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1
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Chihanga T, Xu S, Fultz HN, Nicholson JD, Brombacher MD, Hawkins K, Fay DR, Steil MM, Ni S, Kennedy MA. How Early Can Pancreatic Tumors Be Detected Using NMR-Based Urine Metabolic Profiling? Identification of Early-Stage Biomarkers of Tumor Initiation and Progression in an Orthotopic Xenograft Mouse Model of Pancreatic Cancer. Metabolites 2025; 15:142. [PMID: 40137107 PMCID: PMC11943925 DOI: 10.3390/metabo15030142] [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: 01/17/2025] [Revised: 01/29/2025] [Accepted: 02/02/2025] [Indexed: 03/27/2025] Open
Abstract
Background: Pancreatic cancer is the most lethal of all human cancers. The disease has no obvious symptoms in its early stages and in the majority of cases, the cancer goes undetected until it has advanced to the point that surgery is no longer a viable option or until it has metastasized to other organs. The absence of reliable and sensitive biomarkers for the early detection of pancreatic cancer contributes to the poor ability to detect the disease before it progresses to an untreatable stage. Objectives: Here, an orthotopic xenograft mouse model of pancreatic cancer was investigated to determine if urinary metabolic biomarkers could be identified and used to detect the early formation of pancreatic tumors. Methods: The orthotopic xenograft mouse model of pancreatic cancer was established by injecting human MiaPaCa-2 cells, derived from a male patient aged 65 years with pancreatic adenocarcinoma, into the pancreata of severe combined immunodeficient mice. Orthotopic pancreatic tumors, allowed to grow for eight weeks, were successfully established in the pancreata in 15 out of 20 mice. At the time of sacrifice, tumors were excised and histologically analyzed and the masses and volumes recorded. Urine samples were collected prior to injection, at one-week post injection, and every two weeks afterwards for eight weeks. Results: NMR-based metabolic profiling of the urine samples indicated that 31 metabolites changed significantly over the course of tumor initiation and growth. Longitudinal metabolic profiling analysis indicated an initial increase in activity of the metabolic pathways involved in energy production and/or cell synthesis by cancer cells as required to support tumor growth that was followed by a diminished difference between control and orthotopic mice associated with tumor senescence as the tumors reached 7-8 weeks post injection. Conclusions: The results indicate that NMR-based urinary metabolic profiling may be able to detect the earliest stages of pancreatic tumor initiation and growth, highlighting the potential for translation to human clinical studies.
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Affiliation(s)
| | | | | | | | | | | | | | | | | | - Michael A. Kennedy
- Department of Chemistry and Biochemistry, Miami University, Oxford, OH 45056, USA; (T.C.); (S.X.); (H.N.F.); (J.D.N.); (M.D.B.); (K.H.); (D.R.F.); (S.N.)
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Luan X, Wang X, Bian G, Li X, Gao Z, Liu Z, Zhang Z, Han T, Zhao J, Zhao H, Luan X, Zhu W, Dong L, Guo F. Exosome applications for the diagnosis and treatment of pancreatic ductal adenocarcinoma: An update (Review). Oncol Rep 2025; 53:13. [PMID: 39575479 PMCID: PMC11605277 DOI: 10.3892/or.2024.8846] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2024] [Accepted: 10/30/2024] [Indexed: 11/28/2024] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a malignant neoplasm that typically manifests with subtle clinical manifestations in its early stages and frequently eludes diagnosis until the advanced phases of the disease. The limited therapeutic options available for PDAC significantly contribute to its high mortality rate, highlighting the urgent need for novel biomarkers capable of effectively identifying early clinical manifestations and facilitating precise diagnosis. The pivotal role of cellular exosomes in both the pathogenesis and therapeutic interventions for PDAC has been underscored. Furthermore, researchers have acknowledged the potential of exosomes as targeted drug carriers against regulatory cells in treating PDAC. The present article aims to provide a comprehensive review encompassing recent advancements in utilizing exosomes for elucidating mechanisms underlying disease development, patterns of metastasis, diagnostic techniques and treatment strategies associated with PDAC.
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Affiliation(s)
- Xinchi Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xuezhe Wang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Gang Bian
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Xiaoxuan Li
- Department of Oncology, Key Laboratory of Cancer Molecular and Translational Research, The Affiliated Hospital of Qingdao University, Qingdao, Shandong 266031, P.R. China
| | - Ziru Gao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Zijiao Liu
- School of Clinical and Basic Medicine and Institute of Basic Medicine, Shandong First Medical University and Shandong Academy of Medical Sciences, Jinan, Shandong 250117, P.R. China
| | - Zhishang Zhang
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Tianyue Han
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Jinpeng Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Hongjiao Zhao
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Xinyue Luan
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
| | - Wuhui Zhu
- Department of Hepatobiliary surgery, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Lili Dong
- Department of Gastroenterology, Affiliated Qingdao Third People's Hospital, Qingdao University, Qingdao, Shandong 266041, P.R. China
| | - Feifei Guo
- Pathophysiology Department, School of Basic Medicine, Qingdao University, Qingdao, Shandong 266071, P.R. China
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Jafari SH, Lajevardi ZS, Zamani Fard MM, Jafari A, Naghavi S, Ravaei F, Taghavi SP, Mosadeghi K, Zarepour F, Mahjoubin-Tehran M, Rahimian N, Mirzaei H. Imaging Techniques and Biochemical Biomarkers: New Insights into Diagnosis of Pancreatic Cancer. Cell Biochem Biophys 2024; 82:3123-3144. [PMID: 39026059 DOI: 10.1007/s12013-024-01437-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 07/12/2024] [Indexed: 07/20/2024]
Abstract
Pancreatic cancer (PaC) incidence is increasing, but our current screening and diagnostic strategies are not very effective. However, screening could be helpful in the case of PaC, as recent evidence shows that the disease progresses gradually. Unfortunately, there is no ideal screening method or program for detecting PaC in its early stages. Conventional imaging techniques, such as abdominal ultrasound, CT, MRI, and EUS, have not been successful in detecting early-stage PaC. On the other hand, biomarkers may be a more effective screening tool for PaC and have greater potential for further evaluation compared to imaging. Recent studies on biomarkers and artificial intelligence (AI)-enhanced imaging have shown promising results in the early diagnosis of PaC. In addition to proteins, non-coding RNAs are also being studied as potential biomarkers for PaC. This review consolidates the current literature on PaC screening modalities to provide an organized framework for future studies. While conventional imaging techniques have not been effective in detecting early-stage PaC, biomarkers and AI-enhanced imaging are promising avenues of research. Further studies on the use of biomarkers, particularly non-coding RNAs, in combination with imaging modalities may improve the accuracy of PaC screening and lead to earlier detection of this deadly disease.
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Affiliation(s)
- Seyed Hamed Jafari
- Medical Imaging Research Center, Shiraz University of Medical Sciences, Shiraz, Iran
- Department of Radiology, School of Medicine, Shiraz University of Medical Sciences, Shiraz, Iran
| | - Zahra Sadat Lajevardi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Mohammad Masoud Zamani Fard
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Ameneh Jafari
- Chronic Respiratory Diseases Research Center, NRITLD, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Soroush Naghavi
- Student Research Committee, Iran University of Medical Sciences, Tehran, Iran
| | - Fatemeh Ravaei
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Seyed Pouya Taghavi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Kimia Mosadeghi
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | - Fatemeh Zarepour
- School of Medicine, Kashan University of Medical Sciences, Kashan, Iran
- Student Research Committee, Kashan University of Medical Sciences, Kashan, Iran
| | | | - Neda Rahimian
- Endocrine Research Center, Institute of Endocrinology and Metabolism, Iran University of Medical Sciences (IUMS), Tehran, Iran; Department of Internal Medicine, School of Medicine, Firoozgar Hospital, Iran University of Medical Sciences, Tehran, Iran.
| | - Hamed Mirzaei
- Research Center for Biochemistry and Nutrition in Metabolic Diseases, Institute for Basic Sciences, Kashan University of Medical Sciences, Kashan, Iran.
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Cheng C, Liu Z, Liu D, Chen H, Wang Y, Sun B. LncRNA CCAT1 participates in pancreatic ductal adenocarcinoma progression by forming a positive feedback loop with c-Myc. Carcinogenesis 2024; 45:69-82. [PMID: 37936306 DOI: 10.1093/carcin/bgad076] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2023] [Revised: 10/29/2023] [Accepted: 11/02/2023] [Indexed: 11/09/2023] Open
Abstract
Long noncoding RNAs (lncRNAs) play fundamental roles in cancer development; however, the underlying mechanisms for a large proportion of lncRNAs in pancreatic ductal adenocarcinoma (PDAC) have not been elucidated. The expression of colon cancer-associated transcript-1 (CCAT1) in PDAC specimens and cell lines was measured by quantitative real-time polymerase chain reaction (qRT-PCR). The function of CCAT1 was examined in vitro and in vivo. The interactions among CCAT1, miR-24-3p and c-Myc were determined by bioinformatics analysis, RNA immunoprecipitation (RIP), dual-luciferase reporter assay, and rescue experiments. CCAT1 was significantly increased in PDAC, positively correlated with PDAC progression and predicted a worse prognosis. Furthermore, CCAT1 enhanced Adenosine triphosphate (ATP) production to facilitate PDAC cell proliferation, colony formation and motility in vitro and tumor growth in vivo. CCAT1 may serve as an miR-24-3p sponge, thereby counteracting its repression by c-Myc expression. Reciprocally, c-Myc may act as a transcription factor to alter CCAT1 expression by directly targeting its promoter region, thus forming a positive feedback loop with CCAT1. Collectively, these results demonstrate that a positive feedback loop of CCAT1/miR-24-3p/c-Myc is involved in PDAC development, which may serve as a biomarker and therapeutic target for PDAC.
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Affiliation(s)
- Chundong Cheng
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
| | - Zonglin Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
| | - Danxi Liu
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
| | - Hua Chen
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
| | - Yongwei Wang
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
| | - Bei Sun
- Department of Pancreatic and Biliary Surgery, The First Affiliated Hospital of Harbin Medical University, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
- Key Laboratory of Hepatosplenic Surgery, Ministry of Education, 23 Youzheng Street, Nangang District, Harbin 150001, Heilongjiang, China
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5
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Bhandari K, Kong JS, Morris K, Xu C, Ding WQ. Protein Arginine Methylation Patterns in Plasma Small Extracellular Vesicles Are Altered in Patients with Early-Stage Pancreatic Ductal Adenocarcinoma. Cancers (Basel) 2024; 16:654. [PMID: 38339405 PMCID: PMC10854811 DOI: 10.3390/cancers16030654] [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: 12/31/2023] [Revised: 01/30/2024] [Accepted: 02/01/2024] [Indexed: 02/12/2024] Open
Abstract
Small extracellular vesicles (sEVs) contain lipids, proteins and nucleic acids, which often resemble their cells of origin. Therefore, plasma sEVs are considered valuable resources for cancer biomarker development. However, previous efforts have been largely focused on the level of proteins and miRNAs in plasma sEVs, and the post-translational modifications of sEV proteins, such as arginine methylation, have not been explored. Protein arginine methylation, a relatively stable post-translational modification, is a newly described molecular feature of PDAC. The present study examined arginine methylation patterns in plasma sEVs derived from patients with early-stage PDAC (n = 23) and matched controls. By utilizing the arginine methylation-specific antibodies for western blotting, we found that protein arginine methylation patterns in plasma sEVs are altered in patients with early-stage PDAC. Specifically, we observed a reduction in the level of symmetric dimethyl arginine (SDMA) in plasma sEV proteins derived from patients with early- and late-stage PDAC. Importantly, immunoprecipitation followed by proteomics analysis identified a number of arginine-methylated proteins exclusively present in plasma sEVs derived from patients with early-stage PDAC. These results indicate that arginine methylation patterns in plasma sEVs are potential indicators of PDAC, a new concept meriting further investigation.
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Affiliation(s)
- Kritisha Bhandari
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (J.S.K.)
| | - Jeng Shi Kong
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (J.S.K.)
| | - Katherine Morris
- Department of Surgery, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA
| | - Chao Xu
- Department of Biostatistics & Epidemiology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA;
| | - Wei-Qun Ding
- Department of Pathology, University of Oklahoma Health Sciences Center, Oklahoma City, OK 73104, USA; (K.B.); (J.S.K.)
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6
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Hánělová K, Raudenská M, Masařík M, Balvan J. Protein cargo in extracellular vesicles as the key mediator in the progression of cancer. Cell Commun Signal 2024; 22:25. [PMID: 38200509 PMCID: PMC10777590 DOI: 10.1186/s12964-023-01408-6] [Citation(s) in RCA: 15] [Impact Index Per Article: 15.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/27/2023] [Accepted: 11/24/2023] [Indexed: 01/12/2024] Open
Abstract
Exosomes are small vesicles of endosomal origin that are released by almost all cell types, even those that are pathologically altered. Exosomes widely participate in cell-to-cell communication via transferring cargo, including nucleic acids, proteins, and other metabolites, into recipient cells. Tumour-derived exosomes (TDEs) participate in many important molecular pathways and affect various hallmarks of cancer, including fibroblasts activation, modification of the tumour microenvironment (TME), modulation of immune responses, angiogenesis promotion, setting the pre-metastatic niche, enhancing metastatic potential, and affecting therapy sensitivity and resistance. The unique exosome biogenesis, composition, nontoxicity, and ability to target specific tumour cells bring up their use as promising drug carriers and cancer biomarkers. In this review, we focus on the role of exosomes, with an emphasis on their protein cargo, in the key mechanisms promoting cancer progression. We also briefly summarise the mechanism of exosome biogenesis, its structure, protein composition, and potential as a signalling hub in both normal and pathological conditions. Video Abstract.
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Affiliation(s)
- Klára Hánělová
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Martina Raudenská
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
| | - Michal Masařík
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- Department of Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic
- BIOCEV, First Faculty of Medicine, Charles University, Prumyslova 595, Vestec, CZ-252 50, Czech Republic
| | - Jan Balvan
- Department of Pathological Physiology, Faculty of Medicine, Masaryk University, Kamenice 5, Brno, CZ-625 00, Czech Republic.
