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Tanabe H, Uehara T, Ota H. Cell lineage-specific immunohistochemical markers in biliary intraepithelial neoplasia: Implications for subclassification and grading. Pathol Res Pract 2025; 269:155896. [PMID: 40056752 DOI: 10.1016/j.prp.2025.155896] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/27/2024] [Revised: 03/02/2025] [Accepted: 03/03/2025] [Indexed: 03/10/2025]
Abstract
Biliary intraepithelial neoplasia (BilIN), a precursor to cholangiocarcinoma, is categorized into low- and high-grade based on histological characteristics. Although gastric, intestinal, and biliary phenotypes of BilIN have been identified, detailed analyses of their immunophenotypic profiles using cell lineage-specific markers remain limited. This study aimed to define the immunohistochemical profiles of BilIN lesions, subclassify them based on their immunophenotypes, and correlate these profiles with histological grades. We examined 77 BilIN lesions from extrahepatic bile ducts, including 30 low- and 47 high-grade lesions, using immunohistochemical staining for gastric (claudin-18, MUC5AC), intestinal (cadherin-17, glycoprotein A33), and biliary (carbohydrate sulfotransferase 4) markers, along with progression markers (S100P, IMP3). Expression levels were semiquantitatively scored and correlated with histopathological features. BilIN lesions were classified into four immunophenotypes: gastric (G-type), intestinal (I-type), gastrointestinal (GI-type), and biliary (B-type). Low-grade lesions comprised G- (33.3 %), GI- (40 %), I- (13.3 %), and B-types (13.3 %), while high-grade lesions included G- (40.4 %), GI- (29.8 %), I- (21.3 %), and B-types (8.5 %). In low-grade BilIN, G-type lesions corresponded to gastric mucous cells, I-type to intestinal epithelial cells, and B-type to bile duct epithelial cells, while most GI-type lesions exhibited mixed G- and I-type components. High-grade BilIN differentiation based solely on histological characteristics was challenging to delineate due to overlapping features among I-, GI-, and B-type cells. S100P and IMP3 expression levels were significantly elevated in high-grade lesions, particularly within the I+B-type BilIN group, with no notable differences in G- or GI-type BilIN. Immunophenotypic profiling with lineage-specific markers effectively subclassified BilIN, enhancing the understanding of its histogenesis and progression.
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Affiliation(s)
- Heiwa Tanabe
- Department of Health and Medical Sciences, Shinshu University Graduate School of Medicine, Matsumoto, Japan.
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, Matsumoto, Japan.
| | - Hiroyoshi Ota
- Department of Medical Sciences, Shinshu University Graduate School of Medicine, Science and Technology, Matsumoto, Japan.
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2
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Babu H, Rachel G, Neogi U, Palaniappan AN, Narayanan A, Ponnuraja C, Sundaraj V, Viswanathan VK, Kumar CPG, Tripathy SP, Hanna LE. Accelerated cognitive aging in chronically infected HIV-1 positive individuals despite effective long-term antiretroviral therapy. Metab Brain Dis 2024; 40:32. [PMID: 39570517 DOI: 10.1007/s11011-024-01458-w] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/08/2024] [Accepted: 09/24/2024] [Indexed: 11/22/2024]
Abstract
People living with HIV (PLHIV) are known to be at a higher risk of developing an array of aging-related diseases despite well-adhered combined antiretroviral therapy (cART). The present study aimed to investigate the impact of chronic HIV infection on neurocognitive function in virally suppressed PLHIV. We enrolled HIV-positive individuals randomly from an ART Center in Chennai, South India. A similar number of HIV-uninfected individuals matched for age and gender with the HIV-infected individuals served as controls. All individuals provided a detailed clinical history and underwent neuropsychological assessment using the International HIV Dementia Scale (IHDS). Plasma proteome analysis was performed using the Proximity extension assay (PEA) with the Olink® neuroexploratory panel, and untargeted metabolomics was performed using Ultra-High-Performance Liquid Chromatography/Mass Spectrometry/Mass Spectrometry. Despite a median duration of 9 years on first-line cART and suppressed viremia, a significant proportion of PLHIV registered significant levels of asymptomatic neurocognitive impairment, with 71% of these individuals scoring ≤ 10 in the IHDS test. We also observed significant alterations in a number of proteins and metabolites that are known to be associated with neuroinflammation, neurodegeneration, cognitive impairment, and gastrointestinal cancers, in the PLHIV group. Thus the study provides clinical as well as laboratory evidence to substantiate the presence of asymptomatic neurocognitive impairment in a large proportion of PLHIV, despite adequate cART and undetectable viremia, thereby supporting the view that HIV infection potentiates the risk for accelerated and accentuated neurological aging. This observation highlights the need to devise and implement appropriate intervention strategies for better long term management of HIV-infected persons.
