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1
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Cheng JJ, Matsumoto Y, Dombek GE, Stackhouse KA, Ore AS, Glickman JN, Heimburg-Molinaro J, Cummings RD. Differential expression of CD175 and CA19-9 in pancreatic adenocarcinoma. Sci Rep 2025; 15:4177. [PMID: 39905057 PMCID: PMC11794684 DOI: 10.1038/s41598-025-86988-8] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/16/2024] [Accepted: 01/15/2025] [Indexed: 02/06/2025] Open
Abstract
Alterations in protein glycosylation are observed in many solid tumor types leading to formation of tumor-associated carbohydrate antigens (TACAs). The most common TACA is the Tn antigen (CD175), which is a mucin-type O-GalNAc-Ser/Thr/Tyr glycan in membrane and secreted glycoproteins. In addition, two other TACAs are CA19-9 (sialyl-Lewis a), which is used as a prognostic serum marker for pancreatic cancer, and its isomer sialyl-Lewis x (SLex, CD15s), which is overexpressed in many cancer types and associated with metastasis. While CD175 and other TACAs may be expressed by many human carcinomas, little is known about their differential expression patterns in tumors, thus limiting their use as tissue biomarkers or therapeutic targets. Here we address the clinicopathological relevance of the expression of CA19-9, CD15s, and CD175 in pancreatic ductal adenocarcinoma (PDAC) tissues. Semi-quantitative IHC staining with well-defined monoclonal antibodies demonstrates that CD175 is expressed in all PDAC specimens analyzed. Unexpectedly, however, these TACAs are differentially expressed within PDAC specimens and their glycoproteins, but not significantly expressed in adjacent normal tissues. These data provide avenues for novel therapeutic approaches that could combine CD175- and CA19-9-targeting therapies for PDAC patients.
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Affiliation(s)
- Jane J Cheng
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Yasuyuki Matsumoto
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
- FDA/CDER/OBQ/OBP/DBRRIII, Silver Spring, MD, USA
| | - Gabrielle E Dombek
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Kathryn A Stackhouse
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
- Department of Surgery, Cleveland Clinic, Cleveland, OH, USA
| | - Ana Sofia Ore
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Jonathan N Glickman
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, 330 Brookline Avenue, E106, Boston, MA, 02115, USA
| | - Jamie Heimburg-Molinaro
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA
| | - Richard D Cummings
- Department of Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, 3 Blackfan Circle, CLS-11090, Boston, MA, 02115, USA.
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Corradi C, Gentiluomo M, Adsay V, Sainz J, Camisa PR, Wlodarczyk B, Crippa S, Tavano F, Capurso G, Campa D. Multi-omic markers of intraductal papillary mucinous neoplasms progression into pancreatic cancer. Semin Cancer Biol 2025; 109:25-43. [PMID: 39733817 DOI: 10.1016/j.semcancer.2024.12.005] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/23/2024] [Revised: 12/19/2024] [Accepted: 12/23/2024] [Indexed: 12/31/2024]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most lethal and common form of pancreatic cancer, it has no specific symptoms, and most of the patients are diagnosed when the disease is already at an advanced stage. Chemotherapy typically has only a modest effect, making surgery the most effective treatment option. However, only a small percentage of patients are amenable to surgery. One viable strategy to reduce PDAC death burden associated with the disease is to focus on precursor lesions and identify markers able to predict who will evolve into PDAC. While most PDACs are believed to be preceded by pancreatic intraepithelial neoplasms (PanINs), 5-10 % arise from Intraductal papillary mucinous neoplasms (IPMNs), which are mass-forming cystic lesions that are very common in the general population. IPMNs offer an invaluable model of pancreatic carcinogenesis for researchers to analyse, as well as a target population for PDAC early detection by clinicians. The evolution of IPMN into cancer is a complex and multistep process, therefore the identification of individual markers will not be the solution. In recent years, multiple omics technologies have been instrumental to identify possible biomarkers of IPMN progression and carcinogenesis. The only foreseeable strategy will be to integrate multi-omics data, alongside clinical and morphological features, into a progression score or signature using either standard epidemiologic tools or artificial intelligence. The aim of this manuscript is to review the current knowledge on genetic biomarkers and to briefly mention also additional omics, such as metabolomics, the exposome, the miRNome and epigenomics of IPMNs.
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Affiliation(s)
| | | | - Volkan Adsay
- Department of Pathology, Koç University School of Medicine and Koç University Research Center for Translational Medicine, Istanbul, Turkey
| | - Juan Sainz
- Department of Biochemistry and Molecular Biology, University of Granada, Granada, Spain
| | - Paolo Riccardo Camisa
- Division of Pancreatic Surgery and Transplantation, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Barbara Wlodarczyk
- Department of Digestive Tract Diseases, Medical University of Lodz, Lodz, Poland
| | - Stefano Crippa
- Division of Pancreatic Surgery and Transplantation, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy; Vita-Salute San Raffaele University, Milan, Italy
| | - Francesca Tavano
- Division of Gastroenterology and Research Laboratory, Fondazione IRCCS "Casa Sollievo della Sofferenza" Hospital, San Giovanni Rotondo, Italy
| | - Gabriele Capurso
- Vita-Salute San Raffaele University, Milan, Italy; Pancreato-Biliary Endoscopy and Endosonography Division, Pancreas Translational and Clinical Research Center, IRCCS San Raffaele Scientific Institute, Milan, Italy
| | - Daniele Campa
- Department of Biology, University of Pisa, Pisa, Italy.
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Ruma SA, Vinod R, Jain S, Huhtinen K, Hynninen J, Leivo J, Pettersson K, Sundfeldt K, Gidwani K. MUC1 and glycan probing of CA19-9 captured biomarkers from cyst fluids and serum provides enhanced recognition of ovarian cancer. Sci Rep 2025; 15:3171. [PMID: 39863644 PMCID: PMC11762729 DOI: 10.1038/s41598-025-86735-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2024] [Accepted: 01/13/2025] [Indexed: 01/30/2025] Open
Abstract
Glycosylation changes of circulating proteins carrying the CA19-9 antigen may offer new targets for detection methods to be explored for the diagnosis of epithelial ovarian cancer (EOC). Search for assay designs for targets initially captured by a CA19-9 antigen reactive antibody from human body fluids by probing with fluorescent nanoparticles coated with lectins or antibodies to known EOC associated proteins. CA19-9 antigens were immobilized from ascites fluids, ovarian cyst fluids or serum samples using monoclonal antibody C192 followed by probing of carrier proteins using anti-MUC16, anti-MUC1 and, anti STn antibodies and seven lectins, all separately coated on nanoparticles. Compared to reference CA19-9 and CA125 immunoassays, nanoparticle aided detection using MUC16, Ma695 and STn antibodies and lectin WGA provided, both separately and combined, improved discrimination of EOC and borderline cancers from benign samples when applied to 60 cyst fluid specimens. When applied to a panel of 44 serum samples (EOC N = 24, healthy and benign samples N = 20) two assays, CA19-9Ma695 and CA19-9MUC1, stood out with equally superior separations (p-values < 10-8) of the two groups compared to conventional CA19-9 immunoassay (p-value 0.03).Eu+3 -NP based CA19-9MUC16, CA19-9Ma695, CA19-9STn and CA19-9WGA show promise for improved EOC detection when applied to ascites & cyst fluids. When applied to circulation-derived samples, the two MUC1 based assays, CA19-9Ma695 and CA19-9Ma552 outperformed other assay constructs. Our results call for further validation in larger EOC cohorts preferentially with early stage ovarian cancers and all major histotypes against commonly occurring benign conditions.
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Affiliation(s)
- Shamima Afrin Ruma
- Department of Life Technologies, Division of Biotechnology, University of Turku, Medisiina D, 5th floor, Kiinamyllynkatu 10, 20520, Turku, Finland.
| | - Rufus Vinod
- Department of Life Technologies, Division of Biotechnology, University of Turku, Medisiina D, 5th floor, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Shruti Jain
- Department of Life Technologies, Division of Biotechnology, University of Turku, Medisiina D, 5th floor, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Kaisa Huhtinen
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Johanna Hynninen
- Institute of Biomedicine and FICAN West Cancer Centre, University of Turku and Turku University Hospital, Turku, Finland
| | - Janne Leivo
- Department of Life Technologies, Division of Biotechnology, University of Turku, Medisiina D, 5th floor, Kiinamyllynkatu 10, 20520, Turku, Finland
- InFLAMES Research Flagship, University of Turku, 20014, Turku, Finland
| | - Kim Pettersson
- Department of Life Technologies, Division of Biotechnology, University of Turku, Medisiina D, 5th floor, Kiinamyllynkatu 10, 20520, Turku, Finland
| | - Karin Sundfeldt
- Department of Obstetrics and Gynecology, Institute of Clinical Sciences, Sahlgrenska Center for Cancer Research, University of Gothenburg, Gothenberg, Sweden
| | - Kamlesh Gidwani
- Department of Life Technologies, Division of Biotechnology, University of Turku, Medisiina D, 5th floor, Kiinamyllynkatu 10, 20520, Turku, Finland
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Nakisa A, Sempere LF, Chen X, Qu LT, Woldring D, Crawford HC, Huang X. Tumor-Associated Carbohydrate Antigen 19-9 (CA 19-9), a Promising Target for Antibody-Based Detection, Diagnosis, and Immunotherapy of Cancer. ChemMedChem 2024; 19:e202400491. [PMID: 39230966 PMCID: PMC11648843 DOI: 10.1002/cmdc.202400491] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 08/30/2024] [Accepted: 09/03/2024] [Indexed: 09/06/2024]
Abstract
Carbohydrate antigen 19-9 (CA 19-9) also known as sialyl Lewis A is a tetrasaccharide overexpressed on a wide range of cancerous cells. CA 19-9 has been detected at elevated levels in sera of patients with various types of malignancies, most prominently pancreatic ductal adenocarcinoma. After its identification in 1979, multiple studies have highlighted the significant roles of CA 19-9 in cancer progression, including facilitating extravasation and eventually metastases, proliferation of cancer cells, and suppression of the immune system. Therefore, CA 19-9 has been considered an attractive target for cancer diagnosis, prognosis, and therapy. This review discusses the synthesis of CA 19-9 antigen, elicitation of antibodies through vaccination, development of anti-CA 19-9 monoclonal antibodies, and their applications as imaging tracers and therapeutics for a variety of CA 19-9-positive cancer.
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Affiliation(s)
- Athar Nakisa
- Department of ChemistryMichigan State UniversityEast Lansing, Michigan48824United States
- Institute for Quantitative Health Science and EngineeringMichigan State UniversityEast Lansing, Michigan48824United States
| | - Lorenzo F. Sempere
- Precision Health Program and Department of RadiologyMichigan State UniversityEast Lansing, Michigan48824United States
| | - Xi Chen
- Department of ChemistryUniversity of CaliforniaDavis, California95616USA
| | - Linda T. Qu
- Department of SurgeryMichigan State UniversityEast Lansing, Michigan48824United States
| | - Daniel Woldring
- Institute for Quantitative Health Science and EngineeringMichigan State UniversityEast Lansing, Michigan48824United States
- Department of Chemical Engineering and Materials ScienceMichigan State UniversityEast Lansing, Michigan48824United States
| | - Howard C. Crawford
- Department of SurgeryHenry Ford Health SystemDetroit, Michigan48202United States
- Department of Pharmacology and ToxicologyMichigan State UniversityEast Lansing, Michigan48824United States
| | - Xuefei Huang
- Department of ChemistryMichigan State UniversityEast Lansing, Michigan48824United States
- Institute for Quantitative Health Science and EngineeringMichigan State UniversityEast Lansing, Michigan48824United States
- Department of Biomedical EngineeringMichigan State UniversityEast Lansing, Michigan48824United States
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Bhandare MS, Gupta V, Chaudhari V, Nandy K, Ostwal V, Ramaswamy A, Nashikkar C, Engineer R, Krishnatry R, Shrikhande SV. Differential impact of incrementally elevated CA 19-9 levels on prognosis of resected pancreatic ductal adenocarcinoma. HPB (Oxford) 2024; 26:1237-1247. [PMID: 38944571 DOI: 10.1016/j.hpb.2024.06.004] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 04/29/2024] [Revised: 06/11/2024] [Accepted: 06/12/2024] [Indexed: 07/01/2024]
Abstract
BACKGROUND CA 19-9 is an extremely useful biomarker for pancreatic ductal adenocarcinomas (PDACs). However, the optimal cut-off and prognostic significance at higher cut-offs are yet to be determined. METHODS Retrospective analysis included patients with PDAC who underwent curative resection from January 2010 to May 2020 at Tata Memorial Centre, Mumbai. The pretherapy CA 19-9 was dichotomized using various cut-off levels and analysed. RESULTS In 244 included patients, the median overall survival (OS) for those with CA19-9 level (IU/ml) < or >78, 200, 500, 1000, and 2000 was 27, 24, 23, 22, 21 months versus 18, 16, 15, 14, 13 months; respectively, and was statistically significant (p-value- 0.002, 0.001, 0.002, 0.002 and 0.004, respectively). The number of recurrences and mortality had significant correlation with CA 19-9 cut-offs. On multivariate analysis, adjuvant treatment completion (p-0.004) and decreasing or stable CA19-9 after Neoadjuvant therapy (NAT) (p- 0.031) were associated with improved OS. CONCLUSION The prognostic significance of CA 19-9 was observed at all the cut-off levels examined, beyond mere elevated value as per the standard cut-off level. In patients with high CA19-9 level, surgery should be offered if technically and conditionally feasible, only when a response in CA19-9 level to NAT is achieved.