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7
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Pourali G, Kazemi D, Chadeganipour AS, Arastonejad M, Kashani SN, Pourali R, Maftooh M, Akbarzade H, Fiuji H, Hassanian SM, Ghayour-Mobarhan M, Ferns GA, Khazaei M, Avan A. Microbiome as a biomarker and therapeutic target in pancreatic cancer. BMC Microbiol 2024; 24:16. [PMID: 38183010 PMCID: PMC10768369 DOI: 10.1186/s12866-023-03166-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/11/2023] [Accepted: 12/18/2023] [Indexed: 01/07/2024] Open
Abstract
Studying the effects of the microbiome on the development of different types of cancer has recently received increasing research attention. In this context, the microbial content of organs of the gastrointestinal tract has been proposed to play a potential role in the development of pancreatic cancer (PC). Proposed mechanisms for the pathogenesis of PC include persistent inflammation caused by microbiota leading to an impairment of antitumor immune surveillance and altered cellular processes in the tumor microenvironment. The limited available diagnostic markers that can currently be used for screening suggest the importance of microbial composition as a non-invasive biomarker that can be used in clinical settings. Samples including saliva, stool, and blood can be analyzed by 16 s rRNA sequencing to determine the relative abundance of specific bacteria. Studies have shown the potentially beneficial effects of prebiotics, probiotics, antibiotics, fecal microbial transplantation, and bacteriophage therapy in altering microbial diversity, and subsequently improving treatment outcomes. In this review, we summarize the potential impact of the microbiome in the pathogenesis of PC, and the role these microorganisms might play as biomarkers in the diagnosis and determining the prognosis of patients. We also discuss novel treatment methods being used to minimize or prevent the progression of dysbiosis by modulating the microbial composition. Emerging evidence is supportive of applying these findings to improve current therapeutic strategies employed in the treatment of PC.
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Affiliation(s)
- Ghazaleh Pourali
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Danial Kazemi
- Student Research Committee, Isfahan University of Medical Sciences, Hezar Jerib Street, Isfahan, Iran
| | | | - Mahshid Arastonejad
- Department of Human and Molecular Genetics, Virginia Commonwealth University, Richmond, VA, USA
| | | | - Roozbeh Pourali
- Student Research Committee, Faculty of Veterinary Medicine, Ferdowsi University of Mashhad, Mashhad, Iran
| | - Mina Maftooh
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamed Akbarzade
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Hamid Fiuji
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Seyed Mahdi Hassanian
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Majid Ghayour-Mobarhan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Gordon A Ferns
- Brighton & Sussex Medical School, Department of Medical Education, Falmer, Brighton, Sussex, BN1 9PH, UK
| | - Majid Khazaei
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran
- Basic Sciences Research Institute, Mashhad University of Medical Sciences, Mashhad, Iran
| | - Amir Avan
- Metabolic Syndrome Research Center, Mashhad University of Medical Sciences, Mashhad, Iran.
- College of Medicine, University of Warith Al-Anbiyaa, Karbala, Iraq.
- School of Mechanical, Medical and Process Engineering, Science and Engineering Faculty, Queensland University of Technology, 2 George St, Brisbane City, QLD, 4000, Australia.
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Grewal M, Ahmed T, Javed AA. Current state of radiomics in hepatobiliary and pancreatic malignancies. ARTIFICIAL INTELLIGENCE SURGERY 2023; 3:217-32. [DOI: 10.20517/ais.2023.28] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/05/2025]
Abstract
Rising in incidence, hepatobiliary and pancreatic (HPB) cancers continue to exhibit dismal long-term survival. The overall poor prognosis of HPB cancers is reflective of the advanced stage at which most patients are diagnosed. Late diagnosis is driven by the often-asymptomatic nature of these diseases, as well as a dearth of screening modalities. Additionally, standard imaging modalities fall short of providing accurate and detailed information regarding specific tumor characteristics, which can better inform surgical planning and sequencing of systemic therapy. Therefore, precise therapeutic planning must be delayed until histopathological examination is performed at the time of resection. Given the current shortcomings in the management of HPB cancers, investigations of numerous noninvasive biomarkers, including circulating tumor cells and DNA, proteomics, immunolomics, and radiomics, are underway. Radiomics encompasses the extraction and analysis of quantitative imaging features. Along with summarizing the general framework of radiomics, this review synthesizes the state of radiomics in HPB cancers, outlining its role in various aspects of management, present limitations, and future applications for clinical integration. Current literature underscores the utility of radiomics in early detection, tumor characterization, therapeutic selection, and prognostication for HPB cancers. Seeing as single-center, small studies constitute the majority of radiomics literature, there is considerable heterogeneity with respect to steps of the radiomics workflow such as segmentation, or delineation of the region of interest on a scan. Nonetheless, the introduction of the radiomics quality score (RQS) demonstrates a step towards greater standardization and reproducibility in the young field of radiomics. Altogether, in the setting of continually improving artificial intelligence algorithms, radiomics represents a promising biomarker avenue for promoting enhanced and tailored management of HPB cancers, with the potential to improve long-term outcomes for patients.
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Ahmed AA, Greenhalf W, Palmer DH, Williams N, Worthington J, Arshad T, Haider S, Alexandrou E, Guneri D, Waller ZAE, Neidle S. The Potent G-Quadruplex-Binding Compound QN-302 Downregulates S100P Gene Expression in Cells and in an In Vivo Model of Pancreatic Cancer. Molecules 2023; 28:molecules28062452. [PMID: 36985425 PMCID: PMC10051992 DOI: 10.3390/molecules28062452] [Citation(s) in RCA: 8] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/23/2023] [Revised: 02/26/2023] [Accepted: 02/27/2023] [Indexed: 03/30/2023] Open
Abstract
The naphthalene diimide compound QN-302, designed to bind to G-quadruplex DNA sequences within the promoter regions of cancer-related genes, has high anti-proliferative activity in pancreatic cancer cell lines and anti-tumor activity in several experimental models for the disease. We show here that QN-302 also causes downregulation of the expression of the S100P gene and the S100P protein in cells and in vivo. This protein is well established as being involved in key proliferation and motility pathways in several human cancers and has been identified as a potential biomarker in pancreatic cancer. The S100P gene contains 60 putative quadruplex-forming sequences, one of which is in the promoter region, 48 nucleotides upstream from the transcription start site. We report biophysical and molecular modeling studies showing that this sequence forms a highly stable G-quadruplex in vitro, which is further stabilized by QN-302. We also report transcriptome analyses showing that S100P expression is highly upregulated in tissues from human pancreatic cancer tumors, compared to normal pancreas material. The extent of upregulation is dependent on the degree of differentiation of tumor cells, with the most poorly differentiated, from more advanced disease, having the highest level of S100P expression. The experimental drug QN-302 is currently in pre-IND development (as of Q1 2023), and its ability to downregulate S100P protein expression supports a role for this protein as a marker of therapeutic response in pancreatic cancer. These results are also consistent with the hypothesis that the S100P promoter G-quadruplex is a potential therapeutic target in pancreatic cancer at the transcriptional level for QN-302.
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Affiliation(s)
- Ahmed A Ahmed
- The School of Pharmacy, University College London, London WC1N 1AX, UK
- Guy's Cancer Centre, Guy's Hospital, London SE1 9RT, UK
| | - William Greenhalf
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 7BE, UK
| | - Daniel H Palmer
- Department of Molecular and Clinical Cancer Medicine, University of Liverpool, Liverpool L69 7BE, UK
| | | | | | | | - Shozeb Haider
- The School of Pharmacy, University College London, London WC1N 1AX, UK
| | | | - Dilek Guneri
- The School of Pharmacy, University College London, London WC1N 1AX, UK
| | - Zoe A E Waller
- The School of Pharmacy, University College London, London WC1N 1AX, UK
| | - Stephen Neidle
- The School of Pharmacy, University College London, London WC1N 1AX, UK
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10
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Badheeb M, Abdelrahim A, Esmail A, Umoru G, Abboud K, Al-Najjar E, Rasheed G, Alkhulaifawi M, Abudayyeh A, Abdelrahim M. Pancreatic Tumorigenesis: Precursors, Genetic Risk Factors and Screening. Curr Oncol 2022; 29:8693-8719. [PMID: 36421339 PMCID: PMC9689647 DOI: 10.3390/curroncol29110686] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/17/2022] [Revised: 11/09/2022] [Accepted: 11/14/2022] [Indexed: 11/17/2022] Open
Abstract
Pancreatic cancer (PC) is a highly malignant and aggressive tumor. Despite medical advancement, the silent nature of PC results in only 20% of all cases considered resectable at the time of diagnosis. It is projected to become the second leading cause in 2030. Most pancreatic cancer cases are diagnosed in the advanced stages. Such cases are typically unresectable and are associated with a 5-year survival of less than 10%. Although there is no guideline consensus regarding recommendations for screening for pancreatic cancer, early detection has been associated with better outcomes. In addition to continued utilization of imaging and conventional tumor markers, clinicians should be aware of novel testing modalities that may be effective for early detection of pancreatic cancer in individuals with high-risk factors. The pathogenesis of PC is not well understood; however, various modifiable and non-modifiable factors have been implicated in pancreatic oncogenesis. PC detection in the earlier stages is associated with better outcomes; nevertheless, most oncological societies do not recommend universal screening as it may result in a high false-positive rate. Therefore, targeted screening for high-risk individuals represents a reasonable option. In this review, we aimed to summarize the pathogenesis, genetic risk factors, high-risk population, and screening modalities for PC.
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Affiliation(s)
- Mohamed Badheeb
- Internal Medicine Department, College of Medicine, Hadhramout University, Mukalla 50512, Yemen
| | | | - Abdullah Esmail
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Correspondence: (A.E.); (M.A.)
| | - Godsfavour Umoru
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Karen Abboud
- Department of Pharmacy, Houston Methodist Hospital, Houston, TX 77030, USA
| | - Ebtesam Al-Najjar
- Faculty of Medicine and Health Sciences, University of Science and Technology, Sana’a 15201, Yemen
| | - Ghaith Rasheed
- Faculty of Medicine, The Hashemite University, Zarqa 13133, Jordan
| | | | - Ala Abudayyeh
- Section of Nephrology, Division of Internal Medicine, The University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | - Maen Abdelrahim
- Section of GI Oncology, Department of Medical Oncology, Houston Methodist Cancer Center, Houston, TX 77030, USA
- Weill Cornell Medical College, New York, NY 14853, USA
- Cockrell Center for Advanced Therapeutic Phase I Program, Houston Methodist Research Institute, Houston, TX 77030, USA
- Correspondence: (A.E.); (M.A.)
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11
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Bazeed AY, Day CM, Garg S. Pancreatic Cancer: Challenges and Opportunities in Locoregional Therapies. Cancers (Basel) 2022; 14:cancers14174257. [PMID: 36077794 PMCID: PMC9454856 DOI: 10.3390/cancers14174257] [Citation(s) in RCA: 16] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/08/2022] [Revised: 08/29/2022] [Accepted: 08/29/2022] [Indexed: 12/12/2022] Open
Abstract
Simple Summary Pancreatic cancer is a serious ongoing global health burden, with an overall 5-year survival rate of less than 5%. One major hurdle in the treatment of this disease is the predominantly elderly patient population, leading to their ineligibility for curative surgery and a low rate of successful outcomes. Systemic administration introduces chemo-agents throughout the body via the blood, attacking not only tumours but also healthy organs. When localised interventions are employed, chemo-agents are retained specifically at tumour site, minimizing unwanted toxicity. As a result, there is a growing interest in finding novel localised interventions as alternatives to systemic therapy. Here, we present a detailed review of current locoregional therapies used in pancreatic cancer therapy. This work aims to present a thorough guide for researchers and clinicians intended to employ established and novel localised interventions in the treatment of pancreatic cancer. Furthermore, we present our insights and opinions on the potential ideals to improve these tools. Abstract Pancreatic cancer (PC) remains the seventh leading cause of cancer-related deaths worldwide and the third in the United States, making it one of the most lethal solid malignancies. Unfortunately, the symptoms of this disease are not very apparent despite an increasing incidence rate. Therefore, at the time of diagnosis, 45% of patients have already developed metastatic tumours. Due to the aggressive nature of the pancreatic tumours, local interventions are required in addition to first-line treatments. Locoregional interventions affect a specific area of the pancreas to minimize local tumour recurrence and reduce the side effects on surrounding healthy tissues. However, compared to the number of new studies on systemic therapy, very little research has been conducted on localised interventions for PC. To address this unbalanced focus and to shed light on the tremendous potentials of locoregional therapies, this work will provide a detailed discussion of various localised treatment strategies. Most importantly, to the best of our knowledge, the aspect of localised drug delivery systems used in PC was unprecedentedly discussed in this work. This review is meant for researchers and clinicians considering utilizing local therapy for the effective treatment of PC, providing a thorough guide on recent advancements in research and clinical trials toward locoregional interventions, together with the authors’ insight into their potential improvements.
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12
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Ashok G, Miryala SK, Saju MT, Anbarasu A, Ramaiah S. FN1 encoding fibronectin as a pivotal signaling gene for therapeutic intervention against pancreatic cancer. Mol Genet Genomics 2022; 297:1565-1580. [PMID: 35982245 DOI: 10.1007/s00438-022-01943-w] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/12/2021] [Accepted: 08/08/2022] [Indexed: 10/15/2022]
Abstract
The delayed diagnosis of pancreatic cancer has resulted in rising mortality rate and low survival rate that can be circumvented using potent theranostics biomarkers. The treatment gets complicated with delayed detection resulting in lowered 5-year relative survival rate. In our present study, we employed systems biology approach to identify central genes that play crucial roles in tumor progression. Pancreatic cancer genes collected from various databases were used to construct a statistically significant interactome with 812 genes that was further analysed thoroughly using topological parameters and functional enrichment analysis. The significant genes in the network were then identified based on the maximum degree parameter. The overall survival analysis indicated through hazard ratio [HR] and gene expression [log Fold Change] across pancreatic adenocarcinoma revealed the critical role of FN1 [HR 1.4; log2(FC) 5.748], FGA [HR 0.78; log2(FC) 1.639] FGG [HR 0.9; log2(FC) 1.597], C3 [HR 1.1; log2(FC) 2.637], and QSOX1 [HR 1.4; log2(FC) 2.371]. The functional significance of the identified hub genes signified the enrichment of integrin cell surface interactions and proteoglycan syndecan-mediated cell signaling. The differential expression, low overall survival and functional significance of FN1 gene implied its possible role in controlling metastasis in pancreatic cancer. Furthermore, alternate splice variants of FN1 gene showed 10 protein coding transcripts with conserved cell attachment site and functional domains indicating the variants' potential role in pancreatic cancer. The strong association of the identified hub-genes can be better directed to design potential theranostics biomarkers for metastasized pancreatic tumor.