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Affiliation(s)
- Hemalatha Babu
- Department of Virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis, Chennai, 600031, India
| | - Gladys Rachel
- Department of Virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis, Chennai, 600031, India
- Laboratory Sciences, ICMR-National Institute of Epidemiology, Chennai, 600077, India
| | - Ujjwal Neogi
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152, Huddinge, Sweden
| | | | - Aswathy Narayanan
- Division of Clinical Microbiology, Department of Laboratory Medicine, Karolinska Institutet, 14152, Huddinge, Sweden
| | - Chinnaiyan Ponnuraja
- Department of Virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis, Chennai, 600031, India
| | - Vijila Sundaraj
- Government Hospital of Thoracic Medicine, Tambaram Sanatorium, Chennai, 600047, India
| | | | - C P Girish Kumar
- Laboratory Sciences, ICMR-National Institute of Epidemiology, Chennai, 600077, India
| | - Srikanth P Tripathy
- Department of Virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis, Chennai, 600031, India
| | - Luke Elizabeth Hanna
- Department of Virology and Biotechnology, ICMR-National Institute for Research in Tuberculosis, Chennai, 600031, India.
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Fu D, Zhang B, Fan W, Zeng F, Feng J, Wang X. Fatty acid metabolism prognostic signature predicts tumor immune microenvironment and immunotherapy, and identifies tumorigenic role of MOGAT2 in lung adenocarcinoma. Front Immunol 2024; 15:1456719. [PMID: 39478862 PMCID: PMC11521851 DOI: 10.3389/fimmu.2024.1456719] [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: 06/29/2024] [Accepted: 10/01/2024] [Indexed: 11/02/2024] Open
Abstract
Background Aberrant fatty acid metabolism (FAM) plays a critical role in the tumorigenesis of human malignancies. However, studies on its impact in lung adenocarcinoma (LUAD) are limited. Methods We developed a prognostic signature comprising 10 FAM-related genes (GPR115, SOAT2, CDH17, MOGAT2, COL11A1, TCN1, LGR5, SLC34A2, RHOV, and DKK1) using data from LUAD patients in The Cancer Genome Atlas (TCGA). This signature was validated using six independent LUAD datasets from the Gene Expression Omnibus (GEO). Patients were classified into high- and low-risk groups, and overall survival (OS) was compared by Kaplan-Meier analysis. The signature's independence as a prognostic indicator was assessed after adjusting for clinicopathological features. Receiver operating characteristic (ROC) analysis validated the signature. Tumor immune microenvironment (TIME) was analyzed using ESTIMATE and multiple deconvolution algorithms. Functional assays, including CCK8, cell cycle, apoptosis, transwell, and wound healing assays, were performed on MOGAT2-silenced H1299 cells using CRISPR/Cas9 technology. Results Low-risk group patients exhibited decreased OS. The signature was an independent prognostic indicator and demonstrated strong risk-stratification utility for disease relapse/progression. ROC analysis confirmed the signature's validity across validation sets. TIME analysis revealed higher infiltration of CD8+ T cells, natural killers, and B cells, and lower tumor purity, stemness index, and tumor mutation burden (TMB) in low-risk patients. These patients also showed elevated T cell receptor richness and diversity, along with reduced immune cell senescence. High-risk patients exhibited enrichment in pathways related to resistance to immune checkpoint blockades, such as DNA repair, hypoxia, epithelial-mesenchymal transition, and the G2M checkpoint. LUAD patients receiving anti-PD-1 treatment had lower risk scores among responders compared to non-responders. MOGAT2 was expressed at higher levels in low-risk LUAD patients. Functional assays revealed that MOGAT2 knockdown in H1299 cells promoted proliferation and migration, induced G2 cell cycle arrest, and decreased apoptosis. Conclusions This FAM-related gene signature provides a valuable tool for prognostic stratification and monitoring of TIME and immunotherapy responses in LUAD. MOGAT2 is identified as a potential anti-tumor regulator, offering new insights into its role in LUAD pathogenesis.
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Affiliation(s)
- Denggang Fu
- College of Medicine, Medical University of South Carolina, Charleston, SC, United States
| | - Biyu Zhang
- Key Laboratory of Green Chemical Engineering Process of Ministry of Education, School of Chemical Engineering and Pharmacy, Wuhan Institute of Technology, Wuhan, China
| | - Wenyan Fan
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang, Jiangxi, China
| | - Fanfan Zeng
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang, Jiangxi, China
- Jiangxi Provincial Key Laboratory of Preventive Medicine, School of Public Health, Nanchang University, Nanchang, Jiangxi, China
| | - Jueping Feng
- Department of Oncology, Wuhan Fourth Hospital, Wuhan, Hubei, China
| | - Xin Wang
- Jiangxi Provincial Key Laboratory of Cell Precision Therapy, School of Basic Medical Sciences, Jiujiang University, Jiujiang, Jiangxi, China
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Malmros K, Lindholm A, Vidarsdottir H, Jirström K, Nodin B, Botling J, Mattsson JSM, Micke P, Planck M, Jönsson M, Staaf J, Brunnström H. Diagnostic gastrointestinal markers in primary lung cancer and pulmonary metastases. Virchows Arch 2024; 485:347-357. [PMID: 37349623 PMCID: PMC11329406 DOI: 10.1007/s00428-023-03583-w] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2023] [Revised: 06/05/2023] [Accepted: 06/15/2023] [Indexed: 06/24/2023]
Abstract
Histopathological diagnosis of pulmonary tumors is essential for treatment decisions. The distinction between primary lung adenocarcinoma and pulmonary metastasis from the gastrointestinal (GI) tract may be difficult. Therefore, we compared the diagnostic value of several immunohistochemical markers in pulmonary tumors. Tissue microarrays from 629 resected primary lung cancers and 422 resected pulmonary epithelial metastases from various sites (whereof 275 colorectal cancer) were investigated for the immunohistochemical expression of CDH17, GPA33, MUC2, MUC6, SATB2, and SMAD4, for comparison with CDX2, CK20, CK7, and TTF-1. The most sensitive markers for GI origin were GPA33 (positive in 98%, 60%, and 100% of pulmonary metastases from colorectal cancer, pancreatic cancer, and other GI adenocarcinomas, respectively), CDX2 (99/40/100%), and CDH17 (99/0/100%). In comparison, SATB2 and CK20 showed higher specificity, with expression in 5% and 10% of mucinous primary lung adenocarcinomas and both in 0% of TTF-1-negative non-mucinous primary lung adenocarcinomas (25-50% and 5-16%, respectively, for GPA33/CDX2/CDH17). MUC2 was negative in all primary lung cancers, but positive only in less than half of pulmonary metastases from mucinous adenocarcinomas from other organs. Combining six GI markers did not perfectly separate primary lung cancers from pulmonary metastases including subgroups such as mucinous adenocarcinomas or CK7-positive GI tract metastases. This comprehensive comparison suggests that CDH17, GPA33, and SATB2 may be used as equivalent alternatives to CDX2 and CK20. However, no single or combination of markers can categorically distinguish primary lung cancers from metastatic GI tract cancer.