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Affiliation(s)
- Manish S Bhandare
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai 400012, Maharashtra, India.
| | - Vikas Gupta
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai 400012, Maharashtra, India
| | - Vikram Chaudhari
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai 400012, Maharashtra, India
| | - Kunal Nandy
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai 400012, Maharashtra, India
| | - Vikas Ostwal
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | - Anant Ramaswamy
- Department of Medical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai, Maharashtra, India
| | | | - Reena Engineer
- Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra, India
| | - Rahul Krishnatry
- Department of Radiation Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Parel, Mumbai, Maharashtra, India
| | - Shailesh V Shrikhande
- Gastrointestinal and Hepato-Pancreato-Biliary Service, Department of Surgical Oncology, Tata Memorial Hospital, Homi Bhabha National Institute, Mumbai 400012, Maharashtra, India
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Nakahashi H, Oda T, Shimomura O, Akashi Y, Takahashi K, Miyazaki Y, Furuta T, Kuroda Y, Louphrasitthiphol P, Mathis BJ, Tateno H. Aberrant Glycosylation in Pancreatic Ductal Adenocarcinoma 3D Organoids Is Mediated by KRAS Mutations. JOURNAL OF ONCOLOGY 2024; 2024:1529449. [PMID: 38528852 PMCID: PMC10963106 DOI: 10.1155/2024/1529449] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Figures] [Subscribe] [Scholar Register] [Received: 09/02/2023] [Revised: 01/23/2024] [Accepted: 02/28/2024] [Indexed: 03/27/2024]
Abstract
Aberrant glycosylation in tumor cells is a hallmark during carcinogenesis. KRAS gene mutations are the most well-known oncogenic abnormalities but their association with glycan alterations in pancreatic ductal adenocarcinoma (PDAC) is largely unknown. We employed patient-derived 3D organoids to culture pure live PDAC cells, excluding contamination by fibroblasts and immune cells, to gasp the comprehensive cancer cell surface glycan expression profile using lectin microarray and transcriptomic analyses. Surgical specimens from 24 PDAC patients were digested and embedded into a 3D culture system. Surface-bound glycans of 3D organoids were analyzed by high-density, 96-lectin microarrays. KRAS mutation status and expression of various glycosyltransferases were analyzed by RNA-seq. We successfully established 16 3D organoids: 14 PDAC, 1 intraductal papillary mucinous neoplasm (IPMN), and 1 normal pancreatic duct. KRAS was mutated in 13 (7 G12V, 5 G12D, 1 Q61L) and wild in 3 organoids (1 normal duct, 1 IPMN, 1 PDAC). Lectin reactivity of AAL (Aleuria aurantia) and AOL (Aspergillus oryzae) with binding activity to α1-3 fucose was higher in organoids with KRAS mutants than those with KRAS wild-type. FUT6 (α1-3fucosyltransferase 6) and FUT3 (α1-3/4 fucosyltransferase 3) expression was also higher in KRAS mutants than wild-type. Meanwhile, mannose-binding lectin (rRSL [Ralstonia solanacearum] and rBC2LA [Burkholderia cenocepacia]) signals were higher while those of galactose-binding lectins (rGal3C and rCGL2) were lower in the KRAS mutants. We demonstrated here that PDAC 3D-cultured organoids with KRAS mutations were dominantly covered in increased fucosylated glycans, pointing towards novel treatment targets and/or tumor markers.
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Affiliation(s)
- Hiromitsu Nakahashi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Tatsuya Oda
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Osamu Shimomura
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Yoshimasa Akashi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Kazuhiro Takahashi
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Yoshihiro Miyazaki
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Tomoaki Furuta
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Yukihito Kuroda
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Pakavarin Louphrasitthiphol
- Department of Gastrointestinal and Hepato-Biliary-Pancreatic Surgery, Faculty of Medicine, University of Tsukuba, Tsukuba 305-8575, Japan
| | - Bryan J. Mathis
- International Medical Center, University of Tsukuba Hospital, Tsukuba, Japan
| | - Hiroaki Tateno
- Biotechnology Research Institute for Drug Discovery, National Institute of Advanced Industrial Science and Technology, Tsukuba 305-8568, Japan
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Gu Q, Zhao H, Zhu T, Lu Y, Lin Y, Yuan H, Lan M. Oriented assembly of hydrophilic nanochains modified by porous zirconium-based coordination polymers for glycopeptides analysis. Talanta 2024; 267:125165. [PMID: 37688895 DOI: 10.1016/j.talanta.2023.125165] [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: 04/07/2023] [Revised: 08/21/2023] [Accepted: 09/04/2023] [Indexed: 09/11/2023]
Abstract
Mass spectrometry (MS)-based glycoproteomics research requires additional sample pretreatment to improve the effective identification of low-abundance glycopeptides without interference from non-glycoproteins. Herein, an attractive strategy using resorcinol-formaldehyde (RF) resin and zirconium-based coordination polymer (Zr-BCP) was established to prepare one-dimensional porous coordination polymer composites for glycopeptide enrichment before MS analysis. The obtained Fe3O4@RF@Zr-BCP nanochains feature excellent magnetic response (42.26 emu/g), high hydrophilicity (16.0°), and large specific surface area (140.84 m2/g), which provides abundant affinity sites for specific capture of glycopeptides. The materials exhibit outstanding performance in the enrichment of glycopeptides in terms of sensitivity (15 fmol/μL IgG), selectivity (1:200, molar ratio of IgG/BSA), loading capacity (200 mg/g) and recovery (106.4 ± 3.5%). In addition, the developed method based on Fe3O4@RF@Zr-BCP has been successfully applied to capture glycopeptides in tryptic digest of mouse teratoma cell extracts. It is worth emphasizing that compared with dispersed nanoparticles, the one-dimensional chain structure brings extraordinary reusability to Fe3O4@RF@Zr-BCP nanochains, which is conducive to the rapid cyclic enrichment of glycopeptides. This present work provides a potential enrichment platform for comprehensive glycoprotein analysis, and opens a new avenue for the application of oriented-assembly nanochains.
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Affiliation(s)
- Qinying Gu
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Hongli Zhao
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
| | - Tianyi Zhu
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Yichen Lu
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Yunfan Lin
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Huihui Yuan
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China
| | - Minbo Lan
- Shanghai Key Laboratory of Functional Materials Chemistry, School of Chemistry and Molecular Engineering, East China University of Science and Technology, Shanghai, 200237, People's Republic of China; Research Center of Analysis and Test, East China University of Science and Technology, Shanghai, 200237, People's Republic of China.
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8
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Bahado‐Singh RO, Turkoglu O, Aydas B, Vishweswaraiah S. Precision oncology: Artificial intelligence, circulating cell-free DNA, and the minimally invasive detection of pancreatic cancer-A pilot study. Cancer Med 2023; 12:19644-19655. [PMID: 37787018 PMCID: PMC10587955 DOI: 10.1002/cam4.6604] [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: 05/23/2023] [Revised: 09/18/2023] [Accepted: 09/20/2023] [Indexed: 10/04/2023] Open
Abstract
BACKGROUND Pancreatic cancer (PC) is among the most lethal cancers. The lack of effective tools for early detection results in late tumor detection and, consequently, high mortality rate. Precision oncology aims to develop targeted individual treatments based on advanced computational approaches of omics data. Biomarkers, such as global alteration of cytosine (CpG) methylation, can be pivotal for these objectives. In this study, we performed DNA methylation profiling of pancreatic cancer patients using circulating cell-free DNA (cfDNA) and artificial intelligence (AI) including Deep Learning (DL) for minimally invasive detection to elucidate the epigenetic pathogenesis of PC. METHODS The Illumina Infinium HD Assay was used for genome-wide DNA methylation profiling of cfDNA in treatment-naïve patients. Six AI algorithms were used to determine PC detection accuracy based on cytosine (CpG) methylation markers. Additional strategies for minimizing overfitting were employed. The molecular pathogenesis was interrogated using enrichment analysis. RESULTS In total, we identified 4556 significantly differentially methylated CpGs (q-value < 0.05; Bonferroni correction) in PC versus controls. Highly accurate PC detection was achieved with all 6 AI platforms (Area under the receiver operator characteristics curve [0.90-1.00]). For example, DL achieved AUC (95% CI): 1.00 (0.95-1.00), with a sensitivity and specificity of 100%. A separate modeling approach based on logistic regression-based yielded an AUC (95% CI) 1.0 (1.0-1.0) with a sensitivity and specificity of 100% for PC detection. The top four biological pathways that were epigenetically altered in PC and are known to be linked with cancer are discussed. CONCLUSION Using a minimally invasive approach, AI, and epigenetic analysis of circulating cfDNA, high predictive accuracy for PC was achieved. From a clinical perspective, our findings suggest that that early detection leading to improved overall survival may be achievable in the future.
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Affiliation(s)
- Ray O. Bahado‐Singh
- Department of Obstetrics and GynecologyCorewell Health – William Beaumont University HospitalRoyal OakMichiganUSA
| | - Onur Turkoglu
- Department of Obstetrics and GynecologyCorewell Health – William Beaumont University HospitalRoyal OakMichiganUSA
| | - Buket Aydas
- Department of Care Management AnalyticsBlue Cross Blue Shield of MichiganDetroitMichiganUSA
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9
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Matsumoto Y, Ju T. Aberrant Glycosylation as Immune Therapeutic Targets for Solid Tumors. Cancers (Basel) 2023; 15:3536. [PMID: 37509200 PMCID: PMC10377354 DOI: 10.3390/cancers15143536] [Citation(s) in RCA: 10] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/24/2023] [Revised: 07/01/2023] [Accepted: 07/02/2023] [Indexed: 07/30/2023] Open
Abstract
Glycosylation occurs at all major types of biomolecules, including proteins, lipids, and RNAs to form glycoproteins, glycolipids, and glycoRNAs in mammalian cells, respectively. The carbohydrate moiety, known as glycans on glycoproteins and glycolipids, is diverse in their compositions and structures. Normal cells have their unique array of glycans or glycome which play pivotal roles in many biological processes. The glycan structures in cancer cells, however, are often altered, some having unique structures which are termed as tumor-associated carbohydrate antigens (TACAs). TACAs as tumor biomarkers are glycan epitopes themselves, or glycoconjugates. Some of those TACAs serve as tumor glyco-biomarkers in clinical practice, while others are the immune therapeutic targets for treatment of cancers. A monoclonal antibody (mAb) to GD2, an intermediate of sialic-acid containing glycosphingolipids, is an example of FDA-approved immune therapy for neuroblastoma indication in young adults and many others. Strategies for targeting the aberrant glycans are currently under development, and some have proceeded to clinical trials. In this review, we summarize the currently established and most promising aberrant glycosylation as therapeutic targets for solid tumors.
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Affiliation(s)
- Yasuyuki Matsumoto
- Office of Biotechnology Products, Center for Drug Evaluation and Research, The U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
| | - Tongzhong Ju
- Office of Biotechnology Products, Center for Drug Evaluation and Research, The U.S. Food and Drug Administration, Silver Spring, MD 20993, USA
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10
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Xu Y, Wang Y, Höti N, Clark DJ, Chen SY, Zhang H. The next "sweet" spot for pancreatic ductal adenocarcinoma: Glycoprotein for early detection. MASS SPECTROMETRY REVIEWS 2023; 42:822-843. [PMID: 34766650 PMCID: PMC9095761 DOI: 10.1002/mas.21748] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Received: 07/04/2021] [Revised: 10/07/2021] [Accepted: 10/24/2021] [Indexed: 05/02/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is the most common neoplastic disease of the pancreas, accounting for more than 90% of all pancreatic malignancies. As a highly lethal malignancy, PDAC is the fourth leading cause of cancer-related deaths worldwide with a 5-year overall survival of less than 8%. The efficacy and outcome of PDAC treatment largely depend on the stage of disease at the time of diagnosis. Surgical resection followed by adjuvant chemotherapy remains the only possibly curative therapy, yet 80%-90% of PDAC patients present with nonresectable PDAC stages at the time of clinical presentation. Despite our advancing knowledge of PDAC, the prognosis remains strikingly poor, which is primarily due to the difficulty of diagnosing PDAC at the early stages. Recent advances in glycoproteomics and glycomics based on mass spectrometry have shown that aberrations in protein glycosylation plays a critical role in carcinogenesis, tumor progression, metastasis, chemoresistance, and immuno-response of PDAC and other types of cancers. A growing interest has thus been placed upon protein glycosylation as a potential early detection biomarker for PDAC. We herein take stock of the advancements in the early detection of PDAC that were carried out with mass spectrometry, with special focus on protein glycosylation.