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Affiliation(s)
- Gayathri Ashok
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sravan Kumar Miryala
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Megha Treesa Saju
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Anand Anbarasu
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.,Department of Biotechnology, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India
| | - Sudha Ramaiah
- Medical and Biological Computing Laboratory, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India. .,Department of Bio-Sciences, School of Biosciences and Technology, Vellore Institute of Technology, Vellore, Tamil Nadu, 632014, India.
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13
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ID1 marks the tumorigenesis of pancreatic ductal adenocarcinoma in mouse and human. Sci Rep 2022; 12:13555. [PMID: 35941362 PMCID: PMC9359991 DOI: 10.1038/s41598-022-17827-3] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/28/2022] [Accepted: 08/01/2022] [Indexed: 11/26/2022] Open
Abstract
Pancreatic Ductal Adenocarcinoma (PDAC) is a deadly disease that has an increasing death rate but no effective treatment to now. Although biological and immunological hallmarks of PDAC have been frequently reported recently, early detection and the particularly aggressive biological features are the major challenges remaining unclear. In the current study, we retrieved multiple scRNA-seq datasets and illustrated the genetic programs of PDAC development in genetically modified mouse models. Notably, the transcription levels of Id1 were elevated specifically along with the PDAC development. Pseudotime trajectory analysis revealed that Id1 was closely correlated with the malignancy of PDAC. The gene expression patterns of human PDAC cells were determined by the comparative analysis of the scRNA-seq data on human PDAC and normal pancreas tissues. ID1 levels in human PDAC cancer cells were dramatically increased compared to normal epithelial cells. ID1 deficiency in vitro significantly blunt the invasive tumor-formation related phenotypes. IPA analysis on the differentially expressed genes suggested that EIF2 signaling was the core pathway regulating the development of PDAC. Blocking EFI2 signaling remarkably decreased the expression of ID1 and attenuated the tumor-formation related phenotypes. These observations confirmed that ID1 was regulated by EIF2 signaling and was the critical determinator of PDAC development and progression. This study suggests that ID1 is a potential malignant biomarker of PDAC in both mouse models and human and detecting and targeting ID1 may be a promising strategy to treat or even rescue PDAC.
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14
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Li J, Li Y, Chen S, Duan W, Kong X, Wang Y, Zhou L, Li P, Zhang C, Du L, Wang C. Highly Sensitive Exosome Detection for Early Diagnosis of Pancreatic Cancer Using Immunoassay Based on Hierarchical Surface-Enhanced Raman Scattering Substrate. SMALL METHODS 2022; 6:e2200154. [PMID: 35460217 DOI: 10.1002/smtd.202200154] [Citation(s) in RCA: 22] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 02/02/2022] [Revised: 03/12/2022] [Indexed: 06/14/2023]
Abstract
Exosomes have emerged as potential biomarkers for pancreatic cancer (PaC). However, it is still challenging to get quantitative detection of exosomes with the specific surface receptors. In this study, a highly sensitive detection system is first constructed for the direct quantitation of specific exosomes in real samples using hierarchical surface-enhanced Raman scattering substrate (H-SERS substrate) and rapid enrichment strategy magnetic beads @ exosomes @ SERS detection probes (MEDP). It is found that the detection system (MEDP @ H-SERS substrate) could provide a 3.5 times higher SERS intensity compared with MEDP sandwich immunocomplex only. Moreover, LRG1-positive exosomes (LRG1-Exos) and GPC1-positive exosomes (GPC1-Exos) are chosen to distinguish PaC through exosome proteomics and database screening. The lower limit of detection (LOD) is 15 particles µL-1 using the MEDP @ H-SERS substrate. Significantly, the detection in clinical samples shows that the innovative combination of LRG1-Exos and GPC1-Exos could improve the diagnostic efficiency of PaC, with an area under the operating characteristic curve (AUC) of 0.95. Even for the early-stage PaC, the diagnostic accuracy is still high (AUC = 0.95). Collectively, the findings indicate that the MEDP @ H-SERS substrate has great potential for the early diagnosis of PaC.
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Affiliation(s)
- Juan Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Yanru Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Shuai Chen
- Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, No. 17923, Jingshi Road Jinan, Shandong, 250061, China
| | - Weili Duan
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Xue Kong
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Yunshan Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Lianqun Zhou
- CAS Key Lab of Bio-Medical Diagnostics, Suzhou Institute of Biomedical Engineering and Technology, Chinese Academy of Sciences, No. 88, Keling Road Suzhou, Suzhou, 215163, China
| | - Peilong Li
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Chengpeng Zhang
- Key Laboratory of High Efficiency and Clean Mechanical Manufacture of Ministry of Education, School of Mechanical Engineering, Shandong University, No. 17923, Jingshi Road Jinan, Shandong, 250061, China
| | - Lutao Du
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, The Second Hospital of Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, The Second Hospital of Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
| | - Chuanxin Wang
- Department of Clinical Laboratory, The Second Hospital, Cheeloo College of Medicine, Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
- Shandong Engineering & Technology Research Center for Tumor Marker Detection, The Second Hospital of Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
- Shandong Provincial Clinical Medicine Research Center for Clinical Laboratory, The Second Hospital of Shandong University, No. 247, Beiyuan Street, Jinan, 250033, China
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15
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Jia E, Ren N, Shi X, Zhang R, Yu H, Yu F, Qin S, Xue J. Extracellular vesicle biomarkers for pancreatic cancer diagnosis: a systematic review and meta-analysis. BMC Cancer 2022; 22:573. [PMID: 35606727 PMCID: PMC9125932 DOI: 10.1186/s12885-022-09463-x] [Citation(s) in RCA: 13] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2021] [Accepted: 03/28/2022] [Indexed: 02/14/2023] Open
Abstract
BACKGROUND Extracellular vesicle (EV) biomarkers have promising diagnosis and screening capacity for several cancers, but the diagnostic value for pancreatic cancer (PC) is controversial. The aim of our study was to review the diagnostic performance of EV biomarkers for PC. METHODS We performed a systematic review of PubMed, Medline, and Web Of Science databases from inception to 18 Feb 2022. We identified studies reporting the diagnostic performance of EV biomarkers for PC and summarized the information of sensitivity, specificity, area under the curve (AUC), or receiver operator characteristic (ROC) curve) in according to a pre-designed data collection form. Pooled sensitivity and specificity was calculated using a random-effect model. RESULTS We identified 39 studies, including 2037 PC patients and 1632 noncancerous, seven of which were conducted independent validation tests. Seventeen studies emphasized on EV RNAs, sixteen on EV proteins, and sixteen on biomarker panels. MiR-10b, miR-21, and GPC1 were the most frequently reported RNA and protein for PC diagnosis. For individual RNAs and proteins, the pooled sensitivity and specificity were 79% (95% CI: 77-81%) and 87% (95% CI: 85-89%), 72% (95% CI: 69-74%) and 77% (95% CI: 74-80%), respectively. the pooled sensitivity and specificity of EV RNA combined with protein panels were 84% (95% CI: 81-86%) and 89% (95% CI: 86-91%), respectively. Surprisingly, for early stage (stage I and II) PC EV biomarkers showed excellent diagnostic performance with the sensitivity of 90% (95% CI: 87-93%) and the specificity of 94% (95% CI: 92-95%). Both in sensitivity and subgroup analyses, we did not observe notable difference in pooled sensitivity and specificity. Studies might be limited by the isolation and detection techniques of EVs to a certain extent. CONCLUSIONS EV biomarkers showed appealing diagnostic preference for PC, especially for early stage PC. Solving the deficiency of technologies of isolation and detection EVs has important implications for application these novel noninvasive biomarkers in clinical practice.
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Affiliation(s)
- Erna Jia
- Department of Gastroenterology, The Third Hospital of Jilin University, Changchun, China
| | - Na Ren
- Department of Thoracic Surgery, The Third Hospital of Jilin University, No. 126, Xiantai Street, Jilin, Changchun, China
| | - Xianquan Shi
- Department of Ultrasound, Beijing Friendship Hospital of Capital Medical University, Beijing, China
| | - Rongkui Zhang
- Department of Radiology, The First Hospital of Jilin University, Changchun, China
| | - Haixin Yu
- Department of General Surgery, Union Hospital of Tongji Medical College, Huazhong University of Science and Technology, Wuhan, China
| | - Fan Yu
- Department of Gastroenterology, The Third Hospital of Jilin University, Changchun, China
| | - Shaoyou Qin
- Department of Gastroenterology, The Third Hospital of Jilin University, Changchun, China
| | - Jinru Xue
- Department of Thoracic Surgery, The Third Hospital of Jilin University, No. 126, Xiantai Street, Jilin, Changchun, China.
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16
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Zhang Y, Wu Y, Luo S, Yang C, Zhong G, Huang G, Zhang X, Li B, Liu C, Li L, Yan X, Zheng L, Situ B. DNA Nanowire Guided-Catalyzed Hairpin Assembly Nanoprobe for In Situ Profiling of Circulating Extracellular Vesicle-Associated MicroRNAs. ACS Sens 2022; 7:1075-1085. [PMID: 35312297 DOI: 10.1021/acssensors.1c02717] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
Extracellular vesicle-associated miRNAs (EV-miRNAs) are emerging as a new type of noninvasive biomarker for disease diagnosis. Their relatively low abundance, however, makes accurate detection challenging. Here, we designed a DNA nanowire guided-catalyzed hairpin assembly (NgCHA) nanoprobe for profiling EV-miRNAs. NgCHA showed high penetrability to EVs, which allowed rapid delivery of the probes into EVs. In the presence of targeted miRNAs within EVs, a fluorescent signal could be generated and amplified by confining the catalytic hairpin assembly system within the nanowires, thus greatly enhancing the analytical sensitivity. We showed that EV-miRNAs from various cell lines could be accurately quantified by NgCHA in situ. By using a four-EV-miRNA panel, this platform can identify patients with breast cancer at an early stage with 95.2% sensitivity and 86.7% specificity. Its applications for risk assessment as well as cancer type prediction were also successfully demonstrated. This platform is sensitive, low-cost, and simple compared with current methods. It may thus serve as a promising tool for the noninvasive diagnosis and monitoring of cancers and other diseases through EV-miRNA profiling.
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Affiliation(s)
- Ye Zhang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Yuan Wu
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- School of Basic Medicine, Guangdong Medical University, Dongguan 523808, China
| | - Shihua Luo
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chao Yang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Guangzhi Zhong
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Laboratory Medicine, Guangdong Second Traditional Chinese Medicine Hospital, Guangzhou 510515, China
| | - Guoni Huang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Department of Laboratory Medicine, People’s Hospital of Shenzhen Baoan District, Shenzhen 518100, China
| | - Xiaohe Zhang
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bo Li
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Chunchen Liu
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Ling Li
- School of Basic Medicine, Guangdong Medical University, Dongguan 523808, China
- School of Basic Medical Sciences, Southern Medical University, Guangzhou 510515, China
| | - Xiaohui Yan
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Lei Zheng
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
| | - Bo Situ
- Department of Laboratory Medicine, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
- Guangdong Engineering and Technology Research Center for Rapid Diagnostic Biosensors, Nanfang Hospital, Southern Medical University, Guangzhou 510515, China
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17
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Zhang H, Xing J, Dai Z, Wang D, Tang D. Exosomes: the key of sophisticated cell-cell communication and targeted metastasis in pancreatic cancer. Cell Commun Signal 2022; 20:9. [PMID: 35033111 PMCID: PMC8760644 DOI: 10.1186/s12964-021-00808-w] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2021] [Accepted: 11/21/2021] [Indexed: 02/07/2023] Open
Abstract
Pancreatic cancer is one of the most common malignancies. Unfortunately, the lack of effective methods of treatment and diagnosis has led to poor prognosis coupled with a very high mortality rate. So far, the pathogenesis and progression mechanisms of pancreatic cancer have been poorly characterized. Exosomes are small vesicles secreted by most cells, contain lipids, proteins, and nucleic acids, and are involved in diverse functions such as intercellular communications, biological processes, and cell signaling. In pancreatic cancer, exosomes are enriched with multiple signaling molecules that mediate intercellular communication with control of immune suppression, mutual promotion between pancreas stellate cells and pancreatic cancer cells, and reprogramming of normal cells. In addition, exosomes can regulate the pancreatic cancer microenvironment and promote the growth and survival of pancreatic cancer. Exosomes can also build pre-metastatic micro-ecological niches and facilitate the targeting of pancreatic cancer. The ability of exosomes to load cargo and target allows them to be of great clinical value as a biomarker mediator for targeted drugs in pancreatic cancer. Video Abstract.
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Affiliation(s)
- Huan Zhang
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Juan Xing
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Zhujiang Dai
- Clinical Medical College, Yangzhou University, Yangzhou, Jiangsu Province China
| | - Daorong Wang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225001 China
| | - Dong Tang
- Department of General Surgery, Institute of General Surgery, Northern Jiangsu People’s Hospital, Clinical Medical College, Yangzhou University, Yangzhou, 225001 China
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18
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Barros AG, Pulido CF, Machado M, Brito MJ, Couto N, Sousa O, Melo SA, Mansinho H. Treatment optimization of locally advanced and metastatic pancreatic cancer (Review). Int J Oncol 2021; 59:110. [PMID: 34859257 PMCID: PMC8651228 DOI: 10.3892/ijo.2021.5290] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/11/2021] [Accepted: 10/12/2021] [Indexed: 12/12/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the most lethal malignant tumor types, being the sixth leading cause of mortality worldwide and the fourth in Europe. Globally, it has a mortality/incidence ratio of 98%, and the 5‑year survival rate in Europe is only 3%. Although risk factors, such as obesity, diabetes mellitus, smoking, alcohol consumption and genetic factors, have been identified, the causes of PDAC remain elusive. Additionally, the only curative treatment for PDAC is surgery with negative margins. However, upon diagnosis, ~30% of the patients already present with locally advanced disease. In these cases, a multidisciplinary approach is required to improve disease‑related symptoms and prolong patient survival. In the present article, a comprehensive review of PDAC epidemiology, physiology and treatment is provided. Moreover, guidelines on patient treatment are suggested. Among the different available therapeutic options for the treatment of advanced PDAC, results are modest, most likely due to the complexity of the disease, and so the prognostic remains poor. Molecular approaches based on multi‑omics research are promising and will contribute to groundbreaking personalized medicine. Thus, economic investment that promotes research of pancreatic cancer will be critical to the development of more efficient diagnostic and treatment strategies.
