAC. In the training and validation cohorts, the sensitivity/specificity for a PDAC Panel derived from plasma was 95/100% and 100/100%, respectively; in bile, these were 96/100% and 100/100%. CONCLUSIONS Increased expression of miRNA-10b, -155, and -106b in plasma appears highly accurate in diagnosing PDAC. Additional studies are needed to confirm this Panel and explore its value as a prognostic test.
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Affiliation(s)
- Gregory A Cote
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - A Jesse Gore
- Department of Medicine, Division of Endocrinology, Biochemistry and Molecular Biology, and the Pancreatic Cancer Signature Center at the IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Samantha D McElyea
- Department of Medicine, Division of Endocrinology, Biochemistry and Molecular Biology, and the Pancreatic Cancer Signature Center at the IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Laura E Heathers
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Huiping Xu
- Department of Biostatistics, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Stuart Sherman
- Department of Medicine, Division of Gastroenterology and Hepatology, Indiana University School of Medicine, Indianapolis, Indiana, USA
| | - Murray Korc
- Department of Medicine, Division of Endocrinology, Biochemistry and Molecular Biology, and the Pancreatic Cancer Signature Center at the IU Simon Cancer Center, Indiana University School of Medicine, Indianapolis, Indiana, USA,IU Simon Cancer Center, Indiana University School of Medicine, Walther Hall, R3 C528, 980 West Walnut Street, Indianapolis, Indiana 46202, USA. E-mail:
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41
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Chan A, Prassas I, Dimitromanolakis A, Brand RE, Serra S, Diamandis EP, Blasutig IM. Validation of biomarkers that complement CA19.9 in detecting early pancreatic cancer. Clin Cancer Res 2014; 20:5787-95. [PMID: 25239611 PMCID: PMC4233184 DOI: 10.1158/1078-0432.ccr-14-0289] [Citation(s) in RCA: 103] [Impact Index Per Article: 9.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/05/2023]
Abstract
PURPOSE Pancreatic ductal adenocarcinoma (PDAC) is a significant cause of cancer mortality. Carbohydrate antigen 19.9 (CA19.9), the only tumor marker available to detect and monitor PDAC, is not sufficiently sensitive and specific to consistently differentiate early cancer from benign disease. In this study, we aimed to validate recently discovered serum protein biomarkers for the early detection of PDAC and ultimately develop a biomarker panel that could discriminate PDAC from other benign disease better than the existing marker CA19.9. PATIENTS AND METHODS We performed a retrospective blinded evaluation of 400 serum samples collected from individuals recruited on a consecutive basis. The sample population consisted of 250 individuals with PDAC at various stages, 130 individuals with benign conditions and 20 healthy individuals. The serum levels of each biomarker were determined by ELISAs or automated immunoassay. RESULTS By randomly splitting matched samples into a training (n = 186) and validation (n = 214) set, we were able to develop and validate a biomarker panel consisting of CA19.9, CA125, and LAMC2 that significantly improved the performance of CA19.9 alone. Improved discrimination was observed in the validation set between all PDAC and benign conditions (AUCCA19.9 = 0.80 vs. AUCCA19.9+CA125+LAMC2 = 0.87; P < 0.005) as well as between early-stage PDAC and benign conditions (AUCCA19.9 = 0.69 vs. AUCCA19.9+CA125+LAMC2 = 0.76; P < 0.05) and between early-stage PDAC and chronic pancreatitis (CP; AUCCA19.9 = 0.59 vs. AUCCA19.9+CA125+LAMC2 = 0.74; P < 0.05). CONCLUSIONS The data demonstrate that a serum protein biomarker panel consisting of CA125, CA19.9, and LAMC2 is able to significantly improve upon the performance of CA19.9 alone in detecting PDAC.
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Affiliation(s)
- Alison Chan
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | - Ioannis Prassas
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada
| | | | - Randall E Brand
- University of Pittsburgh, Division of Gastroenterology, Hepatology & Nutrition, Pittsburgh, Pennsylvania
| | - Stefano Serra
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology, University Health Network, Toronto, Ontario, Canada
| | - Eleftherios P Diamandis
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Pathology and Laboratory Medicine, Mount Sinai Hospital, Toronto, Ontario, Canada. Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada
| | - Ivan M Blasutig
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada. Department of Clinical Biochemistry, University Health Network, Toronto, Ontario, Canada.