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Affiliation(s)
- Yuanwei Xu
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Yuefan Wang
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Naseruddin Höti
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - David J Clark
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
| | - Shao-Yung Chen
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
| | - Hui Zhang
- Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, Maryland, USA
- Department of Chemical and Biomolecular Engineering, Johns Hopkins University, Baltimore, Maryland, USA
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11
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Pérez-Ginés V, Torrente-Rodríguez RM, Pedrero M, Martínez-Bosch N, de Frutos PG, Navarro P, Pingarrón JM, Campuzano S. Electrochemical immunoplatform to help managing pancreatic cancer. J Electroanal Chem (Lausanne) 2023. [DOI: 10.1016/j.jelechem.2023.117312] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 03/13/2023]
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12
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Marciel MP, Haldar B, Hwang J, Bhalerao N, Bellis SL. Role of tumor cell sialylation in pancreatic cancer progression. Adv Cancer Res 2022; 157:123-155. [PMID: 36725107 PMCID: PMC11342334 DOI: 10.1016/bs.acr.2022.07.003] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/04/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is one of the deadliest malignancies and is currently the third leading cause of cancer death. The aggressiveness of PDAC stems from late diagnosis, early metastasis, and poor efficacy of current chemotherapies. Thus, there is an urgent need for effective biomarkers for early detection of PDAC and development of new therapeutic strategies. It has long been known that cellular glycosylation is dysregulated in pancreatic cancer cells, however, tumor-associated glycans and their cognate glycosylating enzymes have received insufficient attention as potential clinical targets. Aberrant glycosylation affects a broad range of pathways that underpin tumor initiation, metastatic progression, and resistance to cancer treatment. One of the prevalent alterations in the cancer glycome is an enrichment in a select group of sialylated glycans including sialylated, branched N-glycans, sialyl Lewis antigens, and sialylated forms of truncated O-glycans such as the sialyl Tn antigen. These modifications affect the activity of numerous cell surface receptors, which collectively impart malignant characteristics typified by enhanced cell proliferation, migration, invasion and apoptosis-resistance. Additionally, sialic acids on tumor cells engage inhibitory Siglec receptors on immune cells to dampen anti-tumor immunity, further promoting cancer progression. The goal of this review is to summarize the predominant changes in sialylation occurring in pancreatic cancer, the biological functions of sialylated glycoproteins in cancer pathogenesis, and the emerging strategies for targeting sialoglycans and Siglec receptors in cancer therapeutics.
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Affiliation(s)
- Michael P Marciel
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Barnita Haldar
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Jihye Hwang
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Nikita Bhalerao
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States
| | - Susan L Bellis
- Department of Cell, Developmental and Integrative Biology, University of Alabama at Birmingham, Birmingham, AL, United States.
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13
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Cao L, Huang C, Cui Zhou D, Hu Y, Lih TM, Savage SR, Krug K, Clark DJ, Schnaubelt M, Chen L, da Veiga Leprevost F, Eguez RV, Yang W, Pan J, Wen B, Dou Y, Jiang W, Liao Y, Shi Z, Terekhanova NV, Cao S, Lu RJH, Li Y, Liu R, Zhu H, Ronning P, Wu Y, Wyczalkowski MA, Easwaran H, Danilova L, Mer AS, Yoo S, Wang JM, Liu W, Haibe-Kains B, Thiagarajan M, Jewell SD, Hostetter G, Newton CJ, Li QK, Roehrl MH, Fenyö D, Wang P, Nesvizhskii AI, Mani DR, Omenn GS, Boja ES, Mesri M, Robles AI, Rodriguez H, Bathe OF, Chan DW, Hruban RH, Ding L, Zhang B, Zhang H. Proteogenomic characterization of pancreatic ductal adenocarcinoma. Cell 2021; 184:5031-5052.e26. [PMID: 34534465 PMCID: PMC8654574 DOI: 10.1016/j.cell.2021.08.023] [Citation(s) in RCA: 294] [Impact Index Per Article: 73.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/08/2020] [Revised: 03/19/2021] [Accepted: 08/18/2021] [Indexed: 02/07/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is a highly aggressive cancer with poor patient survival. Toward understanding the underlying molecular alterations that drive PDAC oncogenesis, we conducted comprehensive proteogenomic analysis of 140 pancreatic cancers, 67 normal adjacent tissues, and 9 normal pancreatic ductal tissues. Proteomic, phosphoproteomic, and glycoproteomic analyses were used to characterize proteins and their modifications. In addition, whole-genome sequencing, whole-exome sequencing, methylation, RNA sequencing (RNA-seq), and microRNA sequencing (miRNA-seq) were performed on the same tissues to facilitate an integrated proteogenomic analysis and determine the impact of genomic alterations on protein expression, signaling pathways, and post-translational modifications. To ensure robust downstream analyses, tumor neoplastic cellularity was assessed via multiple orthogonal strategies using molecular features and verified via pathological estimation of tumor cellularity based on histological review. This integrated proteogenomic characterization of PDAC will serve as a valuable resource for the community, paving the way for early detection and identification of novel therapeutic targets.
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Affiliation(s)
- Liwei Cao
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Chen Huang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Daniel Cui Zhou
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yingwei Hu
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - T Mamie Lih
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Sara R Savage
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Karsten Krug
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - David J Clark
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Michael Schnaubelt
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Lijun Chen
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | | | | | - Weiming Yang
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Jianbo Pan
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Bo Wen
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yongchao Dou
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Wen Jiang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Yuxing Liao
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Zhiao Shi
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA
| | - Nadezhda V Terekhanova
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Song Cao
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Rita Jui-Hsien Lu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yize Li
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Ruiyang Liu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Houxiang Zhu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Peter Ronning
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Yige Wu
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Matthew A Wyczalkowski
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA
| | - Hariharan Easwaran
- The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ludmila Danilova
- Department of Oncology, Johns Hopkins University, Baltimore, MD 21205, USA
| | - Arvind Singh Mer
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Seungyeul Yoo
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | - Joshua M Wang
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Wenke Liu
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Benjamin Haibe-Kains
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada
| | - Mathangi Thiagarajan
- Leidos Biomedical Research Inc., Frederick National Laboratory for Cancer Research, Frederick, MD 21702, USA
| | - Scott D Jewell
- Van Andel Research Institute, Grand Rapids, MI 49503, USA
| | | | | | - Qing Kay Li
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Michael H Roehrl
- Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA; Human Oncology and Pathogenesis Program, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA
| | - David Fenyö
- Institute for Systems Genetics, NYU Grossman School of Medicine, New York, NY 10016, USA; Department of Biochemistry and Molecular Pharmacology, NYU Grossman School of Medicine, New York, NY 10016, USA
| | - Pei Wang
- Sema4, a Mount Sinai venture, Stamford, CT 06902, USA
| | | | - D R Mani
- Broad Institute of Massachusetts Institute of Technology and Harvard, Cambridge, MA 02142, USA
| | - Gilbert S Omenn
- Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI 48109, USA
| | - Emily S Boja
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Mehdi Mesri
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Ana I Robles
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Henry Rodriguez
- Office of Cancer Clinical Proteomics Research, National Cancer Institute, Bethesda, MD 20892, USA
| | - Oliver F Bathe
- Departments of Surgery and Oncology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada
| | - Daniel W Chan
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA
| | - Ralph H Hruban
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA; The Sol Goldman Pancreatic Cancer Research Center, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Li Ding
- Department of Medicine, Washington University in St. Louis, St. Louis, MO 631110, USA; McDonnell Genome Institute, Washington University in St. Louis, St. Louis, MO 63108, USA.
| | - Bing Zhang
- Lester and Sue Smith Breast Center, Baylor College of Medicine, Houston, TX 77030, USA; Department of Molecular and Human Genetics, Baylor College of Medicine, Houston, TX 77030, USA.
| | - Hui Zhang
- Department of Pathology, Johns Hopkins University, Baltimore, MD 21231, USA; The Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, MD 21287, USA.
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14
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Luo G, Jin K, Deng S, Cheng H, Fan Z, Gong Y, Qian Y, Huang Q, Ni Q, Liu C, Yu X. Roles of CA19-9 in pancreatic cancer: Biomarker, predictor and promoter. Biochim Biophys Acta Rev Cancer 2021; 1875:188409. [PMID: 32827580 DOI: 10.1016/j.bbcan.2020.188409] [Citation(s) in RCA: 177] [Impact Index Per Article: 44.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/01/2020] [Revised: 06/29/2020] [Accepted: 07/20/2020] [Indexed: 02/07/2023]
Abstract
Carbohydrate antigen 19-9 (CA19-9) is the best validated biomarker and an indicator of aberrant glycosylation in pancreatic cancer. CA19-9 functions as a biomarker, predictor, and promoter in pancreatic cancer. As a biomarker, the sensitivity is approximately 80%, and the major challenges involve false positives in conditions of inflammation and nonpancreatic cancers and false negatives in Lewis-negative Individuals. Lewis antigen status should be determined when using CA19-9 as a biomarker. CA19-9 has screening potential when combined with symptoms and/or risk factors. As a predictor, CA19-9 could be used to assess stage, prognosis, resectability, recurrence, and therapeutic efficacy. Normal baseline levels of CA19-9 are associated with long-term survival. As a promoter, CA19-9 could be used to evaluate the biology of pancreatic cancer. CA19-9 can accelerate pancreatic cancer progression by glycosylating proteins, binding to E-selectin, strengthening angiogenesis, and mediating the immunological response. CA19-9 is an attractive therapeutic target for cancer, and strategies include therapeutic antibodies and vaccines, CA19-9-guided nanoparticles, and inhibition of CA19-9 biosynthesis.
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Affiliation(s)
- Guopei Luo
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Kaizhou Jin
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Shengming Deng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - He Cheng
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Zhiyao Fan
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Yitao Gong
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Yunzhen Qian
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Qiuyi Huang
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Quanxing Ni
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China
| | - Chen Liu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China.
| | - Xianjun Yu
- Department of Pancreatic Surgery, Fudan University Shanghai Cancer Center, China; Department of Oncology, Shanghai Medical College, Fudan University, China; Pancreatic Cancer Institute, Fudan University, Shanghai Pancreatic Cancer Institute, China.
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15
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Salleh S, Thyagarajan A, Sahu RP. Exploiting the relevance of CA 19-9 in pancreatic cancer. JOURNAL OF CANCER METASTASIS AND TREATMENT 2020; 6:31. [PMID: 37822969 PMCID: PMC10566512 DOI: 10.20517/2394-4722.2020.70] [Citation(s) in RCA: 4] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/13/2023]
Abstract
Pancreatic ductal adenocarcinoma (PDAC) is currently the fourth most common cause of cancer-related deaths in the United States. It has a poor prognosis and remains a difficulty to treat malignancy. Over the past several decades, significant efforts have been directed towards developing new approaches to enhance the efficacy of therapeutic regimens for PDAC treatment. In recent years, the measurement of serum carbohydrate antigen 19-9 (CA 19-9) has become one of the most validated and extensively used tumour biomarkers for PDAC. In particular, serum CA 19-9 levels have been explored as a validated tool to predict either the signs of disease progression or the response to treatment. However, despite its clinical relevance, the implications on diagnosis or accurately predicting tumour resectability, and monitoring disease symptoms in PDAC patients remains limited. This current review highlights the recent updates on the applicability of CA 19-9, its exploitation, and challenges in predicting the treatment efficacy and responses in PDAC patients.
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Affiliation(s)
- Syaza Salleh
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA
| | - Anita Thyagarajan
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA
| | - Ravi P Sahu
- Department of Pharmacology and Toxicology, Boonshoft School of Medicine Wright State University, Dayton, OH 45435, USA
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16
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Complementary Use of Carbohydrate Antigens Lewis a, Lewis b, and Sialyl-Lewis a (CA19.9 Epitope) in Gastrointestinal Cancers: Biological Rationale Towards A Personalized Clinical Application. Cancers (Basel) 2020; 12:cancers12061509. [PMID: 32527016 PMCID: PMC7352550 DOI: 10.3390/cancers12061509] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2020] [Revised: 06/03/2020] [Accepted: 06/06/2020] [Indexed: 12/14/2022] Open
Abstract
Carbohydrate antigen 19.9 (CA19.9) is used as a tumor marker for clinical and research purposes assuming that it is abundantly produced by gastrointestinal cancer cells due to a cancer-associated aberrant glycosylation favoring its synthesis. Recent data has instead suggested a different picture, where immunodetection on tissue sections matches biochemical and molecular data. In addition to CA19.9, structurally related carbohydrate antigens Lewis a and Lewis b are, in fact, undetectable in colon cancer, due to the down-regulation of a galactosyltransferase necessary for their synthesis. In the pancreas, no differential expression of CA19.9 or cognate glycosyltransferases occurs in cancer. Ductal cells only express such Lewis antigens in a pattern affected by the relative levels of each glycosyltransferase, which are genetically and epigenetically determined. The elevation of circulating antigens seems to depend on the obstruction of neoplastic ducts and loss of polarity occurring in malignant ductal cells. Circulating Lewis a and Lewis b are indeed promising candidates for monitoring pancreatic cancer patients that are negative for CA19.9, but not for improving the low diagnostic performance of such an antigen. Insufficient biological data are available for gastric and bile duct cancer. Studying each patient in a personalized manner determining all Lewis antigens in the surgical specimens and in the blood, together with the status of the tissue-specific glycosylation machinery, promises fruitful advances in translational research and clinical practice.