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Affiliation(s)
- Anabela G. Barros
- Department of Medical Oncology, University Hospital of Coimbra, 3004-561 Coimbra, Portugal
| | - Catarina F. Pulido
- Department of Medical Oncology, Luz Lisbon Hospital, 1500-650 Lisbon, Portugal
| | - Manuela Machado
- Department of Medical Oncology, Entre o Douro e Vouga Hospital Center (CHEDV), 4520-211 Santa Maria da Feira, Portugal
| | - Maria José Brito
- Pathologic Anatomy Department, Garcia de Orta Hospital, 2805-267 Almada, Portugal
| | - Nuno Couto
- Digestive Unit, Champalimaud Clinical Centre, 4200-135 Porto, Portugal
- Champalimaud Research Centre, 1400-038 Lisbon, 4200-135 Porto, Portugal
| | - Olga Sousa
- Radiotherapy Department, Portuguese Institute of Oncology, 4200-072 Porto, 4200-135 Porto, Portugal
| | - Sónia A. Melo
- i3S-Institute for Research and Innovation in Health of University of Porto, 4200-135 Porto, Portugal
- IPATIMUP-Institute of Molecular Pathology and Immunology of University of Porto, 4200-135 Porto, Portugal
- Faculty of Medicine, University of Porto, 4200-319 Porto, Portugal
| | - Hélder Mansinho
- Hemato-Oncology Department, Garcia de Orta Hospital, 2805-267 Almada, Portugal
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19
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Chang CH, Pauklin S. Extracellular vesicles in pancreatic cancer progression and therapies. Cell Death Dis 2021; 12:973. [PMID: 34671031 PMCID: PMC8528925 DOI: 10.1038/s41419-021-04258-7] [Citation(s) in RCA: 36] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2021] [Revised: 09/08/2021] [Accepted: 09/21/2021] [Indexed: 01/18/2023]
Abstract
Pancreatic cancer (PC) is one of the leading causes of cancer-related death worldwide due to delayed diagnosis and limited treatments. More than 90% of all pancreatic cancers are pancreatic ductal adenocarcinoma (PDAC). Extensive communication between tumour cells and other cell types in the tumour microenvironment have been identified which regulate cancer hallmarks during pancreatic tumorigenesis via secretory factors and extracellular vesicles (EVs). The EV-capsuled factors not only facilitate tumour growth locally, but also enter circulation and reach distant organs to construct a pre-metastatic niche. In this review, we delineate the key factors in pancreatic ductal adenocarcinoma derived EVs that mediate different tumour processes. Also, we highlight the factors that are related to the crosstalk with cancer stem cells/cancer-initiating cells (CSC/CIC), the subpopulation of cancer cells that can efficiently metastasize and resist currently used chemotherapies. Lastly, we discuss the potential of EV-capsuled factors in early diagnosis and antitumour therapeutic strategies.
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Affiliation(s)
- Chao-Hui Chang
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, OX3 7LD, Oxford, UK
| | - Siim Pauklin
- Botnar Research Centre, Nuffield Department of Orthopaedics, Rheumatology and Musculoskeletal Sciences, University of Oxford, Windmill Road, OX3 7LD, Oxford, UK.
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20
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Rah B, Banday MA, Bhat GR, Shah OJ, Jeelani H, Kawoosa F, Yousuf T, Afroze D. Evaluation of biomarkers, genetic mutations, and epigenetic modifications in early diagnosis of pancreatic cancer. World J Gastroenterol 2021; 27:6093-6109. [PMID: 34629822 PMCID: PMC8476336 DOI: 10.3748/wjg.v27.i36.6093] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/07/2021] [Revised: 06/10/2021] [Accepted: 07/13/2021] [Indexed: 02/06/2023] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is one of the deadliest malignancies with an alarming mortality rate. Despite significant advancement in diagnostics and therapeutics, early diagnosis remains elusive causing poor prognosis, marred by mutations and epigenetic modifications in key genes which contribute to disease progression. AIM To evaluate the various biological tumor markers collectively for early diagnosis which could act as prognostic biomarkers and helps in future therapeutics of PC in Kashmir valley. METHODS A total of 50 confirmed PC cases were included in the study to evaluate the levels of carbohydrate antigen 19-9 (CA 19-9), tissue polypeptide specific antigen (TPS), carcinoembryonic antigen (CEA), vascular endothelial growth factor-A (VEGF-A), and epidermal growth factor receptor (EGFR). Mutational analysis was performed to evaluate the mutations in Kirsten rat sarcoma (KRAS), Breast cancer type 2 (BRCA-2), and deleted in pancreatic cancer-4 (DPC-4) genes. However, epigenetic modifications (methylation of CpG islands) were performed in the promoter regions of cyclin-dependent kinase inhibitor 2A (p16; CDKN2A), MutL homolog 1 (hMLH1), and Ras association domain-containing protein 1(RASSF1A) genes. RESULTS We found significantly elevated levels of biological markers CA 19-9 (P ≤ 0.05), TPS (P ≤ 0.05), CEA (P ≤ 0.001), and VEGF (P ≤ 0.001). Molecular genetic analysis revealed that KRAS gene mutation is predominant in codon 12 (16 subjects, P ≤ 0.05), and 13 (12 subjects, P ≤ 0.05). However, we did not find a mutation in DPC-4 (1203G > T) and BRCA-2 (617delT) genes. Furthermore, epigenetic modification revealed that CpG methylation in 21 (P ≤ 0.05) and 4 subjects in the promoter regions of the p16 and hMLH1 gene, respectively. CONCLUSION In conclusion, CA 19-9, TPS, CEA, and VEGF levels were significantly elevated and collectively have potential as diagnostic and prognostic markers in PC. Global data of mutation in the KRAS gene commonly in codon 12 and rare in codon 13 could augment the predisposition towards PC. Additionally, methylation of the p16 gene could also modulate transcription of genes thereby increasing the predisposition and susceptibility towards PC.
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Affiliation(s)
- Bilal Rah
- Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
| | - Manzoor Ahmad Banday
- Department of Medical Oncology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
| | - Gh Rasool Bhat
- Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
| | - Omar J Shah
- Department of Surgical Gastroenterology, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
| | - Humira Jeelani
- Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
| | - Fizalah Kawoosa
- Department of Immunology and Molecular Medicine, Sher-i-Kashmir Institute of Medical Science, Srinagar 190011, Jammu and Kashmir, India
| | - Tahira Yousuf
- Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
| | - Dil Afroze
- Advanced Centre for Human Genetics, Sher-i-Kashmir Institute of Medical Sciences, Srinagar 190011, Jammu and Kashmir, India
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21
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Yang J, Xu R, Wang C, Qiu J, Ren B, You L. Early screening and diagnosis strategies of pancreatic cancer: a comprehensive review. Cancer Commun (Lond) 2021; 41:1257-1274. [PMID: 34331845 PMCID: PMC8696234 DOI: 10.1002/cac2.12204] [Citation(s) in RCA: 140] [Impact Index Per Article: 35.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/15/2021] [Accepted: 07/26/2021] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is a highly malignant digestive system tumor with a poor prognosis. Most pancreatic cancer patients are diagnosed at an advanced stage or even metastasis due to its highly aggressive characteristics and lack of typical early symptoms. Thus, an early diagnosis of pancreatic cancer is crucial for improving its prognosis. Currently, screening is often applied in high‐risk individuals to achieve the early diagnosis of pancreatic cancer. Fully understanding the risk factors of pancreatic cancer and pathogenesis could help us identify the high‐risk population and achieve early diagnosis and timely treatment of pancreatic cancer. Notably, accumulating studies have been undertaken to improve the detection rate of different imaging methods and the diagnostic accuracy of endoscopic ultrasound‐guided fine‐needle aspiration (EUS‐FNA) which is the golden standard for pancreatic cancer diagnosis. In addition, there are currently no biomarkers with sufficient sensitivity and specificity for the diagnosis of pancreatic cancer to be applied in the clinic. As the only serum biomarker approved by the United States Food and Drug Administration, carbohydrate antigen 19‐9 (CA19‐9) is not recommended to be used in the early screening of pancreatic cancer because of its limited specificity. Recently, increasing numbers of studies focused on the discovering of novel serum biomarkers and exploring their combination with CA19‐9 in the detection of pancreatic cancer. Besides, the application of liquid biopsy involving circulating tumor cells (CTCs), circulating tumor DNA (ctDNA), microRNAs (miRNAs), and exosomes in blood and biomarkers in urine, and saliva in pancreatic cancer diagnosis are drawing more and more attention. Furthermore, many innovative technologies such as artificial intelligence, computer‐aided diagnosis system, metabolomics technology, ion mobility spectrometry (IMS) associated technologies, and novel nanomaterials have been tested for the early diagnosis of pancreatic cancer and have shown promising prospects. Hence, this review aims to summarize the recent progress in the development of early screening and diagnostic methods, including imaging, pathological examination, serological examination, liquid biopsy, as well as other potential diagnostic strategies for pancreatic cancer.
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Affiliation(s)
- Jinshou Yang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P. R. China
| | - Ruiyuan Xu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P. R. China
| | - Chengcheng Wang
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P. R. China
| | - Jiangdong Qiu
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P. R. China
| | - Bo Ren
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P. R. China
| | - Lei You
- Department of General Surgery, Peking Union Medical College Hospital, Chinese Academy of Medical Sciences, Peking Union Medical College, Beijing, P. R. China
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22
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Coppola A, La Vaccara V, Fiore M, Farolfi T, Ramella S, Angeletti S, Coppola R, Caputo D. CA19.9 Serum Level Predicts Lymph-Nodes Status in Resectable Pancreatic Ductal Adenocarcinoma: A Retrospective Single-Center Analysis. Front Oncol 2021; 11:690580. [PMID: 34123859 PMCID: PMC8190389 DOI: 10.3389/fonc.2021.690580] [Citation(s) in RCA: 16] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/03/2021] [Accepted: 05/03/2021] [Indexed: 12/12/2022] Open
Abstract
BACKGROUND The choice between upfront surgery or neoadjuvant treatments (NAT) for resectable pancreatic ductal adenocarcinoma (R-PDAC) is controversial. R-PDAC with potential nodal involvement could benefit from NT. Ca (Carbohydrate antigen) 19.9 and serum albumin levels, alone or in combination, have proven their efficacy in assessing PDAC prognosis. The objective of this study was to evaluate the role of Ca 19.9 serum levels in predicting nodal status in R-PDAC. METHODS Preoperative Ca 19.9, as well as serum albumin levels, of 165 patients selected for upfront surgery have been retrospectively collected and correlated to pathological nodal status (N), resection margins status (R) and vascular resections (VR). We further performed ROC curve analysis to identify optimal Ca 19.9 cut-off for pN+, R+ and vascular resection prediction. RESULTS Increased Ca 19.9 levels in 114 PDAC patients were significantly associated with pN+ (p <0.001). This ability, confirmed in all the series by ROC curve analysis (Ca 19.9 ≥32 U/ml), was lost in the presence of hypoalbuminemia. Furthermore, Ca 19.9 at the cut off >418 U/ml was significantly associated with R+ (87% specificity, 36% sensitivity, p 0.014). Ca 19.9, at the cut-off >78 U/ml, indicated a significant trend to predict the need for VR (sensitivity 67%, specificity 53%; p = 0.059). CONCLUSIONS In R-PDAC with normal serum albumin levels, Ca 19.9 predicts pN+ and R+, thus suggesting a crucial role in deciding on NAT.
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Affiliation(s)
| | | | - Michele Fiore
- Radiation Oncology, Campus Bio-Medico University, Rome, Italy
| | - Tommaso Farolfi
- Department of Surgery, Campus Bio-Medico University, Rome, Italy
| | - Sara Ramella
- Radiation Oncology, Campus Bio-Medico University, Rome, Italy
| | - Silvia Angeletti
- Unit of Clinical Laboratory Science, Campus Bio-Medico University, Rome, Italy
| | - Roberto Coppola
- Department of Surgery, Campus Bio-Medico University, Rome, Italy
| | - Damiano Caputo
- Department of Surgery, Campus Bio-Medico University, Rome, Italy
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23
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Vitorino R, Ferreira R, Guedes S, Amado F, Thongboonkerd V. What can urinary exosomes tell us? Cell Mol Life Sci 2021; 78:3265-3283. [PMID: 33507324 PMCID: PMC11072730 DOI: 10.1007/s00018-020-03739-w] [Citation(s) in RCA: 30] [Impact Index Per Article: 7.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 12/06/2020] [Accepted: 12/11/2020] [Indexed: 02/06/2023]
Abstract
Exosomes are involved in a wide variety of biochemical processes in human body homeostasis. Exosomes also provide important information regarding communications among several organ systems. Additionally, they can serve as molecular vehicles to deliver drugs. Therefore, exosomes have received wide attention in current biomedical research for unraveling pathogenic mechanisms of diseases, searching for novel biomarkers, and discovering new drugs. This paper reviews and discusses the significance of urinary exosomes for a better understanding of human disease pathophysiology and their potential use as therapeutic targets. Isolation methods of exosomes and the latest technological advances are also discussed. Furthermore, novel urinary exosomal biomarkers are highlighted with special emphasis on their clinical applicability (particularly sensitivity, specificity, reliability, and other aspects). Finally, future trends for this field are analyzed and our perspectives are provided.
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Affiliation(s)
- Rui Vitorino
- Departamento de Cirurgia e Fisiologia, UnIC, Faculdade de Medicina da Universidade do Porto, Porto, Portugal.
- Department of Medical Sciences, iBiMED, University of Aveiro, Campus Universitário de Santiago, 3810-193, Aveiro, Portugal.
| | - Rita Ferreira
- Department of Chemistry, LAQV-REQUIMTE, Aveiro, Portugal
| | - Sofia Guedes
- Department of Chemistry, LAQV-REQUIMTE, Aveiro, Portugal
| | | | - Visith Thongboonkerd
- Medical Proteomics Unit, Office for Research and Development, Faculty of Medicine Siriraj Hospital, Mahidol University, 6th Floor, SiMR Building, 2 Wanglang Road, Bangkoknoi, Bangkok, 10700, Thailand.