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Affiliation(s)
- Karina Malmros
- Division of Pathology, Department of Clinical Sciences Lund, Lund University, SE-221 00, Lund, Sweden
| | - Andreas Lindholm
- Department of Genetics and Pathology, Laboratory Medicine Region Skåne, SE-205 02, Malmö, Sweden
| | - Halla Vidarsdottir
- Division of Pathology, Department of Clinical Sciences Lund, Lund University, SE-221 00, Lund, Sweden
- Department of Surgery, Landspitali University Hospital, Hringbraut, 101, Reykjavik, Iceland
| | - Karin Jirström
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, SE-221 00, Lund, Sweden
- Department of Genetics and Pathology, Laboratory Medicine Region Skåne, SE-221 85, Lund, Sweden
| | - Björn Nodin
- Division of Oncology and Therapeutic Pathology, Department of Clinical Sciences Lund, Lund University, SE-221 00, Lund, Sweden
| | - Johan Botling
- Department of Immunology, Genetics and Pathology, Uppsala University and Uppsala University Hospital, SE-751 85, Uppsala, Sweden
| | - Johanna S M Mattsson
- Department of Immunology, Genetics and Pathology, Uppsala University and Uppsala University Hospital, SE-751 85, Uppsala, Sweden
| | - Patrick Micke
- Department of Immunology, Genetics and Pathology, Uppsala University and Uppsala University Hospital, SE-751 85, Uppsala, Sweden
| | - Maria Planck
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-223 81, Lund, Sweden
- Division of Respiratory Medicine, Allergology, and Palliative Medicine, Department of Clinical Sciences Lund, Lund University, SE-221 85, Lund, Sweden
| | - Mats Jönsson
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-223 81, Lund, Sweden
| | - Johan Staaf
- Division of Oncology, Department of Clinical Sciences Lund, Lund University, Medicon Village, SE-223 81, Lund, Sweden
- Division of Translational Cancer Research, Department of Laboratory Medicine, Lund University, Medicon Village, SE-223 81, Lund, Sweden
| | - Hans Brunnström
- Division of Pathology, Department of Clinical Sciences Lund, Lund University, SE-221 00, Lund, Sweden.
- Department of Genetics and Pathology, Laboratory Medicine Region Skåne, SE-221 85, Lund, Sweden.
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5
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Ge R, Zhang J, Lu M, Shi Y, Yan S, Xue Z, Wang Z, Lopez-Beltran A, Cheng L. Primary mucinous adenocarcinoma of the urethra: A clinicopathological analysis of 35 cases. Histopathology 2024; 84:753-764. [PMID: 38114291 DOI: 10.1111/his.15118] [Citation(s) in RCA: 2] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/13/2023] [Revised: 10/31/2023] [Accepted: 12/01/2023] [Indexed: 12/21/2023]
Abstract
AIM Primary mucinous adenocarcinoma of the urethra represents an extremely rare entity. We sought to characterise further these tumours' clinicopathological, immunohistochemical and molecular features. METHODS AND RESULTS Thirty-five cases were identified, occurring in 18 males and 17 females. The mean age at diagnosis was 65 years (28-89 years). The main presentation symptoms were haematuria and urinary outlet obstruction. Microscopic analysis revealed that all 35 tumours have stromal dissection by mucin. Ten tumours showed villoglandular dysplasia, nine showed mucinous metaplasia, two showed adenocarcinoma in situ and four showed signet ring cell features. All tumours were immunopositive for CEA, while immunonegative for nuclear β-catenin; 19 of 23 (83%) expressed high molecular weight cytokeratin; 19 of 33 (58%) CK7; 28 of 34 (82%) CK20; 32 of 35 (91%) CDX2; 22 of 27 (81%) cadherin-17 (CDH-17); 26 of 29 (90%) SATB2; and one of 31 (3%) GATA3. Mismatch repair gene products, including MLH1, PMS2, MSH2 and MSH6, were immunopositive, suggesting the MSI-low genotype of mucinous adenocarcinoma of the urethra. BRAF V600E and ALK rearrangements were not detected. During the mean follow-up of 20 months, nine patients either developed distant metastasis or succumbed to the illness. CONCLUSION Our study, encompassing the most extensive series of 35 cases of primary mucinous adenocarcinoma of the urethra, provides crucial insights into its precise diagnosis, management and potential targeted treatments. We found a greater CDX2, SATB2 and CDH17 sensitivity in these urethral tumours for the first time, to our knowledge. We identified characteristics such as an MSI-low profile, non-V600E BRAF mutations and an absence of ALK rearrangements.