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17
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Dorrell R, Pawa S, Zhou Y, Lalwani N, Pawa R. The Diagnostic Dilemma of Malignant Biliary Strictures. Diagnostics (Basel) 2020; 10:diagnostics10050337. [PMID: 32466095 PMCID: PMC7277979 DOI: 10.3390/diagnostics10050337] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 05/15/2020] [Accepted: 05/21/2020] [Indexed: 12/13/2022] Open
Abstract
The differential diagnosis for biliary strictures is broad. However, the likelihood of malignancy is high. Determining the etiology of a biliary stricture requires a comprehensive physical exam, laboratory evaluation, imaging, and ultimately tissue acquisition. Even then, definitive diagnosis is elusive, and many strictures remain indeterminant in origin. This literary review examines the diagnostic dilemma of biliary strictures and presents innovations in both histochemical and endoscopic techniques that have increased the diagnostic power of differentiating benign and malignant strictures. The field of tissue biopsy is revolutionizing with the advent of free DNA mutation profiling, fluorescence in situ hybridization (FISH), and methionyl t-RNA synthetase 1 (MARS 1), which allow for greater testing sensitivity. Endoscopic ultrasound, endoscopic retrograde cholangiopancreatography (ERCP), cholangioscopy, confocal laser endomicroscopy, and intraductal ultrasound build upon existing endoscopic technology to better characterize strictures that would otherwise be indeterminate in etiology. This review uses recent literature to insert innovative technology into the traditional framework of diagnostic methods for malignant biliary strictures.
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Affiliation(s)
- Robert Dorrell
- Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
| | - Swati Pawa
- Division of Gastroenterology, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
| | - Yi Zhou
- Department of Pathology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
| | - Neeraj Lalwani
- Department of Radiology, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
| | - Rishi Pawa
- Division of Gastroenterology, Department of Medicine, Wake Forest School of Medicine, Winston-Salem, NC 27157, USA;
- Correspondence:
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18
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Kriz D, Ansari D, Andersson R. Potential biomarkers for early detection of pancreatic ductal adenocarcinoma. Clin Transl Oncol 2020; 22:2170-2174. [PMID: 32447642 PMCID: PMC7578134 DOI: 10.1007/s12094-020-02372-0] [Citation(s) in RCA: 9] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/16/2020] [Accepted: 05/01/2020] [Indexed: 12/12/2022]
Abstract
Pancreatic cancer has the highest mortality amongst all major organ cancers. Early detection is key to reduce deaths related to pancreatic cancer. However, early detection has been challenged by the lack of non-invasive biomarkers with enough sensitivity and specificity to allow for screening. The gold standard is still carbohydrate antigen (CA 19-9), against which all new biomarkers must be evaluated. In this paper, we describe recent progress in the development of new pancreatic cancer biomarkers, focusing on proteins, metabolites, and genetic and epigenetic biomarkers. Although several promising biomarkers have been identified, they are all derived from retrospective studies and additional prospective studies are needed to confirm their clinical validity.
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Affiliation(s)
- D Kriz
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
| | - D Ansari
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden
| | - R Andersson
- Department of Surgery, Clinical Sciences Lund, Skåne University Hospital, Lund University, Lund, Sweden.
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19
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Engle DD, Tiriac H, Rivera KD, Pommier A, Whalen S, Oni TE, Alagesan B, Lee EJ, Yao MA, Lucito MS, Spielman B, Da Silva B, Schoepfer C, Wright K, Creighton B, Afinowicz L, Yu KH, Grützmann R, Aust D, Gimotty PA, Pollard KS, Hruban RH, Goggins MG, Pilarsky C, Park Y, Pappin DJ, Hollingsworth MA, Tuveson DA. The glycan CA19-9 promotes pancreatitis and pancreatic cancer in mice. Science 2020; 364:1156-1162. [PMID: 31221853 DOI: 10.1126/science.aaw3145] [Citation(s) in RCA: 177] [Impact Index Per Article: 35.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2018] [Revised: 03/25/2019] [Accepted: 05/14/2019] [Indexed: 12/12/2022]
Abstract
Glycosylation alterations are indicative of tissue inflammation and neoplasia, but whether these alterations contribute to disease pathogenesis is largely unknown. To study the role of glycan changes in pancreatic disease, we inducibly expressed human fucosyltransferase 3 and β1,3-galactosyltransferase 5 in mice, reconstituting the glycan sialyl-Lewisa, also known as carbohydrate antigen 19-9 (CA19-9). Notably, CA19-9 expression in mice resulted in rapid and severe pancreatitis with hyperactivation of epidermal growth factor receptor (EGFR) signaling. Mechanistically, CA19-9 modification of the matricellular protein fibulin-3 increased its interaction with EGFR, and blockade of fibulin-3, EGFR ligands, or CA19-9 prevented EGFR hyperactivation in organoids. CA19-9-mediated pancreatitis was reversible and could be suppressed with CA19-9 antibodies. CA19-9 also cooperated with the KrasG12D oncogene to produce aggressive pancreatic cancer. These findings implicate CA19-9 in the etiology of pancreatitis and pancreatic cancer and nominate CA19-9 as a therapeutic target.
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Affiliation(s)
- Dannielle D Engle
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Hervé Tiriac
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Keith D Rivera
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Arnaud Pommier
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Sean Whalen
- Gladstone Institutes, San Francisco, CA 94158, USA
| | - Tobiloba E Oni
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Brinda Alagesan
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Eun Jung Lee
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Melissa A Yao
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Matthew S Lucito
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Benjamin Spielman
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Brandon Da Silva
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Christina Schoepfer
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Kevin Wright
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Brianna Creighton
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Lauren Afinowicz
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Kenneth H Yu
- David M. Rubenstein Center for Pancreatic Cancer Research, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA.,Joan and Sanford I. Weill Medical College, Cornell University, New York, NY 10065, USA
| | - Robert Grützmann
- Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Daniela Aust
- Institute for Pathology, Universitätsklinikum Dresden, 01307 Dresden, Germany
| | - Phyllis A Gimotty
- Department of Biostatistics, Epidemiology and Informatics, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Katherine S Pollard
- Gladstone Institutes, San Francisco, CA 94158, USA.,Department of Epidemiology and Biostatistics, Institute for Human Genetics, Quantitative Biology Institute, Institute for Computational Health Sciences, and Chan Zuckerberg Biohub, University of California, San Francisco, San Francisco, CA 94158, USA
| | - Ralph H Hruban
- Sidney Kimmel Cancer Center, The Sol Goldman Pancreatic Cancer Research Center, and Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Michael G Goggins
- Sidney Kimmel Cancer Center, The Sol Goldman Pancreatic Cancer Research Center, and Department of Pathology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA.,Departments of Medicine and Oncology, School of Medicine, Johns Hopkins University, Baltimore, MD 21231, USA
| | - Christian Pilarsky
- Department of Surgery, Universitätsklinikum Erlangen, 91054 Erlangen, Germany
| | - Youngkyu Park
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA.,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Darryl J Pappin
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA
| | - Michael A Hollingsworth
- Eppley Institute for Research in Cancer and Allied Diseases, University of Nebraska Medical Center, Omaha, NE 68198, USA
| | - David A Tuveson
- Cold Spring Harbor Laboratory, Cold Spring Harbor, NY 11724, USA. .,Lustgarten Foundation Pancreatic Cancer Research Laboratory, Cold Spring Harbor, NY 11724, USA
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20
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Dallos MC, Eisenberger AB, Bates SE. Prevention of Venous Thromboembolism in Pancreatic Cancer: Breaking Down a Complex Clinical Dilemma. Oncologist 2020; 25:132-139. [PMID: 32043768 PMCID: PMC7011653 DOI: 10.1634/theoncologist.2019-0264] [Citation(s) in RCA: 13] [Impact Index Per Article: 2.6] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/04/2019] [Accepted: 07/31/2019] [Indexed: 12/14/2022] Open
Abstract
Venous thromboembolism (VTE) frequently occurs in patients with cancer, and particularly those with pancreatic ductal adenocarcinoma (PDAC). Therapeutic anticoagulation with either low-molecular-weight heparin or a direct oral anticoagulant is clearly beneficial in patients who develop a VTE. However, whether thromboprophylaxis improves patient outcomes remains unclear. Studies assessing this risk show a 10%-25% risk of VTE, with reduction to 5%-10% with thromboprophylaxis but no impact on survival. To aid in the risk stratification of patients, several tools have been developed to identify those at highest risk for a VTE event. However, the clinical application of these risk stratification models has been limited, and most patients, even those at the highest risk, will never have a VTE event. New oral anticoagulants have greatly improved the feasibility of prophylaxis but do show increased risk of bleeding in patients with the underlying gastrointestinal dysfunction frequently found in patients with pancreatic cancer. Recently, several completed clinical trials shed new light on this complicated risk versus benefit decision. Here, we present this recent evidence and discuss important considerations for the clinician in determining whether to initiate thromboprophylaxis in patients with PDAC. IMPLICATIONS FOR PRACTICE: Given the high risk of venous thromboembolism in patients with pancreatic adenocarcinoma (PDAC), whether to initiate prophylactic anticoagulation is a complex clinical decision. This review discusses recent evidence regarding the risk stratification and treatment options for thromboprophylaxis in patients with PDAC, with the goal of providing practicing clinicians with updates on recent developments in the field. This article also highlights important considerations for individualizing the treatment approach for a given patient given the lack of general consensus of uniform recommendations for this patient population.
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Affiliation(s)
- Matthew C. Dallos
- Division of Hematology/Oncology, Columbia University Irving Medical CenterNew YorkNew YorkUSA
| | - Andrew B. Eisenberger
- Division of Hematology/Oncology, Columbia University Irving Medical CenterNew YorkNew YorkUSA
| | - Susan E. Bates
- Division of Hematology/Oncology, Columbia University Irving Medical CenterNew YorkNew YorkUSA
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21
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Pan S, Brentnall TA, Chen R. Proteome alterations in pancreatic ductal adenocarcinoma. Cancer Lett 2020; 469:429-436. [PMID: 31734355 PMCID: PMC9017243 DOI: 10.1016/j.canlet.2019.11.020] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2019] [Revised: 11/08/2019] [Accepted: 11/12/2019] [Indexed: 02/07/2023]
Abstract
Proteins are the essential functional biomolecules profoundly implicated in all aspects of pancreatic tumorigenesis and its progression. While common genomic factors, such as KRAS, TP53, SMAD4, and CDKN2A have been well recognized in association of pancreatic ductal adenocarcinoma (PDAC), our understanding of functional changes at the proteome level merits further investigation. Malignance associated proteome alterations can be attributed to the convoluted outcomes from genetic, epigenetic and environmental factors in initiating and progressing PDAC, and may reflect on changes in protein expressional level, structure, localization, as well as post-translational modifications (PTMs) status. The study of localized or systemic proteome alterations in PDAC, as well as its precursor lesions, such as pancreatic intraepithelial neoplasia (PanIN) and mucinous pancreatic cystic neoplasm, would provide unique perspectives in elucidating functional molecular events underlying PDAC. While efforts have been made, challenges still exist to comprehensively integrate much of the proteomic discovery to the perspectives gained from genomic studies in the context of biomarker discovery. Novel approaches and data from well-defined longitudinal clinical studies and experimental models are needed to facilitate the study of PDAC and precursor lesions for early detection and intervention.
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22
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Munkley J. The glycosylation landscape of pancreatic cancer. Oncol Lett 2019; 17:2569-2575. [PMID: 30854032 PMCID: PMC6388511 DOI: 10.3892/ol.2019.9885] [Citation(s) in RCA: 51] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/31/2018] [Accepted: 12/20/2018] [Indexed: 12/21/2022] Open
Abstract
Pancreatic adenocarcinoma is a lethal disease with a 5-year survival rate of <5%, the lowest of all types of cancer. The diagnosis of pancreatic cancer relies on imaging and tissue biopsy, and the only curative therapy is complete surgical resection. Pancreatic cancer has the propensity to metastasise at an early stage and the majority of patients are diagnosed when surgery is no longer an option. Hence, there is an urgent need to identify biomarkers to enable early diagnosis, and to develop new therapeutic strategies. One approach for this involves targeting cancer-associated glycans. The most widely used serological marker in pancreatic cancer is the carbohydrate antigen CA 19-9 which contains a glycan known as sialyl Lewis A (sLeA). The CA 19-9 assay is used routinely to monitor response to treatment, but concerns have been raised about its sensitivity and specificity as a diagnostic biomarker. In addition to sLeA, a wide range of alterations to other important glycans have been observed in pancreatic cancer. These include increases in the sialyl Lewis X antigen (sLex), an increase in truncated O-glycans (Tn and sTn), increased branched and fucosylated N-glycans, upregulation of specific proteoglycans and galectins, and increased O-GlcNAcylation. Growing evidence supports crucial roles for glycans in all stages of cancer progression, and it is well established that glycans regulate tumour proliferation, invasion and metastasis. The present review describes the biological significance of glycans in pancreatic cancer, and discusses the clinical value of exploiting aberrant glycosylation to improve the diagnosis and treatment of this deadly disease.
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Affiliation(s)
- Jennifer Munkley
- Institute of Genetic Medicine, Newcastle University, International Centre for Life, Newcastle upon Tyne NE1 3BZ, UK
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23
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Farley AM, Braxton DR, Li J, Trounson K, Sakar-Dey S, Nayer B, Ikeda T, Lau KX, Hardikar W, Hasegawa K, Pera MF. Antibodies to a CA 19-9 Related Antigen Complex Identify SOX9 Expressing Progenitor Cells In Human Foetal Pancreas and Pancreatic Adenocarcinoma. Sci Rep 2019; 9:2876. [PMID: 30814526 PMCID: PMC6393509 DOI: 10.1038/s41598-019-38988-8] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/01/2017] [Accepted: 01/11/2019] [Indexed: 12/21/2022] Open
Abstract
The Sialyl Lewis A antigen, or CA 19-9, is the prototype serum biomarker for adenocarcinoma of the pancreas. Despite extensive clinical study of CA 19-9 in gastrointestinal malignancies, surprisingly little is known concerning the specific cell types that express this marker during development, tissue regeneration and neoplasia. SOX9 is a transcription factor that plays a key role in these processes in foregut tissues. We report the biochemistry and tissue expression of the GCTM-5 antigen, a pancreatic cancer marker related to, but distinct from, CA19-9. This antigen, defined by two monoclonal antibodies recognising separate epitopes on a large glycoconjugate protein complex, is co-expressed with SOX9 by foregut ductal progenitors in the developing human liver and pancreas, and in pancreatic adenocarcinoma. These progenitors are distinct from cell populations identified by DCLK1, LGR5, or canonical markers of liver and pancreatic progenitor cells. Co-expression of this antigen complex and SOX9 also characterises the ductal metaplasia of submucosal glands that occurs during the development of Barrett’s oesophagus. The GCTM-5 antigen complex can be detected in the sera of patients with pancreatic adenocarcinoma. The GCTM-5 epitope shows a much more restricted pattern of expression in the normal adult pancreas relative to CA19-9. Our findings will aid in the identification, characterisation, and monitoring of ductal progenitor cells during development and progression of pancreatic adenocarcinoma in man.