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24
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Tang YC, Gottlieb A. Explainable drug sensitivity prediction through cancer pathway enrichment. Sci Rep 2021; 11:3128. [PMID: 33542382 PMCID: PMC7862690 DOI: 10.1038/s41598-021-82612-7] [Citation(s) in RCA: 11] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2020] [Accepted: 01/20/2021] [Indexed: 02/06/2023] Open
Abstract
Computational approaches to predict drug sensitivity can promote precision anticancer therapeutics. Generalizable and explainable models are of critical importance for translation to guide personalized treatment and are often overlooked in favor of prediction performance. Here, we propose PathDSP: a pathway-based model for drug sensitivity prediction that integrates chemical structure information with enrichment of cancer signaling pathways across drug-associated genes, gene expression, mutation and copy number variation data to predict drug response on the Genomics of Drug Sensitivity in Cancer dataset. Using a deep neural network, we outperform state-of-the-art deep learning models, while demonstrating good generalizability a separate dataset of the Cancer Cell Line Encyclopedia as well as provide explainable results, demonstrated through case studies that are in line with current knowledge. Additionally, our pathway-based model achieved a good performance when predicting unseen drugs and cells, with potential utility for drug development and for guiding individualized medicine.
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Affiliation(s)
- Yi-Ching Tang
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA
| | - Assaf Gottlieb
- Center for Precision Health, School of Biomedical Informatics, University of Texas Health Science Center at Houston, Houston, TX, 77030, USA.
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25
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Abstract
ABSTRACT Microorganisms can help maintain homeostasis in humans by providing nutrition, maintaining hormone balance, and regulating inflammatory responses. In the case of imbalances, these microbes can cause various diseases, even malignancy. Pancreatic cancer (PC) is characterized by high tumor invasiveness, distant metastasis, and insensitivity to traditional chemotherapeutic drugs, and it is confirmed that PC is closely related to microorganisms. Recently, most studies based on clinical samples or case reports discussed the positive or negative relationships between microorganisms and PC. However, the specific mechanisms are blurry, especially the involved immunological pathways, and the roles of beneficial flora have usually been ignored. We reviewed studies published through September 2020 as identified using PubMed, MEDLINE, and Web of Science. We mainly introduced the traits of oral, gastrointestinal, and intratumoral microbes in PC and summarized the roles of these microbes in tumorigenesis and tumoral development through immunological pathways, in addition to illustrating the relationships between metabolic diseases with PC by microorganism. In addition, we identified microorganisms as biomarkers for early diagnosis and immunotherapy. This review will be significant for greater understanding the effect of microorganisms in PC and provide more meaningful guidance for future clinical applications.
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Affiliation(s)
- Xin Wei
- From the Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun
| | - Chunlei Mei
- Institute of Reproductive Health, Huazhong University of Science and Technology, Wuhan, China
| | - Xixi Li
- From the Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun
| | - Yingjun Xie
- From the Department of Hepatobiliary and Pancreatic Surgery, The Second Hospital of Jilin University, Changchun
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26
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Kim Y, Yeo I, Huh I, Kim J, Han D, Jang JY, Kim Y. Development and Multiple Validation of the Protein Multi-marker Panel for Diagnosis of Pancreatic Cancer. Clin Cancer Res 2021; 27:2236-2245. [PMID: 33504556 DOI: 10.1158/1078-0432.ccr-20-3929] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/05/2020] [Revised: 12/22/2020] [Accepted: 01/21/2021] [Indexed: 12/24/2022]
Abstract
PURPOSE To develop and validate a protein-based, multi-marker panel that provides superior pancreatic ductal adenocarcinoma (PDAC) detection abilities with sufficient diagnostic performance. EXPERIMENTAL DESIGN A total of 959 plasma samples from patients at multiple medical centers were used. To construct an optimal, diagnostic, multi-marker panel, we applied data preprocessing procedure to biomarker candidates. The multi-marker panel was developed using a training set comprised of 261 PDAC cases and 290 controls. Subsequent evaluations were performed in a validation set comprised of 65 PDAC cases and 72 controls. Further validation was performed in an independent set comprised of 75 PDAC cases and 47 controls. RESULTS A multi-marker panel containing 14 proteins was developed. The multi-marker panel achieved AUCs of 0.977 and 0.953 for the training set and validation set, respectively. In an independent validation set, the multi-marker panel yielded an AUC of 0.928. The diagnostic performance of the multi-marker panel showed significant improvements compared with carbohydrate antigen (CA) 19-9 alone (training set AUC = 0.977 vs. 0.872, P < 0.001; validation set AUC = 0.953 vs. 0.832, P < 0.01; independent validation set AUC = 0.928 vs. 0.771, P < 0.001). When the multi-marker panel and CA 19-9 were combined, the diagnostic performance of the combined panel was improved for all sets. CONCLUSIONS This multi-marker panel and the combined panel showed statistically significant improvements in diagnostic performance compared with CA 19-9 alone and has the potential to complement CA 19-9 as a diagnostic marker in clinical practice.
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Affiliation(s)
- Yoseop Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, College of Engineering, Seoul, Republic of South Korea
| | - Injoon Yeo
- Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of South Korea
| | - Iksoo Huh
- College of Nursing and Research Institute of Nursing Science, Seoul National University, Seoul, Republic of South Korea
| | - Jaenyeon Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, College of Engineering, Seoul, Republic of South Korea
| | - Dohyun Han
- Biomedical Research Institute, Seoul National University Hospital, Seoul, Republic of South Korea
| | - Jin-Young Jang
- Department of Surgery, Seoul National University College of Medicine, Seoul, Republic of South Korea.
| | - Youngsoo Kim
- Interdisciplinary Program in Bioengineering, Seoul National University, College of Engineering, Seoul, Republic of South Korea. .,Institute of Medical and Biological Engineering, Medical Research Center, Seoul National University College of Medicine, Seoul, Republic of South Korea.,Institute of Bioengineering, Seoul National University, Seoul, Republic of South Korea
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27
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Wang S, Bager CL, Karsdal MA, Chondros D, Taverna D, Willumsen N. Blood-based extracellular matrix biomarkers as predictors of survival in patients with metastatic pancreatic ductal adenocarcinoma receiving pegvorhyaluronidase alfa. J Transl Med 2021; 19:39. [PMID: 33478521 PMCID: PMC7819178 DOI: 10.1186/s12967-021-02701-z] [Citation(s) in RCA: 15] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2020] [Accepted: 01/08/2021] [Indexed: 02/07/2023] Open
Abstract
Background Extensive extracellular matrix (ECM) remodeling is a hallmark of metastatic pancreatic ductal adenocarcinoma (mPDA). We investigated fragments of collagen types III (C3M, PRO-C3), VI (PRO-C6), and VIII (C8-C), and versican (VCANM) in plasma as biomarkers for predicting progression-free survival (PFS) and overall survival (OS) in patients with mPDA treated with pegvorhyaluronidase alfa, a biologic that degrades the ECM component hyaluronan (HA), in a randomized phase 2 study (HALO109-202). Methods HALO109-202 comprised a discovery cohort (Stage 1, n = 94) and a validation cohort (Stage 2, n = 95). Plasma ECM biomarkers were analyzed by ELISAs. Univariate Cox regression analysis and Kaplan–Meier plots evaluated predictive associations between biomarkers, PFS and OS in patients treated with pegvorhyaluronidase alfa plus nab-paclitaxel/gemcitabine (PAG) versus nab-paclitaxel/gemcitabine (AG) alone. Results PFS was improved with PAG vs. AG in Stage 1 patients with high C3M/PRO-C3 ratio (median cut-off): median PFS (mPFS) 8.0 vs. 5.3 months, P = 0.031; HR = 0.40; 95% CI 0.17–0.92). High C3M/PRO-C3 ratio was validated in Stage 2 patients by predicting a PFS benefit of PAG vs. AG (mPFS: 8.8 vs. 3.4 months, P = 0.046; HR = 0.46; 95% CI 0.21–0.98). OS was also improved in patients with high C3M/PRO-C3 ratio treated with PAG vs. AG (mOS 13.8 vs 8.5 months, P = 0.009; HR = 0.35; 95% CI 0.16–0.77). Interestingly, high C3M/PRO-C3 ratio predicted for a PFS benefit to PAG vs. AG both in patients with HA-low tumors (HR = 0.36; 95% CI 0.17–0.79) and HA-high tumors (HR = 0.20; 95% CI 0.06–0.69). Conclusions The C3M/PRO-C3 ratio measuring type III collagen turnover in plasma has potential as a blood-based predictive biomarker in patients with mPDA and provides additional value to a HA biopsy when applied for patient selection. Trial registration: NCT01839487. Registered 25 April 2016
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Affiliation(s)
- Song Wang
- Halozyme Therapeutics, Inc., San Diego, CA, USA
| | - Cecilie L Bager
- Nordic Bioscience A/S, Herlev Hovedgade 207, 2730, Herlev, Denmark
| | - Morten A Karsdal
- Nordic Bioscience A/S, Herlev Hovedgade 207, 2730, Herlev, Denmark
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28
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Hussung S, Akhoundova D, Hipp J, Follo M, Klar RFU, Philipp U, Scherer F, von Bubnoff N, Duyster J, Boerries M, Wittel U, Fritsch RM. Longitudinal analysis of cell-free mutated KRAS and CA 19-9 predicts survival following curative resection of pancreatic cancer. BMC Cancer 2021; 21:49. [PMID: 33430810 PMCID: PMC7802224 DOI: 10.1186/s12885-020-07736-x] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/16/2020] [Accepted: 12/15/2020] [Indexed: 02/06/2023] Open
Abstract
Background Novel biomarkers and molecular monitoring tools hold potential to improve outcome for patients following resection of pancreatic ductal adenocarcinoma (PDAC). We hypothesized that the combined longitudinal analysis of mutated cell-free plasma KRAS (cfKRASmut) and CA 19–9 during adjuvant treatment and follow-up might more accurately predict disease course than hitherto available parameters. Methods Between 07/2015 and 10/2018, we collected 134 plasma samples from 25 patients after R0/R1-resection of PDAC during adjuvant chemotherapy and post-treatment surveillance at our institution. Highly sensitive discriminatory multi-target ddPCR assays were employed to screen plasma samples for cfKRASmut. cfKRASmut and CA 19–9 dynamics were correlated with recurrence-free survival (RFS) and overall survival (OS). Patients were followed-up until 01/2020. Results Out of 25 enrolled patients, 76% had undergone R0 resection and 48% of resected PDACs were pN0. 17/25 (68%) of patients underwent adjuvant chemotherapy. Median follow-up was 22.0 months, with 19 out of 25 (76%) patients relapsing during study period. Median RFS was 10.0 months, median OS was 22.0 months. Out of clinicopathologic variables, only postoperative CA 19–9 levels and administration of adjuvant chemotherapy correlated with survival endpoints. cfKRASmut. was detected in 12/25 (48%) of patients, and detection of high levels inversely correlated with survival endpoint. Integration of cfKRASmut and CA 19–9 levels outperformed either individual marker. cfKRASmut outperformed CA 19–9 as dynamic marker since increase during adjuvant chemotherapy and follow-up was highly predictive of early relapse and poor OS. Conclusions Integrated analysis of cfKRASmut and CA 19–9 levels is a promising approach for molecular monitoring of patients following resection of PDAC. Larger prospective studies are needed to further develop this approach and dissect each marker’s specific potential. Supplementary Information The online version contains supplementary material available at 10.1186/s12885-020-07736-x.
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Affiliation(s)
- Saskia Hussung
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany.,Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Dilara Akhoundova
- Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland
| | - Julian Hipp
- Department of Surgery, Freiburg University Medical Center, Freiburg, Germany
| | - Marie Follo
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Rhena F U Klar
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Ulrike Philipp
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Florian Scherer
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Nikolas von Bubnoff
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany
| | - Justus Duyster
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany.,German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany
| | - Melanie Boerries
- German Cancer Consortium (DKTK), partner site Freiburg, German Cancer Research Center (DKFZ), Heidelberg, Germany.,Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,Institute of Medical Bioinformatics and Systems Medicine, University Medical Center Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.,German Cancer Research Center (DKFZ), Heidelberg, Germany
| | - Uwe Wittel
- Department of Surgery, Freiburg University Medical Center, Freiburg, Germany
| | - Ralph M Fritsch
- Department of Medicine I (Hematology, Oncology and Stem Cell Transplantation), Freiburg University Medical Center, Freiburg, Germany. .,Department of Medical Oncology and Hematology, Zurich University Hospital, Raemistrasse 100, 8091, Zürich, Switzerland. .,Comprehensive Cancer Center Freiburg (CCCF), Medical Center - University of Freiburg, Faculty of Medicine, University of Freiburg, Freiburg, Germany.
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29
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Caputo D, Digiacomo L, Cascone C, Pozzi D, Palchetti S, Di Santo R, Quagliarini E, Coppola R, Mahmoudi M, Caracciolo G. Synergistic Analysis of Protein Corona and Haemoglobin Levels Detects Pancreatic Cancer. Cancers (Basel) 2020; 13:93. [PMID: 33396882 PMCID: PMC7796289 DOI: 10.3390/cancers13010093] [Citation(s) in RCA: 16] [Impact Index Per Article: 3.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/27/2020] [Revised: 12/04/2020] [Accepted: 12/24/2020] [Indexed: 12/20/2022] Open
Abstract
Simultaneous detection of multiple analytes from a single biological sample is gaining more attention in the development of more reliable and point-of-care diagnostic devices. We developed a multiplexed strategy that combined outcomes of clinical biomarkers with analysis of the protein corona that forms around graphene oxide sheets upon exposure to patient's plasma. As a paradigmatic case study, we selected pancreatic ductal adenocarcinoma (PDAC), mainly because of the absence of effective detection strategies that resulted in an extremely low five-year survival rate after diagnosis (<10%). Association of protein corona analysis and haemoglobin levels discriminated PDAC patients from healthy volunteers in up to 90% of cases. If further confirmed in larger-cohort studies, this approach may be used in the detection of PDAC.