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Affiliation(s)
- Rongbin Ge
- Department of Pathology and Immunology, Washington University in St Louis, St Louis, MO, USA
| | - Jing Zhang
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Min Lu
- Department of Pathology, Peking University Third Hospital, Peking University Health Science Center, Beijing, China
| | - Yuchuan Shi
- Department of Pathology, Changzheng Hospital, Second Military Medical University, Shanghai, China
| | - Shi Yan
- Department of Urology, Changhai Hospital, Second Military Medical University, Shanghai, China
| | - Zixuan Xue
- Department of Urology, Peking University Third Hospital, Beijing, China
| | - Zongwei Wang
- Department of Surgery, Division of Urologic Surgery, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, USA
| | - Antonio Lopez-Beltran
- Department of Morphological Sciences, Cordoba University Medical School, Cordoba, Spain
| | - Liang Cheng
- Department of Pathology and Laboratory Medicine, Brown University Warren Alpert Medical School, Lifespan Academic Medical Center and the Legorreta Cancer Center at Brown University, Providence, RI, USA
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6
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Jacobsen F, Pushpadevan R, Viehweger F, Freytag M, Schlichter R, Gorbokon N, Büscheck F, Luebke AM, Putri D, Kluth M, Hube-Magg C, Hinsch A, Höflmayer D, Fraune C, Bernreuther C, Lebok P, Sauter G, Minner S, Steurer S, Simon R, Burandt E, Dum D, Lutz F, Marx AH, Krech T, Clauditz TS. Cadherin-17 (CDH17) expression in human cancer: A tissue microarray study on 18,131 tumors. Pathol Res Pract 2024; 256:155175. [PMID: 38452580 DOI: 10.1016/j.prp.2024.155175] [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: 11/01/2023] [Revised: 01/25/2024] [Accepted: 01/25/2024] [Indexed: 03/09/2024]
Abstract
Cadherin-17 (CDH17) is a membranous cell adhesion protein predominantly expressed in intestinal epithelial cells. CDH17 is therefore considered a possible diagnostic and therapeutic target. This study was to comprehensively determine the expression of CDH17 in cancer and to further assess the diagnostic utility of CDH17 immunohistochemistry (IHC). A tissue microarray containing 14,948 interpretable samples from 150 different tumor types and subtypes as well as 76 different normal tissue types was analyzed by IHC. In normal tissues, a membranous CDH17 staining was predominantly seen in the epithelium of the intestine and pancreatic excretory ducts. In tumors, 53 of 150 analyzed categories showed CDH17 positivity including 26 categories with at least one strongly positive case. CDH17 positivity was most common in epithelial and neuroendocrine colorectal neoplasms (50.0%-100%), other gastrointestinal adenocarcinomas (42.7%-61.6%), mucinous ovarian cancer (61.1%), pancreatic acinar cell carcinoma (28.6%), cervical adenocarcinoma (52.6%), bilio-pancreatic adenocarcinomas (40.5-69.8%), and other neuroendocrine neoplasms (5.6%-100%). OnIy 9.9% of 182 pulmonary adenocarcinomas were CDH17 positive. In colorectal adenocarcinomas, reduced CDH17 staining was linked to high pT (p = 0.0147), nodal metastasis (p = 0.0041), V1 (p = 0.0025), L1 (p = 0.0054), location in the right colon (p = 0.0033), and microsatellite instability (p < 0.0001). The CDH17 expression level was unrelated to tumor phenotype in gastric and pancreatic cancer. In summary, our comprehensive overview on CDH17 expression in human tumors identified various tumor entities that might often benefit from anti-CDH17 therapies and suggest utility of CDH17 IHC for the distinction of metastatic gastrointestinal or bilio-pancreatic adenocarcinomas (often positive) from primary pulmonary adenocarcinomas (mostly negative).