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Affiliation(s)
- Alison M Farley
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia.,The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia
| | - David R Braxton
- Department of Pathology and Laboratory Medicine, Emory University School of Medicine, Atlanta, GA, USA
| | - Jonathan Li
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Karl Trounson
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | | | - Bhavana Nayer
- Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India
| | - Tatsuhiko Ikeda
- Institute for Integrated Cell-Materials Science, Kyoto University, Kyoto, Japan
| | - Kevin X Lau
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia
| | - Winita Hardikar
- Royal Childrens Hospital, Parkville, Victoria, Australia.,Childrens Medical Research Institute, Parkville, Victoria, Australia
| | - Kouichi Hasegawa
- Institute for Stem Cell Biology and Regenerative Medicine, Bangalore, India.,Institute for Integrated Cell-Materials Science, Kyoto University, Kyoto, Japan
| | - Martin F Pera
- Department of Anatomy and Neuroscience, University of Melbourne, Melbourne, Victoria, Australia. .,Florey Neuroscience and Mental Health Institute, Parkville, Victoria, Australia. .,The Walter and Eliza Hall Institute of Medical Research, Parkville, Victoria, Australia.
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24
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Zhong A, Qin R, Qin W, Han J, Gu Y, Zhou L, Zhang H, Ren S, Lu R, Guo L, Gu J. Diagnostic Significance of Serum IgG Galactosylation in CA19-9-Negative Pancreatic Carcinoma Patients. Front Oncol 2019; 9:114. [PMID: 30873386 PMCID: PMC6402387 DOI: 10.3389/fonc.2019.00114] [Citation(s) in RCA: 6] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2018] [Accepted: 02/07/2019] [Indexed: 01/21/2023] Open
Abstract
Background: Although Carbohydrate antigen 19-9 (CA19-9) is considered clinically useful and informative for pancreatic carcinoma (PC), false positive results, and false negative results have restricted its clinical use. Especially missed or delayed diagnosis of PC patients with negative CA19-9 value limited the utility. To improve prognosis of PC patients, the discovery of reliable biomarkers to assist CA19-9 is desired. Serum IgG galactosylation based on our previous report was altered in PC patients comparing to healthy controls. The objective of this study was to explore the diagnostic significance of IgG galactosylation in assisting CA19-9 for PC in a comprehensive way. Methods: Serum IgG galactosylation profiles were analyzed by MALDI-MS in cohort 1 (n = 252) and cohort 2 in which all CA19-9 levels were negative (n = 133). In each cohort, not only healthy controls and PC patients but also benign pancreatic disease (BPD) patients were enrolled. Peaks were acquired by the software of MALDI-MS sample acquisition, followed by being processed and analyzed by the software of Progenesis MALDI. IgG Gal-ratio, which was calculated from the relative intensity of peaks G0, G1, and G2 according to the formula (G0/(G1+G2×2)), was employed as an index for indicating the distribution of IgG galactosylation. Results: The Gal-ratio was elevated in PC comparing with that in non-cancer group (healthy controls and BPD). The area under the receiver operating characteristic curve (AUC) of IgG Gal-ratio was higher than that of CA19-9 (0.912 vs. 0.814). The performance was further improved when Gal-ratio and CA19-9 were combined (AUC: 0.928). Meanwhile, Gal-ratio also had great diagnostic value with a sensitivity of 92.31% (AUC: 0.883) in detection of PC at early stage. Notably, IgG Gal-ratio has great sensitivity (90.63%) and specificity (76.81%) in CA19-9-negative PC patients. Conclusions: IgG Gal-ratio had a great performance in detection of PC and could be used to assist CA19-9 in improving diagnosis performance through early stage detection, differentiation from BPD, and PC diagnosis with CA19-9-negative level.
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Affiliation(s)
- Ailing Zhong
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Ruihuan Qin
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Wenjun Qin
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Jing Han
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Yong Gu
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Lei Zhou
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China
| | - Hongqin Zhang
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Shifang Ren
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
| | - Renquan Lu
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Lin Guo
- Department of Clinical Laboratory, Shanghai Cancer Center, Fudan University, Shanghai, China.,Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, China
| | - Jianxin Gu
- NHC Key Laboratory of Glycoconjugates Research, Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Fudan University, Shanghai, China
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25
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Abstract
Alteration of glycosylation, a hallmark of cancer, results in the production of tumor-associated glycans or glycoproteins. These molecules are subsequently secreted or membrane-shed into the blood stream and thus serve as tumor-associated markers. Increased glycosylation in cancer is triggered by overexpression of glycoproteins that carry certain specific glycans, increase or decrease of nucleotide sugar donors and altered expression of glycosyltransferase and glycosidase enzymes. In this chapter, the biochemistry and function of glycoprotein, glycan and enzyme markers are reviewed. These glycosylation markers, applicable for detection and monitoring of cancer, include CA19-9, CA125, CEA, PSA and AFP. Because of their specific affinity to distinct sugar moieties, lectins are useful for developing assays to detect these tumor associated glycans and glycoproteins in clinical samples. As such, various enzyme-linked lectin assays (ELLA) have been developed for diagnosis, monitoring and prognosis. Because glycosylation changes occur early in cancer, the detection of tumor associated glycosylation markers using lectin based assays is an effective strategy to improve diagnosis and treatment resulting better outcomes clinically.
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26
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Staal B, Liu Y, Barnett D, Hsueh P, He Z, Gao C, Partyka K, Hurd MW, Singhi AD, Drake RR, Huang Y, Maitra A, Brand RE, Haab BB. The sTRA Plasma Biomarker: Blinded Validation of Improved Accuracy Over CA19-9 in Pancreatic Cancer Diagnosis. Clin Cancer Res 2019; 25:2745-2754. [PMID: 30617132 DOI: 10.1158/1078-0432.ccr-18-3310] [Citation(s) in RCA: 28] [Impact Index Per Article: 4.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/09/2018] [Revised: 11/21/2018] [Accepted: 01/04/2019] [Indexed: 12/20/2022]
Abstract
PURPOSE The CA19-9 biomarker is elevated in a substantial group of patients with pancreatic ductal adenocarcinoma (PDAC), but not enough to be reliable for the detection or diagnosis of the disease. We hypothesized that a glycan called sTRA (sialylated tumor-related antigen) is a biomarker for PDAC that improves upon CA19-9. EXPERIMENTAL DESIGN We examined sTRA and CA19-9 expression and secretion in panels of cell lines, patient-derived xenografts, and primary tumors. We developed candidate biomarkers from sTRA and CA19-9 in a training set of 147 plasma samples and used the panels to make case-control calls, based on predetermined thresholds, in a 50-sample validation set and a blinded, 147-sample test set. RESULTS The sTRA glycan was produced and secreted by pancreatic tumors and models that did not produce and secrete CA19-9. Two biomarker panels improved upon CA19-9 in the training set, one optimized for specificity, which included CA19-9 and 2 versions of the sTRA assay, and another optimized for sensitivity, which included 2 sTRA assays. Both panels achieved statistical improvement (P < 0.001) over CA19-9 in the validation set, and the specificity-optimized panel achieved statistical improvement (P < 0.001) in the blinded set: 95% specificity and 54% sensitivity (75% accuracy), compared with 97%/30% (65% accuracy). Unblinding produced further improvements and revealed independent, complementary contributions from each marker. CONCLUSIONS sTRA is a validated serological biomarker of PDAC that yields improved performance over CA19-9. The new panels may enable surveillance for PDAC among people with elevated risk, or improved differential diagnosis among patients with suspected pancreatic cancer.
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Affiliation(s)
- Ben Staal
- The Van Andel Research Institute, Grand Rapids, Michigan
| | - Ying Liu
- The Van Andel Research Institute, Grand Rapids, Michigan
| | - Daniel Barnett
- The Van Andel Research Institute, Grand Rapids, Michigan.,Michigan State University, East Lansing, Michigan
| | - Peter Hsueh
- The Van Andel Research Institute, Grand Rapids, Michigan.,Michigan State University, East Lansing, Michigan
| | - Zonglin He
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | - ChongFeng Gao
- The Van Andel Research Institute, Grand Rapids, Michigan
| | - Katie Partyka
- The Van Andel Research Institute, Grand Rapids, Michigan
| | | | - Aatur D Singhi
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Richard R Drake
- Medical University of South Carolina, Charleston, South Carolina
| | - Ying Huang
- Fred Hutchinson Cancer Research Center, Seattle, Washington
| | | | - Randall E Brand
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania
| | - Brian B Haab
- The Van Andel Research Institute, Grand Rapids, Michigan.
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27
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Denis JA, Mazzola A, Nguyen G, Lacorte JM, Brochet C, Larsen AK, Conti F. Transient increase of CA 19-9 serum concentrations in a liver transplant recipient with cystic fibrosis and hepatic abscess: a case report and brief literature review. Clin Biochem 2018; 64:53-56. [PMID: 30342018 DOI: 10.1016/j.clinbiochem.2018.10.009] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/19/2018] [Accepted: 10/17/2018] [Indexed: 12/20/2022]
Abstract
CA 19-9 (carbohydrate antigen 19-9) is a tumor marker widely used for surveillance of patients with pancreatic cancer. However, even high levels of CA 19-9 may not necessarily be cancer-associated thereby complicating the diagnosis. This case report highlights a transient increase of CA 19-9 in a triple transplanted patient with cystic fibrosis and continuous immunosuppression for 20 years who was under antibiotics. This case emphasizes the need for a balanced interpretation of biological results, especially in cases where many confounding factors are present such as diabetes, chronic renal failure, cystic fibrosis and infections. This case also provides an opportunity to formulate a number of recommendations for the interpretation of tumor marker results in order to avoid long and costly further investigations.
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Affiliation(s)
- Jérôme A Denis
- Sorbonne Universities, University Pierre et Marie Curie-Paris 6, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Endocrine and Oncological Biochemistry, Paris, France; INSERM U938, Centre de recherche de Saint-Antoine, Cancer Biology and therapeutics, Paris, France.
| | - Alessandra Mazzola
- Sorbonne Universities, University Pierre et Marie Curie-Paris 6, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Medical Unit of Hepatic Transplantation, Department of Hepato-Gastro-Enterology, 75013 Paris, France
| | - Guillaume Nguyen
- Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Endocrine and Oncological Biochemistry, Paris, France
| | - Jean-Marc Lacorte
- Sorbonne Universities, University Pierre et Marie Curie-Paris 6, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Endocrine and Oncological Biochemistry, Paris, France; INSERM, UMR S U1166, ICAN, Paris, France
| | - Christine Brochet
- Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Department of Endocrine and Oncological Biochemistry, Paris, France
| | - Annette K Larsen
- Sorbonne Universities, University Pierre et Marie Curie-Paris 6, Paris, France; INSERM U938, Centre de recherche de Saint-Antoine, Cancer Biology and therapeutics, Paris, France
| | - Filoména Conti
- Sorbonne Universities, University Pierre et Marie Curie-Paris 6, Paris, France; Assistance Publique-Hôpitaux de Paris (AP-HP), Pitié-Salpêtrière Hospital, Medical Unit of Hepatic Transplantation, Department of Hepato-Gastro-Enterology, 75013 Paris, France; INSERM U938, Centre de recherche de Saint-Antoine, Fibro-inflammatory diseases of metabolic and biliary origin of the liver, Paris, France
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28
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Yuan D, Chen H, Wang S, Liu F, Cheng Y, Fang J. Identification of LEA, a podocalyxin-like glycoprotein, as a predictor for the progression of colorectal cancer. Cancer Med 2018; 7:5155-5166. [PMID: 30277651 PMCID: PMC6198229 DOI: 10.1002/cam4.1765] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/17/2018] [Revised: 07/23/2018] [Accepted: 08/08/2018] [Indexed: 01/11/2023] Open
Abstract
Large external antigen (LEA) is considered as a colorectal cancer (CRC)‐associated antigen, which was found via mAb ND‐1 generated using hybridoma technology, but its molecular features remain unknown. To facilitate the clinical application of LEA, we identified LEA as a podocalyxin‐like protein 1 (PODXL) with molecular weight of approximately 230 kDa, a hyperglycosylated protein, using immunoprecipitation and mass spectrometry in combination, and verified that ND‐1‐recognized epitope is on the terminal sialic acid of LEA. Correlation analysis between LEA and PODXL in molecular weight, immunological cross‐reactivity, and gene expression dependence supported the PODXL identity of the LEA. Moreover, we assessed the clinical significance of the LEA in 89 pairs of primary CRC tissues and adjacent nontumor colorectal tissues using ND‐1 by quantum dot‐based immunohistochemistry (QD‐IHC). High LEA expression was correlated significantly with T stage (P = 0.010). Patients with high LEA expression showed significantly poorer prognosis than those with LEA low expression (P = 0.007). Multivariate analysis indicated LEA expression as an independent predictor. Furthermore, the comparative analysis showed that mAb ND‐1‐based IHC analysis toward sugar residue of PODXL has higher sensitivity and specificity to evaluate the LEA/PODXL expression than mAb 3D3‐based method toward core protein of PODXL in CRC cell lines and clinical samples. In addition, we first found that LEA/PODXL can be secreted in exosomes from cancer cells and CRC patient peripheral blood. Our results demonstrate that LEA is an independent predictor for CRC progression and has the potential to be applied for clinical setting with high sensitivity, high specificity, and noninvasive access.