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42
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McPartlin DA, O'Kennedy RJ. Point-of-care diagnostics, a major opportunity for change in traditional diagnostic approaches: potential and limitations. Expert Rev Mol Diagn 2014; 14:979-98. [PMID: 25300742 DOI: 10.1586/14737159.2014.960516] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
'Point-of-care' (POC) diagnostics are a powerful emerging healthcare approach. They can rapidly provide statistically significant results, are simple to use, do not require specialized equipment and are cost-effective. For these reasons, they have the potential to play a major role in revolutionizing the diagnosis, initiation and monitoring of treatment of major global diseases. This review focuses on antibody-based POC devices that target four major global diseases: cardiovascular diseases, prostate cancer, HIV infection and tuberculosis. The key statistics and pathology of each disease is described in detail, followed by an in-depth discussion on emerging POC devices that target each disease, highlighting their potential and limitations.
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Affiliation(s)
- Daniel A McPartlin
- School of Biotechnology, Dublin City University, Glasnevin, Dublin 9, Co. Dublin, Ireland
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43
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He XY, Yuan YZ. Advances in pancreatic cancer research: Moving towards early detection. World J Gastroenterol 2014; 20:11241-11248. [PMID: 25170208 PMCID: PMC4145762 DOI: 10.3748/wjg.v20.i32.11241] [Citation(s) in RCA: 55] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/27/2013] [Revised: 03/02/2014] [Accepted: 06/05/2014] [Indexed: 02/06/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal forms of cancer. Substantial progress has been made in the understanding of the biology of pancreatic cancer, and advances in patient management have been significant. However, most patients (nearly 80%) who present with locally advanced or metastatic disease have an extremely poor prognosis. Survival is better for those with malignant disease localized to the pancreas, because surgical resection at present offers the only chance of cure. Therefore, the early detection of pancreatic cancer may benefit patients with PDAC. However, its low rate of incidence and the limitations of current screening strategies make early detection difficult. Recent advances in the understanding of the pathogenesis of PDAC suggest that it is possible to detect PDAC in early stages and even identify precursor lesions. The presence of new-onset diabetes mellitus in the early phase of pancreatic cancer may provide clues for its early diagnosis. Advances in the identification of novel circulating biomarkers including serological signatures, autoantibodies, epigenetic markers, circulating tumor cells and microRNAs suggest that they can be used as potential tools for the screening of precursors and early stage PDAC in the future. However, proper screening strategies based on effective screening methodologies need to be tested for clinical application.
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44
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Chan A, Diamandis EP, Blasutig IM. Strategies for discovering novel pancreatic cancer biomarkers. J Proteomics 2012; 81:126-34. [PMID: 23026552 DOI: 10.1016/j.jprot.2012.09.025] [Citation(s) in RCA: 44] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/06/2012] [Revised: 08/17/2012] [Accepted: 09/23/2012] [Indexed: 12/20/2022]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the fourth leading cause of cancer-related deaths in both men and women in Canada and the United States and has the most dismal survival rates among any solid malignancy. Most patients are diagnosed with pancreatic cancer once the disease has progressed into an advanced or metastatic stage, making the only curative approach of resection surgery impossible. The persistent delayed or missed diagnosis of pancreatic cancer can be attributed to the absence of early symptoms and the lack of efficient non-invasive screening or diagnostic tests in clinical practice. Given that earlier diagnosis is critical for ameliorating patients' survival rates, there is an urgent need for biomarkers with enough sensitivity and specificity to help diagnose pancreatic cancer early. Serological biomarkers provide a minimally invasive and efficient way of detecting pancreatic cancer, however, there is currently no marker with sufficient diagnostic sensitivity and specificity to identify early cancer patients. This review focuses on the classical tumor markers for PDAC as well as emerging markers. In addition, we will discuss an integrative proteomic approach used in our lab to identify a panel of biomarkers that have the potential to allow the early detection of PDAC.This article is part of a Special Issue entitled: From protein structures to clinical applications.
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Affiliation(s)
- Alison Chan
- Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada
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