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Affiliation(s)
- Frank Jacobsen
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ramesh Pushpadevan
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Viehweger
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Morton Freytag
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ria Schlichter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Natalia Gorbokon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Franziska Büscheck
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas M Luebke
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Devita Putri
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Martina Kluth
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Claudia Hube-Magg
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andrea Hinsch
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Doris Höflmayer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christoph Fraune
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Christian Bernreuther
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Patrick Lebok
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Guido Sauter
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Sarah Minner
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Stefan Steurer
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Ronald Simon
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
| | - Eike Burandt
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David Dum
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Florian Lutz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - Andreas H Marx
- Department of Pathology, Academic Hospital Fuerth, Fuerth, Germany
| | - Till Krech
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany; Institute of Pathology, Clinical Center Osnabrueck, Osnabrueck, Germany
| | - Till S Clauditz
- Institute of Pathology, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
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7
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Jung P, Glaser SP, Han J, Popa A, Pisarsky L, Feng N, Geyer A, Haderk F, Alpar D, Bristow C, Schmittner S, Traexler PE, Mahendra M, Poehn B, Gandhi P, Fiorelli R, Awate S, Budano N, Martin F, Albrecht C, Drobits-Handl B, Anand SS, Kasturirangan S, Trapani F, Schweifer N, Marszalek JR, Tontsch-Grunt U, Pearson M, Heffernan TP, Kraut N, Vellano CP, García-Martínez JM. A TRAILR2/CDH3 bispecific antibody demonstrates selective apoptosis and tumor regression in CDH3-positive pancreatic cancer. MAbs 2024; 16:2438173. [PMID: 39654063 PMCID: PMC11633135 DOI: 10.1080/19420862.2024.2438173] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2024] [Revised: 11/29/2024] [Accepted: 12/01/2024] [Indexed: 12/13/2024] Open
Abstract
Exploitation of extrinsic apoptosis signaling via TRAILR2 activation represents a promising therapeutic concept in cancer treatment. The limited clinical success of previous TRAILR2 agonistic agents, to date, has been ascribed to either poor efficacy or hepatotoxicity. TR2/CDH3 BAB is a human bispecific antibody that relies on binding both CDH3 and TRAILR2 on cell surfaces to achieve TRAILR2 hyperclustering and efficient apoptosis induction by TRAILR2 signaling selectively in CDH3-expressing tumor cells. We demonstrate target-dependent TR2/CDH3 BAB anti-tumor activity in CRISPR/Cas9-engineered TRAILR2 or CDH3 knock-out cells. By utilizing the cell line screening platform PRISM, we found selective TR2/CDH3 BAB efficacy in various cancer types, such as pancreatic, gastric, colorectal, and triple negative breast cancer. The efficacy of TR2/CDH3 BAB correlated with caspase activation in cancer cell lines and in xenograft tumor tissues. In pancreatic ductal adenocarcinoma (PDAC), where patient benefit from current cytotoxic therapy options is unsatisfactory, a close to uniform cell surface expression of CDH3 and TRAILR2 was observed, which will qualify the majority of PDAC patients for TR2/CDH3 BAB-based treatment. TR2/CDH3 BAB demonstrated anti-tumor activity in a panel of PDAC patient-derived xenograft models, including tumor regressions. By combining TR2/CDH3 BAB with chemotherapeutic agents, deeper and more sustained anti-tumor responses were observed when compared to monotherapy. Together with the potential to deliver a favorable safety profile, these data support clinical testing of TR2/CDH3 BAB in patients with PDAC.
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Affiliation(s)
- Peter Jung
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Stefan P. Glaser
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Jing Han
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Alexandra Popa
- Global Computational Biology and Digital Sciences, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Laura Pisarsky
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Ningping Feng
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Antonia Geyer
- Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Franziska Haderk
- Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | - Donat Alpar
- Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Christopher Bristow
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Susanne Schmittner
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Paula-Elena Traexler
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Mikhila Mahendra
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Birgit Poehn
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Poojabahen Gandhi
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Roberto Fiorelli
- Translational Medicine & Clinical Pharmacology, Boehringer Ingelheim Pharma GmbH & Co KG, Biberach, Germany
| | - Sanket Awate
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Nicole Budano
- Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Florian Martin
- Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Christoph Albrecht
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Barbara Drobits-Handl
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Sathanandam S. Anand
- Boehringer Ingelheim Pharmaceuticals, Inc., Nonclinical Drug Safety, Ridgefield, CT, USA
| | - Srinath Kasturirangan
- Boehringer Ingelheim Pharmaceuticals, Inc., Biotherapeutics Discovery, Ridgefield, CT, USA
| | - Francesca Trapani
- Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Norbert Schweifer
- Translational Medicine & Clinical Pharmacology, Oncology Translational Science, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Joseph R. Marszalek
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Ulrike Tontsch-Grunt
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Mark Pearson
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Timothy P. Heffernan
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
| | - Norbert Kraut
- Cancer Research Therapeutic Area, Boehringer Ingelheim RCV GmbH & Co KG, Vienna, Austria
| | - Christopher P. Vellano
- Translational Research to Advance Therapeutics and Innovation in Oncology (TRACTION) Platform, Therapeutics Discovery Division, University of Texas MD Anderson Cancer Center, Houston, TX, USA