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Affiliation(s)
- Dezheng Yuan
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Hang Chen
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Shuo Wang
- Analytical Instrumentation Center, Shenyang Agricultural University, Shenyang, China
| | - Furong Liu
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Yajie Cheng
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
| | - Jin Fang
- Department of Cell Biology, Key Laboratory of Cell Biology, Ministry of Public Health, Key Laboratory of Medical Cell Biology, Ministry of Education, China Medical University, Shenyang, China
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Abstract
Approximately 75% of patients with pancreatic ductal adenocarcinoma are diagnosed with advanced cancer, which cannot be safely resected. The most commonly used biomarker CA19-9 has inadequate sensitivity and specificity for early detection, which we define as Stage I/II cancers. Therefore, progress in next-generation biomarkers is greatly needed. Recent reports have validated a number of biomarkers, including combination assays of proteins and DNA mutations; however, the history of translating promising biomarkers to clinical utility suggests that several major hurdles require careful consideration by the medical community. The first set of challenges involves nominating and verifying biomarkers. Candidate biomarkers need to discriminate disease from benign controls with high sensitivity and specificity for an intended use, which we describe as a two-tiered strategy of identifying and screening high-risk patients. Community-wide efforts to share samples, data, and analysis methods have been beneficial and progress meeting this challenge has been achieved. The second set of challenges is assay optimization and validating biomarkers. After initial candidate validation, assays need to be refined into accurate, cost-effective, highly reproducible, and multiplexed targeted panels and then validated in large cohorts. To move the most promising candidates forward, ideally, biomarker panels, head-to-head comparisons, meta-analysis, and assessment in independent data sets might mitigate risk of failure. Much more investment is needed to overcome these challenges. The third challenge is achieving clinical translation. To moonshot an early detection test to the clinic requires a large clinical trial and organizational, regulatory, and entrepreneurial know-how. Additional factors, such as imaging technologies, will likely need to improve concomitant with molecular biomarker development. The magnitude of the clinical translational challenge is uncertain, but interdisciplinary cooperation within the PDAC community is poised to confront it.
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Goh SK, Gold G, Christophi C, Muralidharan V. Serum carbohydrate antigen 19-9 in pancreatic adenocarcinoma: a mini review for surgeons. ANZ J Surg 2017; 87:987-992. [PMID: 28803454 DOI: 10.1111/ans.14131] [Citation(s) in RCA: 29] [Impact Index Per Article: 3.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/22/2017] [Accepted: 05/24/2017] [Indexed: 12/12/2022]
Abstract
The optimal management of oncological conditions is reflected by the careful interpretation of investigations for screening, diagnosis, staging, prognostication and surveillance. Serum tumour markers are examples of commonly requested tests in conjunction with other imaging and endoscopic tests that are used to help clinicians to stratify therapeutic decisions. Serum carbohydrate antigen 19-9 (CA19-9) is a key biomarker for pancreatic cancers. Although this biomarker is considered clinically useful and informative, clinicians are often challenged by the accurate interpretation of elevated serum CA19-9 levels. Recognizing the pitfalls of normal and abnormal serum CA19-9 concentrations will facilitate its appropriate use. In this review, we appraised the biomarker, serum CA19-9, and highlighted the clinical utility and limitations of serum CA19-9 in the investigation and management of pancreatic cancers.
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Affiliation(s)
- Su Kah Goh
- Hepato-Pancreato-Biliary and Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
| | - Grace Gold
- Hepato-Pancreato-Biliary and Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
| | - Christopher Christophi
- Hepato-Pancreato-Biliary and Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
| | - Vijayaragavan Muralidharan
- Hepato-Pancreato-Biliary and Transplant Unit, Austin Hospital, Melbourne, Victoria, Australia
- Department of Surgery, The University of Melbourne, Melbourne, Victoria, Australia
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31
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Connecting genetic risk to disease end points through the human blood plasma proteome. Nat Commun 2017; 8:14357. [PMID: 28240269 PMCID: PMC5333359 DOI: 10.1038/ncomms14357] [Citation(s) in RCA: 451] [Impact Index Per Article: 56.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/10/2016] [Accepted: 12/16/2016] [Indexed: 12/29/2022] Open
Abstract
Genome-wide association studies (GWAS) with intermediate phenotypes, like changes in metabolite and protein levels, provide functional evidence to map disease associations and translate them into clinical applications. However, although hundreds of genetic variants have been associated with complex disorders, the underlying molecular pathways often remain elusive. Associations with intermediate traits are key in establishing functional links between GWAS-identified risk-variants and disease end points. Here we describe a GWAS using a highly multiplexed aptamer-based affinity proteomics platform. We quantify 539 associations between protein levels and gene variants (pQTLs) in a German cohort and replicate over half of them in an Arab and Asian cohort. Fifty-five of the replicated pQTLs are located in trans. Our associations overlap with 57 genetic risk loci for 42 unique disease end points. We integrate this information into a genome-proteome network and provide an interactive web-tool for interrogations. Our results provide a basis for novel approaches to pharmaceutical and diagnostic applications. Individual genetic variation can affect the levels of protein in blood, but detailed data sets linking these two types of data are rare. Here, the authors carry out a genome-wide association study of levels of over a thousand different proteins, and describe many new SNP-protein interactions.
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Selectin Ligands Sialyl-Lewis a and Sialyl-Lewis x in Gastrointestinal Cancers. BIOLOGY 2017; 6:biology6010016. [PMID: 28241499 PMCID: PMC5372009 DOI: 10.3390/biology6010016] [Citation(s) in RCA: 68] [Impact Index Per Article: 8.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/10/2017] [Revised: 02/17/2017] [Accepted: 02/20/2017] [Indexed: 12/20/2022]
Abstract
The tetrasaccharide structures Siaα2,3Galβ1,3(Fucα1,4)GlcNAc and Siaα2,3Galβ1,4(Fucα1,3)GlcNAc constitute the epitopes of the carbohydrate antigens sialyl-Lewis a (sLea) and sialyl-Lewis x (sLex), respectively, and are the minimal requirement for selectin binding to their counter-receptors. Interaction of sLex expressed on the cell surface of leucocytes with E-selectin on endothelial cells allows their arrest and promotes their extravasation. Similarly, the rolling of cancer cells ectopically expressing the selectin ligands on endothelial cells is potentially a crucial step favoring the metastatic process. In this review, we focus on the biosynthetic steps giving rise to selectin ligand expression in cell lines and native tissues of gastrointestinal origin, trying to understand whether and how they are deregulated in cancer. We also discuss the use of such molecules in the diagnosis of gastrointestinal cancers, particularly in light of recent data questioning the ability of colon cancers to express sLea and the possible use of circulating sLex in the early detection of pancreatic cancer. Finally, we reviewed the data dealing with the mechanisms that link selectin ligand expression in gastrointestinal cells to cancer malignancy. This promising research field seems to require additional data on native patient tissues to reach more definitive conclusions.
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Pan S, Brentnall TA, Chen R. Glycoproteins and glycoproteomics in pancreatic cancer. World J Gastroenterol 2016; 22:9288-9299. [PMID: 27895417 PMCID: PMC5107693 DOI: 10.3748/wjg.v22.i42.9288] [Citation(s) in RCA: 47] [Impact Index Per Article: 5.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/29/2016] [Revised: 08/23/2016] [Accepted: 09/14/2016] [Indexed: 02/06/2023] Open
Abstract
Aberrations in protein glycosylation and polysaccharides play a pivotal role in pancreatic tumorigenesis, influencing cancer progression, metastasis, immuno-response and chemoresistance. Abnormal expression in sugar moieties can impact the function of various glycoproteins, including mucins, surface receptors, adhesive proteins, proteoglycans, as well as their effectors and binding ligands, resulting in an increase in pancreatic cancer invasiveness and a cancer-favored microenvironment. Recent advance in glycoproteomics, glycomics and other chemical biology techniques have been employed to better understand the complex mechanism of glycosylation events and how they orchestrate molecular activities in genomics, proteomics and metabolomics implicated in pancreatic adenocarcinoma. A variety of strategies have been demonstrated targeting protein glycosylation and polysaccharides for diagnostic and therapeutic development.
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Aronica A, Avagliano L, Caretti A, Tosi D, Bulfamante GP, Trinchera M. Unexpected distribution of CA19.9 and other type 1 chain Lewis antigens in normal and cancer tissues of colon and pancreas: Importance of the detection method and role of glycosyltransferase regulation. Biochim Biophys Acta Gen Subj 2016; 1861:3210-3220. [PMID: 27535614 DOI: 10.1016/j.bbagen.2016.08.005] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Revised: 07/29/2016] [Accepted: 08/12/2016] [Indexed: 12/20/2022]
Abstract
BACKGROUND CA19.9 antigen has been assumed as an abundant product of cancer cells, due to the reactivity found by immunohistochemical staining of cancer tissues with anti-CA19.9 antibody. METHODS Expression and biosynthesis of type 1 chain Lewis antigens in the colon and the pancreas were studied by immunodetection in tissue sections and lysates, quantification of glycosyltransferase transcripts, bisulfite sequencing, and chromatin immunoprecipitation assays. RESULTS CA19.9 was poorly detectable in normal colon mucosa and almost undetectable in colon cancer, while it was easily detected in the pancreatic ducts, together with Lewis b antigen, under both normal and cancer conditions. B3GALT5 transcripts were down-regulated in colon cancer, while they remained expressed in pancreatic cancer. Even ST3GAL3 transcript appeared well expressed in the pancreas but poorly in the colon, irrespective of normal or cancer conditions. CpG islands flanking B3GALT5 native promoter presented an extremely low degree of methylation in pancreatic cancer with respect to colon cancer. In a DNA region about 1kb away from the B3GALT5 retroviral promoter, a stretch of CG dinucleotides presented a methylation pattern potentially associated with transcription. Such a DNA region and the transcription factor binding site provided overlapping results by chromatin immunoprecipitation assays, corroborating the hypothesis. CONCLUSIONS CA19.9 appears as a physiological product whose synthesis strongly depends on the tissue specific and epigenetically-regulated expression of B3GALT5 and ST3GAL3. GENERAL SIGNIFICANCE CA19.9 and other Lewis antigens acquire tumor marker properties in the pancreas due to mechanisms giving rise to reabsorption into vessels and elevation in circulating levels.
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Affiliation(s)
- Adele Aronica
- Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy
| | - Laura Avagliano
- Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy
| | - Anna Caretti
- Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy
| | - Delfina Tosi
- Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy
| | - Gaetano Pietro Bulfamante
- Department of Health Sciences, San Paolo Hospital Medical School, University of Milan, 20142 Milano, Italy; Unit of Human Pathology, Cytogenetics and Molecular Biology, ASST Santi Paolo e Carlo, 20142 Milano, Italy
| | - Marco Trinchera
- Department of Medicine Clinical and Experimental (DMCS), University of Insubria Medical School, 21100 Varese, Italy.
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35
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D’Costa JJ, Goldsmith JC, Wilson JS, Bryan RT, Ward DG. A Systematic Review of the Diagnostic and Prognostic Value of Urinary Protein Biomarkers in Urothelial Bladder Cancer. Bladder Cancer 2016; 2:301-317. [PMID: 27500198 PMCID: PMC4969711 DOI: 10.3233/blc-160054] [Citation(s) in RCA: 70] [Impact Index Per Article: 7.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
For over 80 years, cystoscopy has remained the gold-standard for detecting tumours of the urinary bladder. Since bladder tumours have a tendency to recur and progress, many patients are subjected to repeated cystoscopies during long-term surveillance, with the procedure being both unpleasant for the patient and expensive for healthcare providers. The identification and validation of bladder tumour specific molecular markers in urine could enable tumour detection and reduce reliance on cystoscopy, and numerous classes of biomarkers have been studied. Proteins represent the most intensively studied class of biomolecule in this setting. As an aid to researchers searching for better urinary biomarkers, we report a comprehensive systematic review of the literature and a searchable database of proteins that have been investigated to date. Our objective was to classify these proteins as: 1) those with robustly characterised sensitivity and specificity for bladder cancer detection; 2) those that show potential but further investigation is required; 3) those unlikely to warrant further investigation; and 4) those investigated as prognostic markers. This work should help to prioritise certain biomarkers for rigorous validation, whilst preventing wasted effort on proteins that have shown no association whatsoever with the disease, or only modest biomarker performance despite large-scale efforts at validation.