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Affiliation(s)
- Damiano Caputo
- Department of Surgery, University Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy; (D.C.); (C.C.); (R.C.)
| | - Luca Digiacomo
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy; (L.D.); (D.P.); (S.P.); (R.D.S.)
| | - Chiara Cascone
- Department of Surgery, University Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy; (D.C.); (C.C.); (R.C.)
| | - Daniela Pozzi
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy; (L.D.); (D.P.); (S.P.); (R.D.S.)
| | - Sara Palchetti
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy; (L.D.); (D.P.); (S.P.); (R.D.S.)
| | - Riccardo Di Santo
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy; (L.D.); (D.P.); (S.P.); (R.D.S.)
| | - Erica Quagliarini
- Department of Chemistry, Sapienza University of Rome, P.le Aldo Moro 5, 00185 Rome, Italy;
| | - Roberto Coppola
- Department of Surgery, University Campus Bio-Medico di Roma, Via Alvaro del Portillo 200, 00128 Rome, Italy; (D.C.); (C.C.); (R.C.)
| | - Morteza Mahmoudi
- Department of Radiology and Precision Health Program, Michigan State University, East Lansing, MI 48824, USA;
| | - Giulio Caracciolo
- Department of Molecular Medicine, Sapienza University of Rome, Viale Regina Elena 291, 00161 Rome, Italy; (L.D.); (D.P.); (S.P.); (R.D.S.)
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Bushnell GG, Orbach SM, Ma JA, Crawford HC, Wicha MS, Jeruss JS, Shea LD. Disease-induced immunomodulation at biomaterial scaffolds detects early pancreatic cancer in a spontaneous model. Biomaterials 2020; 269:120632. [PMID: 33418200 DOI: 10.1016/j.biomaterials.2020.120632] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2020] [Revised: 11/17/2020] [Accepted: 12/20/2020] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer has the worst prognosis of all cancers due to disease aggressiveness and paucity of early detection platforms. We developed biomaterial scaffolds that recruit metastatic tumor cells and reflect the immune dysregulation of native metastatic sites. While this platform has shown promise in orthotopic breast cancer models, its potential in other models is untested. Herein, we demonstrate that scaffolds recruit disseminated pancreatic cells in the KPCY model of spontaneous pancreatic cancer prior to adenocarcinoma formation (3-fold increase in scaffold YFP + cells). Furthermore, immune cells at the scaffolds differentiate early- and late-stage disease with greater accuracy (0.83) than the natural metastatic site (liver, 0.50). Early disease was identified by an approximately 2-fold increase in monocytes. Late-stage disease was marked by a 1.5-2-fold increase in T cells and natural killer cells. The differential immune response indicated that the scaffolds could distinguish spontaneous pancreatic cancer from spontaneous breast cancer. Collectively, our findings demonstrate the utility of scaffolds to reflect immunomodulation in two spontaneous models of tumorigenesis, and their particular utility for identifying early disease stages in the aggressive KPCY pancreatic cancer model. Such scaffolds may serve as a platform for early detection of pancreatic cancer to improve treatment and prognosis.
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Affiliation(s)
- Grace G Bushnell
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Sophia M Orbach
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jeffrey A Ma
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Howard C Crawford
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Molecular & Integrative Physiology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Max S Wicha
- Department of Internal Medicine, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Jacqueline S Jeruss
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Surgery, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Pathology, University of Michigan, Ann Arbor, MI, 48109, USA
| | - Lonnie D Shea
- Department of Biomedical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA; Department of Chemical Engineering, University of Michigan, Ann Arbor, MI, 48109, USA.
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Yang KS, Lin HY, Curley C, Welch MW, Wolpin B, Lee H, Weissleder R, Im H, Castro CM. Bead-Based Extracellular Vesicle Analysis Using Flow Cytometry. ADVANCED BIOSYSTEMS 2020; 4:e2000203. [PMID: 33103361 PMCID: PMC7718389 DOI: 10.1002/adbi.202000203] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 10/08/2020] [Indexed: 01/09/2023]
Abstract
Extracellular vesicles (EVs) represent promising circulating biomarkers for cancers, but their high-throughput analyses in clinical settings prove challenging due to lack of simple, fast, and robust EV assays. Here, a bead-based EV assay detected by flow cytometry is described, which integrates EV capture using microbeads with EV protein analyses by flow cytometry. The assay is fast (<4 h for 48 samples), robust, and compatible with conventional flow cytometry instruments for high-throughput EV analysis. With the method, a panel of pancreatic cancer biomarkers in EVs from plasma samples of pancreatic cancer patients is successfully analyzed. The assay is readily translatable to other biomarkers or cancer types and can be run with standard materials on conventional flow cytometers, making it highly flexible and adaptable to diverse research and clinical needs.
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Affiliation(s)
- Katherine S. Yang
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Radiology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Hsing-Ying Lin
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | - Caleigh Curley
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
| | | | | | - Hakho Lee
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Radiology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Ralph Weissleder
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Radiology, Massachusetts General Hospital, Boston, MA, 02114, USA
- Department of Systems Biology, Harvard Medical School, Boston, MA 02115, USA
| | - Hyungsoon Im
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
- Department of Radiology, Massachusetts General Hospital, Boston, MA, 02114, USA
| | - Cesar M. Castro
- Center for Systems Biology, Massachusetts General Hospital, Boston, MA 02114, USA
- Massachusetts General Hospital Cancer Center, Boston, MA 02114, USA
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Consul N. Prognostic Imaging Biomarkers for Pancreatic Ductal Adenocarcinoma Extracted from Structured Radiologist Reports. Radiol Imaging Cancer 2020; 2:e209032. [PMID: 33778751 PMCID: PMC7983650 DOI: 10.1148/rycan.2020209032] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 06/12/2023]
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Wang J, Zhang H, Sun X, Wang X, Ren T, Huang Y, Zhang R, Zheng B, Guo W. Exosomal PD-L1 and N-cadherin predict pulmonary metastasis progression for osteosarcoma patients. J Nanobiotechnology 2020; 18:151. [PMID: 33092576 PMCID: PMC7579953 DOI: 10.1186/s12951-020-00710-6] [Citation(s) in RCA: 59] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2020] [Accepted: 10/10/2020] [Indexed: 02/08/2023] Open
Abstract
BACKGROUND Recent studies indicated that exosomal programmed death-ligand 1 (PD-L1) derived from cancers could induce immunosuppression and tumor pathogenesis. However, it is unclear how exosomes influence osteosarcoma (OS) progression and whether PD-L1 also exists in serum exosomes (Sr-exosomes) of patients with osteosarcoma. We examined serum exosomes from 70 OS patients, 9 patients with benign tumors and 22 healthy donors. OS-derived exosomes were functionally evaluated in vivo and in vitro. RESULTS The characteristics of exosomes derived from OS patient serum and OS cell lines were confirmed by several methods. We found OS patients had a higher level of exosomal PD-L1 compared to healthy donors. Meanwhile, OS patients with pulmonary metastasis also showed a relatively higher level of exosomal PD-L1 than patients without metastasis. Next, bioinformatic analysis demonstrated that Sr-exosomes isolated from OS patients may involve in the important process of immune function and cancer pathogenesis for OS patients. Co-expression network centered with PD-L1 among Sr-exosomal differently expressed mRNA demonstrated exosomal N-cadherin had a close relationship with exosomal PD-L1 expression. Then, we confirmed higher level of Sr-exosomal N-cadherin in OS patients with pulmonary metastasis compared to ones without metastasis. Furthermore, we elucidated osteosarcoma-derived exosomes and exosomal-PD-L1 promoted the pulmonary metastasis in metastatic models. ROC (Receiver Operating Characteristic Curve) analysis showed AUC (Area Under Curve) of 0.823 for exosomal PD-L1, 0.806 for exosomal N-cadherin and 0.817 for exosomal N-cadherin/E-cadherin to distinguish OS patients with pulmonary metastasis from ones without metastasis. CONCLUSIONS Osteosarcoma stimulates pulmonary metastasis by releasing exosomes, that carry PD-L1 and N-cadherin. Detection of exosomal PD-L1 and N-cadherin from serum of OS patients may predict pulmonary metastasis progression for OS patients.
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Affiliation(s)
- Jun Wang
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Hongliang Zhang
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Xin Sun
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Xiaofang Wang
- Beijing Key Laboratory of Bio-Characteristic Profiling for Evaluation of Rational Drug Use, International Cooperation & Joint Laboratoryof Bio-Characteristic Profiling for Evaluation of Rational Drug Use, Beijing Shijitan Hospital, Capital Medical University,, Beijing, 100038, China
| | - Tingting Ren
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Yi Huang
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Ranxin Zhang
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Bingxin Zheng
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China
| | - Wei Guo
- Peking University People's Hospital, Musculoskeletal Tumor Center, No. 11 Xizhimen South Street, Beijing, 100044, China.
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Gyllensten U, Bosdotter Enroth S, Stålberg K, Sundfeldt K, Enroth S. Preoperative Fasting and General Anaesthesia Alter the Plasma Proteome. Cancers (Basel) 2020; 12:cancers12092439. [PMID: 32867270 PMCID: PMC7564209 DOI: 10.3390/cancers12092439] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/06/2020] [Revised: 08/22/2020] [Accepted: 08/26/2020] [Indexed: 01/15/2023] Open
Abstract
Background: Blood plasma collected at time of surgery is an excellent source of patient material for investigations into disease aetiology and for the discovery of novel biomarkers. Previous studies on limited sets of proteins and patients have indicated that pre-operative fasting and anaesthesia can affect protein levels, but this has not been investigated on a larger scale. These effects could produce erroneous results in case-control studies if samples are not carefully matched. Methods: The proximity extension assay (PEA) was used to characterize 983 unique proteins in a total of 327 patients diagnosed with ovarian cancer and 50 age-matched healthy women. The samples were collected either at time of initial diagnosis or before surgery under general anaesthesia. Results: 421 of the investigated proteins (42.8%) showed statistically significant differences in plasma abundance levels comparing samples collected at time of diagnosis or just before surgery under anaesthesia. Conclusions: The abundance levels of the plasma proteome in samples collected before incision, i.e., after short-time fasting and under general anaesthesia differs greatly from levels in samples from awake patients. This emphasizes the need for careful matching of the pre-analytical conditions of samples collected from controls to cases at time of surgery in the discovery as well as clinical use of protein biomarkers.
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Affiliation(s)
- Ulf Gyllensten
- Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-751 08 Uppsala, Sweden;
| | | | - Karin Stålberg
- Department of Women’s and Children’s Health, Uppsala University, SE-751 85 Uppsala, Sweden;
| | - Karin Sundfeldt
- Department of Obstetrics and Gynaecology, Institute of Clinical Sciences, Sahlgrenska Academy at Gothenburg University, SE-416 85 Gothenburg, Sweden;
| | - Stefan Enroth
- Department of Immunology, Genetics, and Pathology, Biomedical Center, Science for Life Laboratory (SciLifeLab) Uppsala, Box 815, Uppsala University, SE-751 08 Uppsala, Sweden;
- Correspondence: ; Tel.: +46-18-4714913
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Jiao H, Zeng L, Yang S, Zhang J, Lou W. Knockdown EIF3C Suppresses Cell Proliferation and Increases Apoptosis in Pancreatic Cancer Cell. Dose Response 2020; 18:1559325820950061. [PMID: 32973416 PMCID: PMC7493259 DOI: 10.1177/1559325820950061] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 04/02/2020] [Accepted: 05/29/2020] [Indexed: 11/16/2022] Open
Abstract
Increasing evidence shows that eukaryotic initiation factor subunit (EIF3C) plays a crucial role in development of tumors. However, the underlying roles of EIF3Cin the development of pancreatic cancer (PC) remain unknown. In this study, we examined the expression of EIF3C in PC tissues, their adjacent normal tissues and 3 cell lines (SW1990, PANC-1 and AsPC-1). Moreover, the EIF3C-shRNA lentivirus was constructed to suppress EIF3C expression. Following this, the cell colony formation assay was employed to evaluate proliferation ability of PC cells. Meanwhile, the cell cycle and apoptotic assays were also performed by flow cytometry. We found that level of EIF3C in PC tissues was significantly increased compared with that in adjacent normal tissues. Furthermore, the knockdown of EIF3C can significantly reduce cell proliferation, block cell cycle in G2/M and induce apoptosis in both SW1990 and PANC-1 cells. Our findings suggest that EIF3C plays a crucial role in the progression of PC and may be a potential target in the treatment of PC.
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Affiliation(s)
- Heng Jiao
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Lingxiao Zeng
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
| | - Shengsheng Yang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China
| | - Jianpeng Zhang
- Department of Biochemistry and Molecular Biology, College of Basic Medical Sciences, Second Military Medical University, Shanghai, China
| | - Wenhui Lou
- Department of General Surgery, Zhongshan Hospital, Fudan University, Shanghai, China
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Braun LM, Lagies S, Guenzle J, Fichtner-Feigl S, Wittel UA, Kammerer B. Metabolic Adaptation during nab-Paclitaxel Resistance in Pancreatic Cancer Cell Lines. Cells 2020; 9:cells9051251. [PMID: 32438599 PMCID: PMC7290296 DOI: 10.3390/cells9051251] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/02/2020] [Revised: 05/05/2020] [Accepted: 05/15/2020] [Indexed: 12/13/2022] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) correlates with high mortality and is about to become one of the major reasons for cancer-related mortality in the next decades. One reason for that high mortality is the limited availability of effective chemotherapy as well as the intrinsic or acquired resistance against it. Here, we report the impact of nab-paclitaxel on the cellular metabolome of PDAC cell lines. After establishment of nab-paclitaxel resistant cell lines, comparison of parental and resistant PDAC cell lines by metabolomics and biochemical assessments revealed altered metabolism, enhanced viability and reduced apoptosis. The results unveiled that acute nab-paclitaxel treatment affected primary metabolism to a minor extent. However, acquisition of resistance led to altered metabolites in both cell lines tested. Specifically, aspartic acid and carbamoyl-aspartic acid were differentially abundant, which might indicate an increased de novo pyrimidine synthesis. This pathway has already shown a similar behavior in other cancerous entities and thus might serve in the future as vulnerable target fighting resistance acquisition occurring in common malignancies.
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Affiliation(s)
- Lukas M. Braun
- Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; (L.M.B.); (S.L.)
- Department of General- and Visceral Surgery, University of Freiburg Medical Center Faculty of Medicine, 79106 Freiburg, Germany; (J.G.); (S.F.-F.)
| | - Simon Lagies
- Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; (L.M.B.); (S.L.)
- Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany
- Institute of Biology II, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany
| | - Jessica Guenzle
- Department of General- and Visceral Surgery, University of Freiburg Medical Center Faculty of Medicine, 79106 Freiburg, Germany; (J.G.); (S.F.-F.)
| | - Stefan Fichtner-Feigl
- Department of General- and Visceral Surgery, University of Freiburg Medical Center Faculty of Medicine, 79106 Freiburg, Germany; (J.G.); (S.F.-F.)
| | - Uwe A. Wittel
- Department of General- and Visceral Surgery, University of Freiburg Medical Center Faculty of Medicine, 79106 Freiburg, Germany; (J.G.); (S.F.-F.)
- Correspondence: (U.A.W.); (B.K.); Tel.: +49-761-270-25090 (U.A.W.); +49-761-203-97137 (B.K.)
| | - Bernd Kammerer
- Center for Biological Systems Analysis ZBSA, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany; (L.M.B.); (S.L.)
- Spemann Graduate School of Biology and Medicine, Albert-Ludwigs-University Freiburg, 79104 Freiburg, Germany
- BIOSS Centre for Biological Signalling Studies, University of Freiburg, 79104 Freiburg, Germany
- Correspondence: (U.A.W.); (B.K.); Tel.: +49-761-270-25090 (U.A.W.); +49-761-203-97137 (B.K.)
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Rivera-Báez L, Lohse I, Lin E, Raghavan S, Owen S, Harouaka R, Herman K, Mehta G, Lawrence TS, Morgan MA, Cuneo KC, Nagrath S. Expansion of Circulating Tumor Cells from Patients with Locally Advanced Pancreatic Cancer Enable Patient Derived Xenografts and Functional Studies for Personalized Medicine. Cancers (Basel) 2020; 12:cancers12041011. [PMID: 32326109 PMCID: PMC7225920 DOI: 10.3390/cancers12041011] [Citation(s) in RCA: 29] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/01/2020] [Revised: 04/03/2020] [Accepted: 04/14/2020] [Indexed: 12/22/2022] Open
Abstract
Improvement in pancreatic cancer treatment represents an urgent medical goal that has been hampered by the lack of predictive biomarkers. Circulating Tumor Cells (CTCs) may be able to overcome this issue by allowing the monitoring of therapeutic response and tumor aggressiveness through ex vivo expansion. The successful expansion of CTCs is challenging, due to their low numbers in blood and the high abundance of blood cells. Here, we explored the utility of pancreatic CTC cultures as a preclinical model for treatment response. CTCs were isolated from ten patients with locally advanced pancreatic cancer using the Labyrinth, a biomarker independent, size based, inertial microfluidic separation device. Three patient-derived CTC samples were successfully expanded in adherent and spheroid cultures. Molecular and functional characterization was performed on the expanded CTC lines. CTC lines exhibited KRAS mutations, consistent with pancreatic cancers. Additionally, we evaluated take rate and metastatic potential in vivo and examined the utility of CTC lines for cytotoxicity assays. Patient derived expanded CTCs successfully generated patient derived xenograft (PDX) models with a 100% take rate. Our results demonstrate that CTC cultures are possible and provide a valuable resource for translational pancreatic cancer research, while also providing meaningful insight into the development of distant metastasis, as well as treatment resistance.
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Affiliation(s)
- Lianette Rivera-Báez
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Ines Lohse
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
| | - Eric Lin
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Shreya Raghavan
- Department of Materials Science and Engineering, University of Michigan, Ann Arbor, MI 48109, USA;
| | - Sarah Owen
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Ramdane Harouaka
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Kirk Herman
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Geeta Mehta
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
| | - Theodore S. Lawrence
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Meredith A. Morgan
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
| | - Kyle C. Cuneo
- Department of Radiation Oncology, University of Michigan Medical School, Ann Arbor, MI 48109, USA; (I.L.); (K.H.); (M.A.M.)
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
- Veterans Administration Ann Arbor Healthcare System, Ann Arbor, MI 48105, USA
- Correspondence: (K.C.C.); (S.N.)
| | - Sunitha Nagrath
- Department of Chemical Engineering, University of Michigan, Ann Arbor, MI 48105, USA; (L.R.-B.); (E.L.); (S.O.)
- Biointerfaces Institute, University of Michigan, Ann Arbor, MI 48105, USA;
- Department of Internal Medicine, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI 48109, USA; (R.H.); (T.S.L.)
- Correspondence: (K.C.C.); (S.N.)
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Salomon RE, Tan KR, Vaughan A, Adynski H, Muscatell KA. Minimally-invasive methods for examining biological changes in response to chronic stress: A scoping review. Int J Nurs Stud 2020; 103:103419. [PMID: 31945603 PMCID: PMC7067628 DOI: 10.1016/j.ijnurstu.2019.103419] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/13/2018] [Revised: 09/05/2019] [Accepted: 09/06/2019] [Indexed: 12/14/2022]
Abstract
BACKGROUND Nurse researchers are increasingly interested in incorporating biological indicators related to chronic stress, or repeated or constant exposure to psychological stressors. Minimally invasive collection methods may improve access to vulnerable populations. OBJECTIVE To map biological indicators measured through minimally invasive methods investigating biological changes in response to chronic stress. DESIGN, DATA SOURCES, AND METHODS The paper seeks to answer two questions: What are the characteristics of the minimally-invasive methods used to measure the biological correlates of chronic stress? What are the limitations regarding the use of the minimally-invasive methods and/or biological indicators identified above? Authors completed a scoping review following guidelines from the Joanna Briggs Institute Manual and the Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) extension for Scoping Reviews. A literature search was completed in PubMed, PsycINFO, and Scopus. 2518 articles were screened and 145 studies were included. Data were extracted using a standardized extraction tool, compiled, and coded. RESULTS Studies included minimally-invasive methods to measure the hypothalamic-adrenal-pituitary axis (N = 173), immune and inflammatory markers (N = 118), and adult neurogenesis (N = 6). Cortisol was most frequently measured (N = 136), usually in saliva (N = 86). Studies included a variety of limitations for the methods and indicators, including concerns about timing and accuracy of collection, frequency of sampling, and controlling for acute stressors. CONCLUSIONS Nurse researchers have access to many minimally-invasive methods to measure altered biological processes related to chronic stress. A gap identified by this review is the paucity of minimally-invasive methods for investigating neurogenesis; the measurement of brain derived neurotrophic factor in plasma is a distal proxy and further research is needed to test the response of peripheral levels to psychosocial stress interventions. Additionally, while this scoping review allows nurse researchers to consider possible biological indicators to include in their research, future research is still needed on some of the basic premises of stress research, including agreement on the conceptualization of chronic stress.
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Affiliation(s)
- Rebecca E Salomon
- School of Nursing, University of California San Francisco, 2 Koret Way, UCSF Box 0608, San Francisco, CA 94143-0608, USA.
| | - Kelly R Tan
- School of Nursing, University of California San Francisco, 2 Koret Way, UCSF Box 0608, San Francisco, CA 94143-0608, USA.
| | - Ashley Vaughan
- School of Nursing, University of California San Francisco, 2 Koret Way, UCSF Box 0608, San Francisco, CA 94143-0608, USA.
| | - Harry Adynski
- School of Nursing, University of California San Francisco, 2 Koret Way, UCSF Box 0608, San Francisco, CA 94143-0608, USA.
| | - Keely A Muscatell
- Department of Psychology and Neuroscience, University of North Carolina at Chapel Hill, Campus Box #3270, 235 E. Cameron Avenue, Chapel Hill, NC 27599-3270, USA; Lineberger Comprehensive Cancer Center, University of North Carolina at Chapel Hill, Campus Box #7295, 450 West Drive, Chapel Hill, NC 27599-7295, USA.
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Kamatham S, Shahjehan F, Kasi PM. Circulating Tumor DNA-Based Detection of Microsatellite Instability and Response to Immunotherapy in Pancreatic Cancer. Front Pharmacol 2020; 11:23. [PMID: 32116700 PMCID: PMC7025641 DOI: 10.3389/fphar.2020.00023] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/10/2019] [Accepted: 01/08/2020] [Indexed: 12/14/2022] Open
Abstract
Pancreatic cancer is an aggressive malignancy with poor survival. Research has indicated the association of few genetic aberrations with pancreatic cancer. The data regarding the prevalence of microsatellite instability in pancreatic cancer is diverse and controversial. However, it could be an actionable target in pancreatic cancer especially due to availability of immune checkpoint inhibitors which has demonstrated promising results in different types of cancers. We present a case of pancreatic cancer whose microsatellite instability status was identified on liquid biopsy (circulating tumor DNA testing). Our patient showed a dramatic ongoing durable response to immunotherapy. We were able to do serial monitoring with liquid biopsy that showed clinical utility and validity.
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Affiliation(s)
- Saivaishnavi Kamatham
- Department of Cancer Biology/Pathology, Wayne State University, Detroit, MI, United States
| | - Faisal Shahjehan
- Department of Internal Medicine, Conemaugh Memorial Medical Center, Johnstown, PA, United States
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Sturque J, Berquet A, Loison-Robert LS, Ahossi V, Zwetyenga N. Interest of studying the saliva metabolome, transcriptome and microbiome in screening for pancreatic cancer. JOURNAL OF STOMATOLOGY, ORAL AND MAXILLOFACIAL SURGERY 2019; 120:554-558. [DOI: 10.1016/j.jormas.2019.04.013] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/22/2018] [Revised: 04/16/2019] [Accepted: 04/22/2019] [Indexed: 12/20/2022]
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Blsakova A, Kveton F, Kasak P, Tkac J. Antibodies against aberrant glycans as cancer biomarkers. Expert Rev Mol Diagn 2019; 19:1057-1068. [PMID: 31665948 DOI: 10.1080/14737159.2020.1687295] [Citation(s) in RCA: 10] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/24/2022]
Abstract
Introduction: The review provides a comprehensive overview about applicability of serological detection of autoantibodies against aberrant glycans as cancer biomarkers.Areas covered: Clinical usefulness of autoantibodies as cancer biomarkers is discussed for seven types of cancers with sensitivity and specificity of such biomarkers provided. Moreover, an option of using serological antibodies against a non-natural form of sialic acid - N-glycolylneuraminic acid (Neu5Gc), which is taken into our bodies together with red meat, as a potential cancer biomarker is discussed shortly as well.Expert opinion: In the final part of the review, we discuss what measures need to be applied for selective implementation of autoantibody assays into a clinical practice. Moreover, we discuss key challenges ahead for reliable and robust detection of autoantibodies against aberrant glycans as biomarkers for disease diagnostics and for stratification of cancer patients.
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Affiliation(s)
- Anna Blsakova
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Filip Kveton
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
| | - Peter Kasak
- Center for Advanced Materials, Qatar University, Doha, Qatar
| | - Jan Tkac
- Institute of Chemistry, Slovak Academy of Sciences, Bratislava, Slovakia
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Gupta N, Park JE, Tse W, Low JK, Kon OL, McCarthy N, Sze SK. ERO1α promotes hypoxic tumor progression and is associated with poor prognosis in pancreatic cancer. Oncotarget 2019; 10:5970-5982. [PMID: 31666928 PMCID: PMC6800261 DOI: 10.18632/oncotarget.27235] [Citation(s) in RCA: 25] [Impact Index Per Article: 4.2] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/15/2019] [Accepted: 09/24/2019] [Indexed: 01/04/2023] Open
Abstract
Pancreatic cancer is a leading cause of mortality worldwide due to the difficulty of detecting early-stage disease and our poor understanding of the mediators that drive progression of hypoxic solid tumors. We therefore used a heavy isotope 'pulse/trace' proteomic approach to determine how hypoxia (Hx) alters pancreatic tumor expression of proteins that confer treatment resistance, promote metastasis, and suppress host immunity. Using this method, we identified that hypoxia stress stimulates pancreatic cancer cells to rapidly translate proteins that enhance metastasis (NOTCH2, NCS1, CD151, NUSAP1), treatment resistance (ABCB6), immune suppression (NFIL3, WDR4), angiogenesis (ANGPT4, ERO1α, FOS), alter cell metabolic activity (HK2, ENO2), and mediate growth-promoting cytokine responses (CLK3, ANGPTL4). Database mining confirmed that elevated gene expression of these hypoxia-induced mediators is significantly associated with poor patient survival in various stages of pancreatic cancer. Among these proteins, the oxidoreductase enzyme ERO1α was highly sensitive to induction by hypoxia stress across a range of different pancreatic cancer cell lines and was associated with particularly poor prognosis in human patients. Consistent with these data, genetic deletion of ERO1α substantially reduced growth rates and colony formation by pancreatic cancer cells when assessed in a series of functional assays in vitro. Accordingly, when transferred into a mouse xenograft model, ERO1α-deficient tumor cells exhibited severe growth restriction and negligible disease progression in vivo. Together, these data indicate that ERO1α is potential prognostic biomarker and novel drug target for pancreatic cancer therapy.
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Affiliation(s)
- Nikhil Gupta
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Jung Eun Park
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Wilford Tse
- School of Biological Sciences, Nanyang Technological University, Singapore
| | - Jee Keem Low
- Department of Surgery, Tan Tock Seng Hospital, Singapore
| | - Oi Lian Kon
- National Cancer Centre Singapore, Division of Medical Sciences, Singapore
| | - Neil McCarthy
- Centre for Immunobiology, The Blizard Institute, Bart’s and The London School of Medicine and Dentistry, Queen Mary University of London, United Kingdom
| | - Siu Kwan Sze
- School of Biological Sciences, Nanyang Technological University, Singapore
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Shin HS, Jung SB, Park S, Dua P, Lee DK. ALPPL2 Is a Potential Diagnostic Biomarker for Pancreatic Cancer-Derived Extracellular Vesicles. MOLECULAR THERAPY-METHODS & CLINICAL DEVELOPMENT 2019; 15:204-210. [PMID: 31687420 PMCID: PMC6819892 DOI: 10.1016/j.omtm.2019.08.016] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 05/24/2019] [Accepted: 08/22/2019] [Indexed: 02/07/2023]
Abstract
Pancreatic cancer is an aggressive malignancy that often goes undiagnosed in the early stages. Non-invasive, early, and accurate diagnosis is therefore undoubtedly the "holy grail" of pancreatic cancer research. However, despite extensive research efforts, there is no definitive biomarker for this cancer. Previously, we identified alkaline phosphatase placental-like 2 (ALPPL2) as a diagnostic biomarker for pancreatic ductal adenocarcinoma and developed a 2'-fluoro modified RNA aptamer toward it. In this study, we show that ALPPL2 is present in pancreatic cancer extracellular vesicles (EVs) and therefore has potential application in liquid biopsy-based diagnostic strategies. We also developed ALPPL2 direct and sandwich aptamer-linked immobilized sorbent assay (ALISA) for EVs, which could sensitively and specifically detect the protein. We believe that our ALISA format may have a potential diagnostic utility in screening pancreatic-cancer-derived EVs.