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8
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Garousi B, Rezaei Z, Nazerian Y, Yasaghi Y, Alaei M, Bahrami Zanjanbar D, Tavasol A, Khoshrou A, Khademolhosseini S, Mirfakhraee H. Differentiation of gastric adenocarcinoma and pancreatic adenocarcinoma using immunohistochemistry biomarkers: a systematic review and meta-analysis study. GASTROENTEROLOGY AND HEPATOLOGY FROM BED TO BENCH 2024; 17:324-337. [PMID: 40406435 PMCID: PMC12094505 DOI: 10.22037/ghfbb.v17i4.3057] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 07/07/2024] [Accepted: 10/10/2024] [Indexed: 05/26/2025]
Abstract
Aim This survey aimed to assess the differentiation of Gastric adenocarcinoma (GA) and pancreatic adenocarcinoma (PA) via immunohistochemistry biomarkers. Background GA and PA are two gastrointestinal malignancies with similarities in immunohistochemical features, making the diagnosis complex in some cases. Methods We searched international databases, including Google Scholar, Web of Science, PubMed, Embase, PROQUEST, and Cochrane Library, using appropriate keywords. The variance of each study was calculated using the binomial distribution formula, with all data analyzed by R version 16. Pooled odds ratios (OR), 95% confidence intervals (CI), and the I² test were calculated to evaluate the effectiveness of various immunohistochemistry biomarkers. Publication bias was assessed using funnel plots plus Begg's and Egger's tests. Results Based on the finding of our study, four potent biomarkers which can distinguish GA from PA were Cadherin 17 (CDH17) with pooled OR= 3.73 (95% CI 1.58 to 8.87), P value=0.003, and I2=55.5%; Caudal-type homeobox 2 (CDX2) with pooled OR=8.99 (95% CI 4.52 to 17.90), P value= <0.001, and I2=52.2%; CK7 with pooled OR= 0.15 (95% CI 0.04 to 0.57), P value= 0.005, and I2=56.6%; CK20 with pooled OR=2.06 (95% CI 1.38 to 3.08), P value= <0.001, and I2=0%. Conclusion Our study identified CDH17, COX-2, CK7, and CK20 as potent IHC biomarkers for differentiating PA and GA. Incorporating these biomarkers into routine diagnostics is essential for improving accuracy in challenging cases, ultimately aiding timely treatment decisions and improving patient outcomes.
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Affiliation(s)
- Behzad Garousi
- Department of Pathology, Karolinska Institute, Stockholm, Sweden
| | | | - Yasaman Nazerian
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Younes Yasaghi
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Maryam Alaei
- School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Dorsa Bahrami Zanjanbar
- Brazil Pharmaceutical Science Research Center, Tehran Medical Sciences, Islamic Azad University, Tehran, Iran
- GI Pharmacology Interest Group (GPIG), Universal Scientific Education and Research Network (USERN), Tehran, Iran
| | - Arian Tavasol
- Student Research Committee, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran
| | - Alireza Khoshrou
- Student Research Committee, School of Medicine, Mashhad University of Medical Sciences, Mashhad, Iran
| | | | - Hosna Mirfakhraee
- Firoozabadi Clinical Research Development Unit (FACRDU), Iran University of Medical Sciences, Tehran, Iran
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9
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Huang J, Chen G, Li H. An Update on the Role of Immunohistochemistry in the Evaluation of Pancreatic/Liver/Gastrointestinal Luminal Tract Disorders. Arch Pathol Lab Med 2023; 147:1374-1382. [PMID: 37134268 DOI: 10.5858/arpa.2022-0462-ra] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 02/02/2023] [Indexed: 05/05/2023]
Abstract
CONTEXT.— Immunohistochemistry serves as an ancillary diagnostic tool for a wide variety of neoplastic and nonneoplastic disorders, including infections, workup of inflammatory conditions, and subtyping neoplasms of the pancreas/liver/gastrointestinal luminal tract. In addition, immunohistochemistry is also used to detect a variety of prognostic and predictive molecular biomarkers for carcinomas of the pancreas, liver, and gastrointestinal luminal tract. OBJECTIVE.— To highlight an update on the role of immunohistochemistry in the evaluation of pancreatic/liver/gastrointestinal luminal tract disorders. DATA SOURCES.— Literature review and authors' research data and personal practice experience were used. CONCLUSIONS.— Immunohistochemistry is a valuable tool, assisting in the diagnosis of problematic tumors and benign lesions of the pancreas, liver, and gastrointestinal luminal tract, and also in the prediction of prognosis and therapeutic response for carcinomas of the pancreas, liver, and gastrointestinal luminal tract.
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Affiliation(s)
- Jialing Huang
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania (Huang, Li)
| | - Guoli Chen
- The Department of Pathology, PennState Health, Hershey, Pennsylvania (Chen)
| | - Hongjie Li
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania (Huang, Li)
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10
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Dong Y, Xia P, Xu X, Shen J, Ding Y, Jiang Y, Wang H, Xie X, Zhang X, Li W, Li Z, Wang J, Zhao SC. Targeted delivery of organic small-molecule photothermal materials with engineered extracellular vesicles for imaging-guided tumor photothermal therapy. J Nanobiotechnology 2023; 21:442. [PMID: 37993888 PMCID: PMC10666357 DOI: 10.1186/s12951-023-02133-5] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/24/2023] [Accepted: 09/28/2023] [Indexed: 11/24/2023] Open
Abstract
Imaging-guided photothermal therapy (PTT) for cancers recently gathered increasing focus thanks to its precise diagnosis and potent therapeutic effectiveness. Croconaine (CR) dyes demonstrate potential in expanding utility for near infrared (NIR) dyes in bio-imaging/theranostics. However, reports on CR dyes for PTT are scarce most likely due to the short of the efficacious delivery strategies to achieve specific accumulation in diseased tissues to induce PTT. Extracellular vesicles (EVs) are multifunctional nanoparticle systems that function as safe platform for disease theragnostics, which provide potential benefits in extensive biomedical applications. Here, we developed a novel delivery system for photothermal molecules based on a CR dye that exerts photothermal activity through CDH17 nanobody-engineered EVs. The formed CR@E8-EVs showed strong NIR absorption, excellent photothermal performance, good biological compatibility and superb active tumor-targeting capability. The CR@E8-EVs can not only visualize and feature the tumors through CR intrinsic property as a photoacoustic imaging (PAI) agent, but also effectively retard the tumor growth under laser irradiation to perform PTT. It is expected that the engineered EVs will become a novel delivery vehicle of small organic photothermal agents (SOPTAs) in future clinical PTT applications.