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Affiliation(s)
- Jamie J. D’Costa
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - James C. Goldsmith
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Jayne S. Wilson
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
- Cancer Research UK Clinical Trials Unit, Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Richard T. Bryan
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
| | - Douglas G. Ward
- Institute of Cancer and Genomic Sciences, College of Medical and Dental Sciences, University of Birmingham, Birmingham, UK
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36
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37
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Soares AC, Soares JC, Shimizu FM, Melendez ME, Carvalho AL, Oliveira ON. Controlled Film Architectures to Detect a Biomarker for Pancreatic Cancer Using Impedance Spectroscopy. ACS APPLIED MATERIALS & INTERFACES 2015; 7:25930-7. [PMID: 26539972 DOI: 10.1021/acsami.5b08666] [Citation(s) in RCA: 29] [Impact Index Per Article: 2.9] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/20/2023]
Abstract
The need for analytical devices for detecting cancer at early stages has motivated research into nanomaterials where synergy is sought to achieve high sensitivity and selectivity in low-cost biosensors. In this study, we developed a film architecture combining self-assembled monolayer (SAM) and layer-by-layer (LbL) films of polysaccharide chitosan and the protein concanavalin A, on which a layer of anti-CA19-9 antibody was adsorbed. Using impedance spectroscopy with this biosensor, we were capable of detecting low concentrations of the antigen CA19-9, an important biomarker for pancreatic cancer. The limit of detection of 0.69U/mL reached is sufficient for detecting pancreatic cancer at very early stages. The selectivity of the biosensor was inferred from a series of control experiments with samples of cell lines that were tested positive (HT29) and negative (SW620) for the biomarker CA19-9, in addition to the lack of changes in the capacitance value for other analytes and antigen that are not related to this type of cancer. The high sensitivity and selectivity are ascribed to the very specific antigen-antibody interaction, which was confirmed with PM-IRRAS and atomic force microscopy. Also significant is that used information visualization methods to show that different cell lines and commercial samples containing distinct concentrations of CA19-9 and other analytes can be easily distinguished from each other. These computational methods are generic and may be used in optimization procedures to tailor biosensors for specific purposes, as we demonstrated here by comparing the performance of two film architectures in which the concentration of chitosan was varied.
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Affiliation(s)
- Andrey C Soares
- São Carlos Institute of Physics, University of São Paulo , 13560-970 São Carlos, São Paulo Brazil
- São Carlos School of Engineering, University of São Paulo , 13560-000 São Carlos, São Paulo, Brazil
| | - Juliana C Soares
- São Carlos Institute of Physics, University of São Paulo , 13560-970 São Carlos, São Paulo Brazil
| | - Flavio M Shimizu
- São Carlos Institute of Physics, University of São Paulo , 13560-970 São Carlos, São Paulo Brazil
| | | | - André L Carvalho
- Barretos Cancer Hospital , 14784-400 Barretos, São Paulo, Brazil
| | - Osvaldo N Oliveira
- São Carlos Institute of Physics, University of São Paulo , 13560-970 São Carlos, São Paulo Brazil
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38
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Haab BB, Huang Y, Balasenthil S, Partyka K, Tang H, Anderson M, Allen P, Sasson A, Zeh H, Kaul K, Kletter D, Ge S, Bern M, Kwon R, Blasutig I, Srivastava S, Frazier ML, Sen S, Hollingsworth MA, Rinaudo JA, Killary AM, Brand RE. Definitive Characterization of CA 19-9 in Resectable Pancreatic Cancer Using a Reference Set of Serum and Plasma Specimens. PLoS One 2015; 10:e0139049. [PMID: 26431551 PMCID: PMC4592020 DOI: 10.1371/journal.pone.0139049] [Citation(s) in RCA: 28] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/18/2015] [Accepted: 09/07/2015] [Indexed: 01/05/2023] Open
Abstract
The validation of candidate biomarkers often is hampered by the lack of a reliable means of assessing and comparing performance. We present here a reference set of serum and plasma samples to facilitate the validation of biomarkers for resectable pancreatic cancer. The reference set includes a large cohort of stage I-II pancreatic cancer patients, recruited from 5 different institutions, and relevant control groups. We characterized the performance of the current best serological biomarker for pancreatic cancer, CA 19–9, using plasma samples from the reference set to provide a benchmark for future biomarker studies and to further our knowledge of CA 19–9 in early-stage pancreatic cancer and the control groups. CA 19–9 distinguished pancreatic cancers from the healthy and chronic pancreatitis groups with an average sensitivity and specificity of 70–74%, similar to previous studies using all stages of pancreatic cancer. Chronic pancreatitis patients did not show CA 19–9 elevations, but patients with benign biliary obstruction had elevations nearly as high as the cancer patients. We gained additional information about the biomarker by comparing two distinct assays. The two CA 9–9 assays agreed well in overall performance but diverged in measurements of individual samples, potentially due to subtle differences in antibody specificity as revealed by glycan array analysis. Thus, the reference set promises be a valuable resource for biomarker validation and comparison, and the CA 19–9 data presented here will be useful for benchmarking and for exploring relationships to CA 19–9.
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Affiliation(s)
- Brian B. Haab
- Van Andel Research Institute, Grand Rapids, MI, United States of America
| | - Ying Huang
- Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | | | - Katie Partyka
- Van Andel Research Institute, Grand Rapids, MI, United States of America
| | - Huiyuan Tang
- Van Andel Research Institute, Grand Rapids, MI, United States of America
| | | | - Peter Allen
- Memorial Sloan Kettering Cancer Center, New York, NY, United States of America
| | - Aaron Sasson
- University of Nebraska Medical Center, Omaha, NE, United States of America
| | - Herbert Zeh
- University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America
| | - Karen Kaul
- Northshore University Healthsystems, Evanston, IL, United States of America
| | - Doron Kletter
- Palo Alto Research Center, Palo Alto, CA, United States of America
| | - Shaokui Ge
- Fred Hutchinson Cancer Research Center, Seattle, WA, United States of America
| | - Marshall Bern
- Palo Alto Research Center, Palo Alto, CA, United States of America
| | - Richard Kwon
- University of Michigan, Ann Arbor, MI, United States of America
| | | | | | - Marsha L. Frazier
- The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Subrata Sen
- The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | | | - Jo Ann Rinaudo
- National Cancer Institute, Rockville, MD, United States of America
| | - Ann M. Killary
- The University of Texas MD Anderson Cancer Center, Houston, TX, United States of America
| | - Randall E. Brand
- University of Pittsburgh Medical Center, Pittsburgh, PA, United States of America
- * E-mail:
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Fernandes E, Peixoto A, Neves M, Afonso LP, Santos LL, Ferreira JA. Humoral response against sialyl-Le(a) glycosylated protein species in esophageal cancer: Insights for immunoproteomic studies. Electrophoresis 2015; 36:2902-7. [PMID: 26333169 DOI: 10.1002/elps.201500270] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/14/2015] [Revised: 07/13/2015] [Accepted: 08/12/2015] [Indexed: 12/18/2022]
Abstract
Esophageal cancers (ECs) show poor prognosis and decreased overall survival due to late diagnosis and ineffective therapeutics, urging the introduction of novel biomarkers to aid disease management. The levels of sialyl-Lewis(a) antigen (sLe(a) ) are frequently increased in digestive tumours, which has been explored in serological non-invasive prognostication (CA19-9 test); however, with low sensitivity and specificity. Autoantibodies against cancer antigens are considered the next generation biomarkers, as they are present in circulation long before tumour-associated proteins. Based on these observations we have mined the serum of EC patients (n = 7) for antibodies against sLe(a) -glycosylated protein species. All EC were positive for sLe(a) , irrespectively of their histological nature but only two patients showed elevated CA19-9. Moreover, IgG titers, with emphasis on IgG1, were elevated in EC patients in comparison to the control group. SLe(a) -glycoproteins were then extracted from tumours of patients with negative CA19-9, isolated by immunoprecipitation and blotted with patients IgG. Autoantibodies against sLe(a) -glycosylated proteins were detected in all cases. Different SLe(a) -glycoproteins were observed for tumours of distinct histological natures, which now require identification and validation in larger patient sets. This preliminary data suggests that antoantibodies against sLe(a) glycosylated proteins hold potential for non-invasive diagnosis in CA19-9 negative cases and sets the rational for future immunoproteomic studies envisaging highly specific EC biomarkers.
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Affiliation(s)
- Elisabete Fernandes
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Institute of Biomedical Sciences of Abel Salazar, University of Porto, Porto, Portugal
| | - Andreia Peixoto
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal
| | - Manuel Neves
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal
| | - Luís Pedro Afonso
- Department of Pathology, Portuguese Institute of Oncology of Porto, Porto, Portugal
| | - Lúcio Lara Santos
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Health School of University of Fernando Pessoa, Porto, Portugal.,Department of Surgical Oncology, Portuguese Institute for Oncology, Porto, Portugal
| | - José Alexandre Ferreira
- Experimental Pathology and Therapeutics Group, Portuguese Institute of Oncology, Porto, Portugal.,Mass Spectrometry Centre, QOPNA, Department of Chemistry of the University of Aveiro, Aveiro, Portugal
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40
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Pan S, Brentnall TA, Chen R. Proteomics analysis of bodily fluids in pancreatic cancer. Proteomics 2015; 15:2705-15. [PMID: 25780901 DOI: 10.1002/pmic.201400476] [Citation(s) in RCA: 46] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/13/2014] [Revised: 02/06/2015] [Accepted: 03/13/2015] [Indexed: 12/12/2022]
Abstract
Proteomics study of pancreatic cancer using bodily fluids emphasizes biomarker discovery and clinical application, presenting unique prospect and challenges. Depending on the physiological nature of the bodily fluid and its proximity to pancreatic cancer, the proteomes of bodily fluids, such as pancreatic juice, pancreatic cyst fluid, blood, bile, and urine, can be substantially different in terms of protein constitution and the dynamic range of protein concentration. Thus, a comprehensive discovery and specific detection of cancer-associated proteins within these varied fluids is a complex task, requiring rigorous experiment design and a concerted approach. While major challenges still remain, fluid proteomics studies in pancreatic cancer to date have provided a wealth of information in revealing proteome alterations associated with pancreatic cancer in various bodily fluids.
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Affiliation(s)
- Sheng Pan
- Department of Medicine, University of Washington, Seattle, WA, USA
| | | | - Ru Chen
- Department of Medicine, University of Washington, Seattle, WA, USA
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41
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Tang H, Hsueh P, Kletter D, Bern M, Haab B. The detection and discovery of glycan motifs in biological samples using lectins and antibodies: new methods and opportunities. Adv Cancer Res 2015; 126:167-202. [PMID: 25727148 DOI: 10.1016/bs.acr.2014.11.003] [Citation(s) in RCA: 21] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/18/2022]
Abstract
Recent research has uncovered unexpected ways that glycans contribute to biology, as well as new strategies for combatting disease using approaches involving glycans. To make full use of glycans for clinical applications, we need more detailed information on the location, nature, and dynamics of glycan expression in vivo. Such studies require the use of specimens acquired directly from patients. Effective studies of clinical specimens require low-volume assays, high precision measurements, and the ability to process many samples. Assays using affinity reagents-lectins and glycan-binding antibodies-can meet these requirements, but further developments are needed to make the methods routine and effective. Recent advances in the use of glycan-binding proteins involve improved determination of specificity using glycan arrays; the availability of databases for mining and analyzing glycan array data; lectin engineering methods; and the ability to quantitatively interpret lectin measurements. Here, we describe many of the challenges and opportunities involved in the application of these new approaches to the study of biological samples. The new tools hold promise for developing methods to improve the outcomes of patients afflicted with diseases characterized by aberrant glycan expression.
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Affiliation(s)
- Huiyuan Tang
- Van Andel Research Institute, Grand Rapids, MI, USA
| | - Peter Hsueh
- Van Andel Research Institute, Grand Rapids, MI, USA
| | | | | | - Brian Haab
- Van Andel Research Institute, Grand Rapids, MI, USA.
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42
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Farina A, Delhaye M, Lescuyer P, Dumonceau JM. Bile proteome in health and disease. Compr Physiol 2014; 4:91-108. [PMID: 24692135 DOI: 10.1002/cphy.c130016] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/16/2022]
Abstract
The study of bile proteins could improve the understanding of physiological processes involved in the regulation of the hepato-biliary system. Researchers have tried for years to investigate the bile proteome but, until recently, only a few tens of proteins were known. The advent of proteomics, availing of large-scale analytical devices paired with potent bioinformatic resources, lately allowed the identification of thousands of proteins in bile. Nevertheless, the knowledge of their role in the hepato-biliary system still represents almost a "blank page in the book of physiology." In this review, we first guide the reader through the historical phases of the analysis of bile protein content, emphasizing the recent progresses achieved through the use of proteomic techniques. Thereafter, we deeply explore the involvement of bile proteins in health and disease, with a particular focus on the discovery of biomarkers for biliary tract malignancies.