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Affiliation(s)
- Hye-Su Shin
- Global Research Laboratory of RNAi Medicine, Department of Chemistry, Sungkyunkwan University, Suwon, Korea
| | - Sang Baek Jung
- Nano Materials Chemistry Lab, Department of Chemistry, Sungkyunkwan University, Suwon, Korea
| | - Sungho Park
- Nano Materials Chemistry Lab, Department of Chemistry, Sungkyunkwan University, Suwon, Korea
| | - Pooja Dua
- Department of Microbiology, Goa University, India
| | - Dong Ki Lee
- Global Research Laboratory of RNAi Medicine, Department of Chemistry, Sungkyunkwan University, Suwon, Korea.,CEO, OliX Pharmaceuticals Inc., South Korea
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Litman-Zawadzka A, Łukaszewicz-Zając M, Mroczko B. Novel potential biomarkers for pancreatic cancer - A systematic review. Adv Med Sci 2019; 64:252-257. [PMID: 30844662 DOI: 10.1016/j.advms.2019.02.004] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/02/2018] [Revised: 11/16/2018] [Accepted: 02/22/2019] [Indexed: 12/12/2022]
Abstract
BACKGROUND It is estimated that in developed countries the incidence rate of pancreatic cancer (PC) will continue to rise and by 2020 will be the second most fatal cancer. The mortality of PC patients closely parallels the incidence rate, as this malignancy remains asymptomatic until it reaches an advanced stage of disease. Thus, novel biochemical markers that improve the management of PC patients are necessary. The aim of the work that follows is to investigate whether selected inflammatory mediators might be used in the diagnosis of PC, with the aim of improving the prognosis for PC patients. METHODS We performed a thorough search for literature pertaining to our investigation via the MEDLINE/PubMed database. RESULTS It has been proved that certain inflammatory mediators might be involved in tumor progression, such as growth, proliferation, migration and angiogenesis of tumor cells. In the present review, we summarized and referred to a number of original papers concerning the clinical significance of selected cytokines and specific inflammatory proteins such as C-reactive protein, as well as of various matrix metalloproteinases and their tissue inhibitors, as potential biomarkers for PC in comparison to well-established tumor markers for this malignancy. CONCLUSION Presented proteins might be potential biomarkers in the diagnosis and progression of PC.
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Affiliation(s)
- Ala Litman-Zawadzka
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland
| | | | - Barbara Mroczko
- Department of Neurodegeneration Diagnostics, Medical University of Bialystok, Bialystok, Poland; Department of Biochemical Diagnostics, Medical University of Bialystok, Bialystok, Poland.
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Profiling surface proteins on individual exosomes using a proximity barcoding assay. Nat Commun 2019; 10:3854. [PMID: 31451692 PMCID: PMC6710248 DOI: 10.1038/s41467-019-11486-1] [Citation(s) in RCA: 164] [Impact Index Per Article: 27.3] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/08/2018] [Accepted: 07/08/2019] [Indexed: 01/08/2023] Open
Abstract
Exosomes have been implicated in numerous biological processes, and they may serve as important disease markers. Surface proteins on exosomes carry information about their tissues of origin. Because of the heterogeneity of exosomes it is desirable to investigate them individually, but this has so far remained impractical. Here, we demonstrate a proximity-dependent barcoding assay to profile surface proteins of individual exosomes using antibody-DNA conjugates and next-generation sequencing. We first validate the method using artificial streptavidin-oligonucleotide complexes, followed by analysis of the variable composition of surface proteins on individual exosomes, derived from human body fluids or cell culture media. Exosomes from different sources are characterized by the presence of specific combinations of surface proteins and their abundance, allowing exosomes to be separately quantified in mixed samples to serve as markers for tissue-specific engagement in disease. The use of antibodies to capture and profile exosomes limits the number of target proteins that can be detected. Here the authors develop a proximity-dependent barcoding assay that allows profiling of 38 surface proteins on individual exosomes from heterogeneous samples such as serum and seminal fluid.
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Wu H, Chen X, Ji J, Zhou R, Liu J, Ni W, Qu L, Ni H, Ni R, Bao B, Xiao M. Progress of Exosomes in the Diagnosis and Treatment of Pancreatic Cancer. Genet Test Mol Biomarkers 2019; 23:215-222. [PMID: 30793953 DOI: 10.1089/gtmb.2018.0235] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/13/2022] Open
Abstract
Pancreatic cancer (PC) is a digestive system tumor that is highly malignant, with an increasing incidence rate, poor prognosis, and a low 5-year survival rate. The overwhelming majority of patients with PC are in an advanced stage at the time of diagnosis and have lost the opportunity for radical surgery. The efficacy of radiotherapy and chemotherapy for PC is very poor. Therefore, it is of great significance to explore the mechanisms of PC development and new therapeutic targets. Exosomes are extracellular vesicles that mediate the exchange of substances and information between cells. In recent years, exosomes have been shown to play a key role in the development and progression of PC and might be useful for both its diagnosis and treatment. This article reviews the composition and function of exosomes and their roles in the development, diagnosis, and treatment of PC.
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Affiliation(s)
- Hongpei Wu
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
- 2 Medical College, Nantong University, Nantong, P.R. China
| | - Xiaojun Chen
- 3 Office of Infection Management, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Jie Ji
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
- 2 Medical College, Nantong University, Nantong, P.R. China
| | - Rui Zhou
- 2 Medical College, Nantong University, Nantong, P.R. China
| | - Jinxia Liu
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Wenkai Ni
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Lishuai Qu
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Hongbing Ni
- 4 Department of Laboratory Medicine, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Runzhou Ni
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Baijun Bao
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
| | - Mingbing Xiao
- 1 Department of Gastroenterology, Affiliated Hospital of Nantong University, Nantong, P.R. China
- 5 Research Center of Clinical Medicine, Affiliated Hospital of Nantong University, Nantong, P.R. China
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Moschovis D, Vasilaki E, Tzouvala M, Karamanolis G, Katifelis H, Legaki E, Vezakis A, Aravantinos G, Gazouli M. Association between genetic polymorphisms in long non-coding RNAs and pancreatic cancer risk. Cancer Biomark 2019; 24:117-123. [PMID: 30475759 DOI: 10.3233/cbm-181959] [Citation(s) in RCA: 20] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/30/2022]
Abstract
BACKGROUND Long non-coding RNAs (lncRNAs) are emerging as candidate biomarkers of cancer, having regulatory functions in both oncogenic and tumor-suppressive pathways. Concerning pancreatic cancer (PC), deregulation of lncRNAs involved in tumor initiation, invasion, and metastasis seem to play a key role. However, data is scarce about regulatory mechanism of lncRNA expression. OBJECTIVE The aim of our study was to investigate the contribution of two lncRNAs polymorphisms (rs1561927 and rs4759313 of PVT1 and HOTAIR, respectively) in PC susceptibility. METHODS A case-control study was conducted analysing rs1561927 and rs4759313 polymorphisms using DNA collected in a population-based case-control study of pancreatic cancer (111 pancreatic ductal adenocarcinoma cases (PDAC), 56 pancreatic neuroendocrine tumor (PNET), and 125 healthy controls). RESULTS Regarding the PVT1 rs1561927 polymorphism the G allele was significantly overrepresented in both PDAC and PNET patients compared to the controls, while the presence of the HOTAIR rs4759314 G allele was found to be overrepresented in the PNET patients only compared to the controls. The PVT1 rs1561927 AG/GG genotypes were associated with poor overall survival in PDAC patients. CONCLUSIONS Our results suggested that polymorphisms of these two lncRNA polymorphisms implicated in pancreatic carcinogenesis. Further large-scale and functional studies are needed to confirm our results.
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Affiliation(s)
- D Moschovis
- Department of Gastroenterology, General Hospital of Nikea and Piraeus "Agios Panteleimon", Nikea, Greece
| | - E Vasilaki
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - M Tzouvala
- Department of Gastroenterology, General Hospital of Nikea and Piraeus "Agios Panteleimon", Nikea, Greece
| | - G Karamanolis
- Academic Department of Gastroenterology, Laiko General Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - H Katifelis
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - E Legaki
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - A Vezakis
- Second Department of Surgery, Aretaieion University Hospital, Medical School, National and Kapodistrian University of Athens, Athens, Greece
| | - G Aravantinos
- Second Department of Medical Oncology, Agii Anargiri Cancer Hospital, Athens, Greece
| | - M Gazouli
- Department of Basic Medical Sciences, Laboratory of Biology, Medical School, National and Kapodistrian University of Athens, Athens, Greece
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Sattar Z, Ali S, Hussain I, Sattar F, Hussain S, Ahmad S. Diagnosis of pancreatic cancer. THERANOSTIC APPROACH FOR PANCREATIC CANCER 2019:51-68. [DOI: 10.1016/b978-0-12-819457-7.00002-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Mori T, Hamaya Y, Uotani T, Yamade M, Iwaizumi M, Furuta T, Miyajima H, Osawa S, Sugimoto K. Prevalence of elevated microsatellite alterations at selected tetranucleotide repeats in pancreatic ductal adenocarcinoma. PLoS One 2018; 13:e0208557. [PMID: 30532127 PMCID: PMC6285458 DOI: 10.1371/journal.pone.0208557] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 11/19/2018] [Indexed: 01/29/2023] Open
Abstract
Pancreatic ductal adenocarcinoma (PDAC) prognosis remains poor even after complete resection owing to no valuable biomarkers for recurrence and chemosensitivity. Tumors not expressing MSH3 show elevated microsatellite alterations at selected tetranucleotide repeats (EMAST). EMAST reportedly occurs in several tumors. In colorectal cancer (CRC), EMAST was reportedly correlated with 5-fluorouracil (5-FU) sensitivity. However, EMAST prevalence in PDAC and its significance as a prognostic biomarker are unknown. This study aimed to investigate EMAST prevalence in PDAC and the associations between EMAST and pathological factors, EMAST and prognosis, and EMAST and MSH3 expression via immunohistochemistry (IHC). We assessed 40 PDAC patients undergoing surgery. Genomic DNA was extracted from tumors and normal tissues. EMAST and microsatellite instability-high (MSI-H) were analyzed using five polymorphic tetranucleotide markers and five mononucleotide markers, respectively. Tumor sections were stained for MSH3, and staining intensity was evaluated via the Histoscore (H-score). Eighteen of 40 (45%) PDAC patients were EMAST-positive; however, none were MSI-H-positive. Clinicopathological characteristics including overall survival (OS) and recurrence-free survival (RFS) were not significantly different between EMAST-positive and EMAST-negative patients (P = 0.45, 0.98 respectively). IHC was performed to evaluate MSH3 protein expression levels for the PDAC tissue specimens. H-scores of EMAST-positive patients ranged from 0 to 300 (median, 40) and those of EMAST-negative patients ranged from 0 to 300 (median, 170). MSH3 protein was not significantly downregulated in EMAST-positive patients (P = 0.07). This study is a preliminary study and the number of cases investigated was small, and thus, study of a larger cohort will reveal the clinical implication of EMAST.
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Affiliation(s)
- Taiki Mori
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Yasushi Hamaya
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahiro Uotani
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Mihoko Yamade
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Moriya Iwaizumi
- Laboratory Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Takahisa Furuta
- Center for Clinical Research, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Hiroaki Miyajima
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
| | - Satoshi Osawa
- Department of Endoscopic and Photodynamic Medicine, Hamamatsu, Japan
| | - Ken Sugimoto
- First Department of Medicine, Hamamatsu University School of Medicine, Hamamatsu, Japan
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Sanh N, Fadul H, Hussein N, Lyn-Cook BD, Hammons G, Ramos-Cardona XE, Mohamed K, Mohammed SI. Proteomics Profiling of Pancreatic Cancer and Pancreatitis for Biomarkers Discovery. ACTA ACUST UNITED AC 2018; 9. [PMID: 31032145 DOI: 10.4172/2157-7013.1000287] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Pancreatic cancer is one of the most aggressive malignancies with an increase in incidence predicted, particularly in African Americans. Pancreatic cancer is considered a silent disease with poor prognosis and a lack of early biomarkers for detection. Proteomics has been applied in many diseases for identifying or discovering biomarkers. It has long been suggested that chronic pancreatitis may be a risk factor for developing pancreatic cancer. This study identified proteins that are altered in expression in pancreatic cancer and pancreatitis compared to normal using proteomic technology. Proteins were extracted from laser captured micro-dissected tissues and separated in 2-DPAGE and imaged. The protein profiles of pancreatic cancer and pancreatitis are similar but differed with the protein profile of normal adjacent tissues. Representative proteins, overexpressed in tumor and pancreatitis but not normal tissues, were excised from gels, subjected to in-gel digestion, and analyzed by MALDI-TOF mass spectrometry. Proteins identified included transferrin, ER-60 protein, proapolipoprotein, tropomyosin 1, alpha 1 actin precursor, ACTB protein, and gamma 2 propeptide, aldehyde dehydrogenase 1A1, pancreatic lipase and annexin A1. Several proteins, which were shown in pancreatic cancer, were also observed in pancreatitis samples. Understanding the role of these specific proteins and their mechanistic action will give insights into their involvement in pancreatic cancers.
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Affiliation(s)
- N Sanh
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - H Fadul
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - N Hussein
- Franklin College, IUPUI- Indiana University Purdue University Indianapolis, Indianapolis, USA
| | - B D Lyn-Cook
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA
| | - G Hammons
- Division of Biochemical Toxicology, National Center for Toxicological Research, Jefferson, USA
| | - X E Ramos-Cardona
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
| | - K Mohamed
- Radiation and Isotopes Center Khartoum (RICK), Sudan
| | - S I Mohammed
- Department of Comparative Pathobiology and Purdue University Center for Cancer Research, Purdue University, West Lafayette, USA
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