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Affiliation(s)
- Yafang Dong
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510500, P. R. China
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
| | - Peng Xia
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, Hubei, 430072, P. R. China
| | - Xiaolong Xu
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
| | - Jing Shen
- Department of Oncology, Department of Infectious Disease, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
| | - Youbin Ding
- Department of Medical Imaging, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510630, P. R. China
| | - Yuke Jiang
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
| | - Huifang Wang
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
| | - Xin Xie
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China
| | - Xiaodong Zhang
- Department of Medical Imaging, The Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510630, P. R. China
| | - Weihua Li
- Medical imaging department, Shenzhen Second People's Hospital/the First Affiliated Hospital, Shenzhen University Health Science Center, Shenzhen, Guangdong, 518035, P. R. China.
| | - Zhijie Li
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China.
| | - Jigang Wang
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510500, P. R. China.
- Department of Nephrology, Shenzhen Key Laboratory of Kidney Diseases, Shenzhen Clinical Research Centre for Geriatrics, Shenzhen People's Hospital, The First Affiliated Hospital, Southern University of Science and Technology, Shenzhen, Guangdong, 518020, P. R. China.
- State Key Laboratory for Quality Ensurance and Sustainable Use of Dao-di Herbs, Artemisinin Research Center, Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, P. R. China.
- Department of Oncology, the Affiliated Hospital of Southwest Medical University, Luzhou, Sichuan, P. R. China.
| | - Shan-Chao Zhao
- Department of Urology, the Third Affiliated Hospital of Southern Medical University, Guangzhou, Guangdong, 510500, P. R. China.
- Department of Urology, Nanfang Hospital, Southern Medical University, Guangzhou, Guangdong, 510515, P. R. China.
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11
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Tian W, Zhao J, Wang W. Targeting CDH17 with Chimeric Antigen Receptor-Redirected T Cells in Small Cell Lung Cancer. Lung 2023; 201:489-497. [PMID: 37823901 DOI: 10.1007/s00408-023-00648-0] [Citation(s) in RCA: 2] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2023] [Accepted: 10/04/2023] [Indexed: 10/13/2023]
Abstract
BACKGROUND Chimeric antigen receptor T cell (CAR-T) therapy stands as a precise and targeted approach in the treatment of malignancies. In this study, we investigated the feasibility of targeting Cadherin 17 (CDH17) with CDH17 CAR-T cells as a therapeutic modality for small cell lung cancer (SCLC). METHODS CDH17 expression levels were assessed in human SCLC tumor tissues and cell lines using qPCR and Western blot. Subsequently, we established CDH17 CAR-T cells and assessed their cytotoxicity by co-culturing them with various SCLC cell lines at different effector-to-target (E:T) ratios, complemented by ELISA assays. To ascertain the specificity of CDH17 CAR-T cells, we conducted experiments on SCLC cells with and without CDH17 expression (shRNAs). Furthermore, we employed an SCLC xenograft model to evaluate the in vivo efficacy of CDH17 CAR-T cells. RESULTS Our results revealed a significant upregulation of CDH17 in both SCLC tissues and cell lines. CDH17 CAR-T cells exhibited robust cytotoxic activity against SCLC cells in vitro, while demonstrating no cytotoxicity towards CDH17-deficient SCLC cells and HEK293 cells that lack CDH17 expression. Importantly, the production of IFN-γ and TNF-α by CDH17 CAR-T cells correlated with their cytotoxic potency. Additionally, treatment with CDH17 CAR-T cells significantly decelerated the growth rate of SCLC-derived xenograft tumors in vivo. Remarkably, no significant difference in body weight was observed between the control group and the group treated with CDH17 CAR-T cells. CONCLUSIONS The preclinical data open further venues for the clinical use of CDH17 CAR-T cells as an immunotherapeutic strategy for SCLC treatment.
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Affiliation(s)
- Wen Tian
- Second Department of Oncology, Cangzhou Central Hospital, NO.16 Xinhua West Road, Cangzhou, 061000, Hebei, China.