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Affiliation(s)
- Annarita Farina
- Biomedical Proteomics Research Group, Department of Human Protein Sciences, Geneva University, Geneva, Switzerland
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Pan S, Chen R, Tamura Y, Crispin DA, Lai LA, May DH, McIntosh MW, Goodlett DR, Brentnall TA. Quantitative glycoproteomics analysis reveals changes in N-glycosylation level associated with pancreatic ductal adenocarcinoma. J Proteome Res 2014; 13:1293-306. [PMID: 24471499 PMCID: PMC3993895 DOI: 10.1021/pr4010184] [Citation(s) in RCA: 77] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/20/2022]
Abstract
Glycosylation plays an important role in epithelial cancers, including pancreatic ductal adenocarcinoma. However, little is known about the glycoproteome of the human pancreas or its alterations associated with pancreatic tumorigenesis. Using quantitative glycoproteomics approach, we investigated protein N-glycosylation in pancreatic tumor tissue in comparison with normal pancreas and chronic pancreatitis tissue. The study lead to the discovery of a roster of glycoproteins with aberrant N-glycosylation level associated with pancreatic cancer, including mucin-5AC (MUC5AC), carcinoembryonic antigen-related cell adhesion molecule 5 (CEACAM5), insulin-like growth factor binding protein (IGFBP3), and galectin-3-binding protein (LGALS3BP). Pathway analysis of cancer-associated aberrant glycoproteins revealed an emerging phenomenon that increased activity of N-glycosylation was implicated in several pancreatic cancer pathways, including TGF-β, TNF, NF-kappa-B, and TFEB-related lysosomal changes. In addition, the study provided evidence that specific N-glycosylation sites within certain individual proteins can have significantly altered glycosylation occupancy in pancreatic cancer, reflecting the complexity of the molecular mechanisms underlying cancer-associated glycosylation events.
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Affiliation(s)
- Sheng Pan
- The Division of Gastroenterology, Department of Medicine, University of Washington , 1959 North East Pacific Street, Seattle, Washington 98195, United States
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Rho JH, Lampe PD. High-Throughput Analysis of Plasma Hybrid Markers for Early Detection of Cancers. Proteomes 2014; 2:1-17. [PMID: 28250367 PMCID: PMC5302729 DOI: 10.3390/proteomes2010001] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/26/2013] [Revised: 12/17/2013] [Accepted: 01/08/2014] [Indexed: 12/29/2022] Open
Abstract
Biomarkers for the early detection of cancer in the general population have to perform with high sensitivity and specificity in order to prevent the costs associated with over-diagnosis. There are only a few current tissue or blood markers that are recommended for generalized cancer screening. Despite the recognition that combinations of multiple biomarkers will likely improve their utility, biomarker panels are usually limited to a single class of molecules. Tissues and body fluids including plasma and serum contain not only proteins, DNA and microRNAs that are differentially expressed in cancers but further cancer specific information might be gleaned by comparing different classes of biomolecules. For example, the level of a certain microRNA might be related to the level of a particular protein in a cancer specific manner. Proteins might have cancer-specific post-translational modifications (e.g., phosphorylation or glycosylation) or lead to the generation of autoantibodies. Most currently approved biomarkers are glycoproteins. Autoantibodies can be produced as a host's early surveillance response to cancer-specific proteins in pre-symptomatic and pre-diagnostic stages of cancer. Thus, measurement of the level of a protein, the level of its glycosylation or phosphorylation and whether autoantibodies are produced to it can yield multi-dimensional information on each protein. We consider specific proteins that show consistent cancer-specific changes in two or three of these measurements to be "hybrid markers". We hypothesize these markers will suffer less variation between different individuals since one component can act to "standardize" the other measurement. As a proof of principle, a 180 plasma sample set consisting of 120 cases (60 colon cancers and 60 adenomas) and 60 controls were analyzed using our high-density antibody array for changes in their protein, IgG-complex and sialyl-Lewis A (SLeA) modified proteins. At p < 0.05, expression changes in 1,070 proteins, 49 IgG-complexes (11 present in the protein list) and 488 Lewis X-modified proteins (57 on the protein list) were observed. The biomarkers significant on both lists are potential hybrid markers. Thus, plasma hybrid markers have the potential to create a new class of early detection markers of cancers.
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Affiliation(s)
- Jung-Hyun Rho
- Translational Research Program, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
| | - Paul D Lampe
- Translational Research Program, Human Biology and Public Health Sciences Divisions, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue North, Seattle, WA 98109, USA.
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Discovery of sialyl Lewis A and Lewis X modified protein cancer biomarkers using high density antibody arrays. J Proteomics 2013; 96:291-9. [PMID: 24185138 DOI: 10.1016/j.jprot.2013.10.030] [Citation(s) in RCA: 46] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/31/2013] [Revised: 10/05/2013] [Accepted: 10/19/2013] [Indexed: 01/14/2023]
Abstract
UNLABELLED We report on a high-dimensional method to globally profile glycoproteins that are modified with sialyl Lewis A or Lewis X glycans. Specifically, glycoproteins in serum or plasma are fractionated on a high-density antibody microarray (i.e., each are localized to their specific antibody spot) and are specifically detected via fluorescently labeled anti-sialyl Lewis A or anti-Lewis X antibodies with quantification in a microarray scanner. Non-glycosylated proteins or glycoproteins with other glycan motifs do not interfere with this assay. The whole process is very rapid and applicable for high-throughput screening without the need for purification of glycoproteins from the samples. Using these methods, sialyl Lewis A or Lewis X moieties were found to be expressed on many previously unreported secreted or membrane associated proteins. Furthermore, the combination of sialyl Lewis A or Lewis X content with protein level increased the ability of certain glycoproteins to distinguish 30 patients with stage III and IV colon cancer from 60 control samples. Thus, this highly sensitive method is capable of discovering novel specific glycan modifications on proteins, many of which will likely be useful for disease detection and monitoring. BIOLOGICAL SIGNIFICANCE In this paper, we show that we can detect cancer-specific glycan modifications on thousands of proteins using a high-density antibody array paired with a glycan specific antibody to probe the bound glycoproteins. To our knowledge, our array is by far the largest and densest that has ever been used for global profiling of specific glycan modification on proteins. Analysis of colon cancer patient plasma for sialyl Lewis A and Lewis X modifications revealed previously unknown protein carriers of these modifications and significant increases in these specific glycans on some proteins in people with cancer versus healthy controls, suggesting this method could be used to discover novel biomarkers.
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Fallon BP, Curnutte B, Maupin KA, Partyka K, Choi S, Brand RE, Langmead CJ, Tembe W, Haab BB. The Marker State Space (MSS) method for classifying clinical samples. PLoS One 2013; 8:e65905. [PMID: 23750276 PMCID: PMC3672150 DOI: 10.1371/journal.pone.0065905] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2013] [Accepted: 04/30/2013] [Indexed: 01/30/2023] Open
Abstract
The development of accurate clinical biomarkers has been challenging in part due to the diversity between patients and diseases. One approach to account for the diversity is to use multiple markers to classify patients, based on the concept that each individual marker contributes information from its respective subclass of patients. Here we present a new strategy for developing biomarker panels that accounts for completely distinct patient subclasses. Marker State Space (MSS) defines “marker states” based on all possible patterns of high and low values among a panel of markers. Each marker state is defined as either a case state or a control state, and a sample is classified as case or control based on the state it occupies. MSS was used to define multi-marker panels that were robust in cross validation and training-set/test-set analyses and that yielded similar classification accuracy to several other classification algorithms. A three-marker panel for discriminating pancreatic cancer patients from control subjects revealed subclasses of patients based on distinct marker states. MSS provides a straightforward approach for modeling highly divergent subclasses of patients, which may be adaptable for diverse applications.
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Affiliation(s)
- Brian P. Fallon
- Laboratory of Cancer Immunodiagnostics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Bryan Curnutte
- Laboratory of Cancer Immunodiagnostics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Kevin A. Maupin
- Laboratory of Cancer Immunodiagnostics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Katie Partyka
- Laboratory of Cancer Immunodiagnostics, Van Andel Institute, Grand Rapids, Michigan, United States of America
| | - Sunguk Choi
- Carnegie Mellon University, Pittsburgh, Pennsylvania, United States of America
| | - Randall E. Brand
- University of Pittsburgh Medical Center, Pittsburgh, Pennsylvania, United States of America
| | | | - Waibhav Tembe
- Translational Genomics Research Institute, Phoenix, Arizona, United States of America
| | - Brian B. Haab
- Laboratory of Cancer Immunodiagnostics, Van Andel Institute, Grand Rapids, Michigan, United States of America
- * E-mail:
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Usefulness of MALDI-TOF/MS identification of low-MW fragments in sera for the differential diagnosis of pancreatic cancer. Pancreas 2013; 42:622-32. [PMID: 23271396 DOI: 10.1097/mpa.0b013e318273096c] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/05/2023]
Abstract
OBJECTIVES To identify new biomarkers of pancreatic cancer (PaCa), we performed MALDI-TOF/MS analysis of sera from 22 controls, 51 PaCa, 37 chronic pancreatitis, 24 type II diabetes mellitus (DM), 29 gastric cancer (GC), and 24 chronic gastritis (CG). METHODS Sera were purified by Sep-Pak C18 before MALDI-TOF/MS Anchorchip analysis. RESULTS Features present in at least 5% of all spectra were selected (n = 160, m/z range, 1200-5000). At univariate analysis, 2 features (m/z 2049 and 2305) correlated with PaCa, 3 (m/z 1449, 1605, and 2006) with DM. No feature characterized gastric cancer or chronic gastritis. Ten-fold cross-validation binary recursive partitioning trees were obtained for patients' classification. The tree (CA 19-9, age, m/z 2006, 2599, 2753, and 4997), built considering only patients with diabetes, allowed a distinction between DM [area under the receiver operating characteristic curve (AUC), 0.997], chronic pancreatitis (AUC, 0.968), and PaCa (AUC, 0.980), with an overall correct classification rate of 89%. The tree including CA 19-9, 1550, and 2937 m/z features, achieved an AUC of 0.970 in distinguishing localized from advanced PaCa. MALDI-TOF-TOF analysis revealed the 1550 feature as a fragment of Apo-A1, which was determined as whole protein and demonstrated to be closely correlated with PaCa. CONCLUSIONS The findings made demonstrate a role for serum peptides identified using MALDI-TOF/MS for addressing PaCa diagnosis.
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Chandler K, Goldman R. Glycoprotein disease markers and single protein-omics. Mol Cell Proteomics 2013; 12:836-45. [PMID: 23399550 PMCID: PMC3617330 DOI: 10.1074/mcp.r112.026930] [Citation(s) in RCA: 49] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2012] [Revised: 02/07/2013] [Indexed: 12/14/2022] Open
Abstract
Glycoproteins are well represented among biomarkers for inflammatory and cancer diseases. Secreted and membrane-associated glycoproteins make excellent targets for noninvasive detection. In this review, we discuss clinically applicable markers of cancer diseases and methods for their analysis. High throughput discovery continues to supply marker candidates with unusual glycan structures, altered glycoprotein abundance, or distribution of site-specific glycoforms. Improved analytical methods are needed to unlock the potential of these discoveries in validated clinical assays. A new generation of targeted quantitative assays is expected to advance the use of glycoproteins in early detection of diseases, molecular disease classification, and monitoring of therapeutic interventions.
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Affiliation(s)
- Kevin Chandler
- From the Departments of ‡Biochemistry and Molecular and Cellular Biology and
| | - Radoslav Goldman
- From the Departments of ‡Biochemistry and Molecular and Cellular Biology and
- ¶Oncology, Georgetown University, Washington, D.C. 20057
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CA19.9 antigen circulating in the serum of colon cancer patients: Where is it from? Int J Biochem Cell Biol 2013; 45:792-7. [DOI: 10.1016/j.biocel.2013.01.004] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2012] [Revised: 12/03/2012] [Accepted: 01/08/2013] [Indexed: 01/17/2023]
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Remmers N, Anderson JM, Linde EM, DiMaio DJ, Lazenby AJ, Wandall HH, Mandel U, Clausen H, Yu F, Hollingsworth MA. Aberrant expression of mucin core proteins and o-linked glycans associated with progression of pancreatic cancer. Clin Cancer Res 2013; 19:1981-93. [PMID: 23446997 DOI: 10.1158/1078-0432.ccr-12-2662] [Citation(s) in RCA: 132] [Impact Index Per Article: 11.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
PURPOSE Mucin expression is a common feature of most adenocarcinomas and features prominently in current attempts to improve diagnosis and therapy for pancreatic cancer and other adenocarcinomas. We investigated the expression of a number of mucin core proteins and associated O-linked glycans expressed in pancreatic adenocarcinoma-sialyl Tn (STn), Tn, T antigen, sialyl Lewis A (CA19-9), sialyl Lewis C (SLeC), Lewis X (LeX), and sialyl LeX (SLeX)-during the progression of pancreatic cancer from early stages to metastatic disease. EXPERIMENTAL DESIGN Immunohistochemical analyses of mucin and associated glycan expression on primary tumor and liver metastatic tumor samples were conducted with matched sets of tissues from 40 autopsy patients diagnosed with pancreatic adenocarcinoma, 14 surgically resected tissue samples, and 8 normal pancreata. RESULTS There were significant changes in mucin expression patterns throughout disease progression. MUC1 and MUC4 were differentially glycosylated as the disease progressed from early pancreatic intraepithelial neoplasias to metastatic disease. De novo expression of several mucins correlated with increased metastasis indicating a potentially more invasive phenotype, and we show the expression of MUC6 in acinar cells undergoing acinar to ductal metaplasia. A "cancer field-effect" that included changes in mucin protein expression and glycosylation in the adjacent normal pancreas was also seen. CONCLUSIONS There are significant alterations in mucin expression and posttranslational processing during progression of pancreatic cancer from early lesions to metastasis. The results are presented in the context of how mucins influence the biology of tumor cells and their microenvironment during progression of pancreatic cancer.
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Affiliation(s)
- Neeley Remmers
- Department of Biochemistry and Molecular Biology, University of Nebraska Medical Center, Omaha, Nebraska 68198, USA
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