| | - Jinhui Zhao
- Medical Oncology, Cangzhou Central Hospital Hejian Branch, NO.32 Jingkai South Street, Hejian, 062450, Hebei, China
| | - Wenzhong Wang
- Medical Oncology, Cancer Hospital of HuanXing ChaoYang District Beijing, NO.1 Lvjiaying Nanlijia, Chaoyang District, Beijing, 100020, China
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12
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Pan Z, Wang Y, Wang M, Wang Y, Zhu X, Gu S, Zhong C, An L, Shan M, Damas J, Halstead MM, Guan D, Trakooljul N, Wimmers K, Bi Y, Wu S, Delany ME, Bai X, Cheng HH, Sun C, Yang N, Hu X, Lewin HA, Fang L, Zhou H. An atlas of regulatory elements in chicken: A resource for chicken genetics and genomics. SCIENCE ADVANCES 2023; 9:eade1204. [PMID: 37134160 PMCID: PMC10156120 DOI: 10.1126/sciadv.ade1204] [Citation(s) in RCA: 16] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/05/2023]
Abstract
A comprehensive characterization of regulatory elements in the chicken genome across tissues will have substantial impacts on both fundamental and applied research. Here, we systematically identified and characterized regulatory elements in the chicken genome by integrating 377 genome-wide sequencing datasets from 23 adult tissues. In total, we annotated 1.57 million regulatory elements, representing 15 distinct chromatin states, and predicted about 1.2 million enhancer-gene pairs and 7662 super-enhancers. This functional annotation of the chicken genome should have wide utility on identifying regulatory elements accounting for gene regulation underlying domestication, selection, and complex trait regulation, which we explored. In short, this comprehensive atlas of regulatory elements provides the scientific community with a valuable resource for chicken genetics and genomics.
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Affiliation(s)
- Zhangyuan Pan
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Ying Wang
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Mingshan Wang
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650000, China
| | - Yuzhe Wang
- State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China
| | - Xiaoning Zhu
- State Key Laboratory for Agrobiotechnology, China Agricultural University, Beijing 100193, China
| | - Shenwen Gu
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Conghao Zhong
- National Engineering Laboratory for Animal Breeding and Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, China Agricultural University, Beijing 100193, China
| | - Liqi An
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Mingzhu Shan
- Institute of Animal Science, Chinese Academy of Agricultural Sciences, Beijing 100193, China
| | - Joana Damas
- The Genome Center, University of California, Davis, CA 95616, USA
| | - Michelle M Halstead
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Dailu Guan
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Nares Trakooljul
- Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
| | - Klaus Wimmers
- Research Institute for Farm Animal Biology (FBN), Dummerstorf, Germany
- Faculty of Agricultural and Environmental Sciences, University Rostock, Rostock, Germany
| | - Ye Bi
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Shang Wu
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Mary E Delany
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Xuechen Bai
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
| | - Hans H Cheng
- USDA-ARS, Avian Disease and Oncology Laboratory, East Lansing, MI 48823, USA
| | - Congjiao Sun
- National Engineering Laboratory for Animal Breeding and Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, China Agricultural University, Beijing 100193, China
| | - Ning Yang
- National Engineering Laboratory for Animal Breeding and Key Laboratory of Animal Genetics, Breeding and Reproduction, Ministry of Agriculture and Rural Affairs, China Agricultural University, Beijing 100193, China
| | - Xiaoxiang Hu
- State Key Laboratory of Genetic Resources and Evolution, Kunming Institute of Zoology, Chinese Academy of Sciences, Kunming, Yunnan 650000, China
| | - Harris A Lewin
- The Genome Center, University of California, Davis, CA 95616, USA
- Department of Evolution and Ecology, University of California, Davis, CA 95616, USA
| | - Lingzhao Fang
- Center for Quantitative Genetics and Genomics, Aarhus University, Aarhus, 8000, DK
- MRC Human Genetics Unit at the Institute of Genetics and Cancer, The University of Edinburgh, Edinburgh, EH4 2XU, UK
| | - Huaijun Zhou
- Department of Animal Science, University of California, Davis, Davis 95616, CA, USA
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13
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Ma J, Xu X, Fu C, Xia P, Tian M, Zheng L, Chen K, Liu X, Li Y, Yu L, Zhu Q, Yu Y, Fan R, Jiang H, Li Z, Yang C, Xu C, Long Y, Wang J, Li Z. CDH17 nanobodies facilitate rapid imaging of gastric cancer and efficient delivery of immunotoxin. Biomater Res 2022; 26:64. [PMID: 36435809 PMCID: PMC9701387 DOI: 10.1186/s40824-022-00312-3] [Citation(s) in RCA: 23] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2022] [Accepted: 10/27/2022] [Indexed: 11/28/2022] Open
Abstract
BACKGROUND It is highly desirable to develop new therapeutic strategies for gastric cancer given the low survival rate despite improvement in the past decades. Cadherin 17 (CDH17) is a membrane protein highly expressed in cancers of digestive system. Nanobody represents a novel antibody format for cancer targeted imaging and drug delivery. Nanobody targeting CHD17 as an imaging probe and a delivery vehicle of toxin remains to be explored for its theragnostic potential in gastric cancer. METHODS Naïve nanobody phage library was screened against CDH17 Domain 1-3 and identified nanobodies were extensively characterized with various assays. Nanobodies labeled with imaging probe were tested in vitro and in vivo for gastric cancer detection. A CDH17 Nanobody fused with toxin PE38 was evaluated for gastric cancer inhibition in vitro and in vivo. RESULTS Two nanobodies (A1 and E8) against human CDH17 with high affinity and high specificity were successfully obtained. These nanobodies could specifically bind to CDH17 protein and CDH17-positive gastric cancer cells. E8 nanobody as a lead was extensively determined for tumor imaging and drug delivery. It could efficiently co-localize with CDH17-positive gastric cancer cells in zebrafish embryos and rapidly visualize the tumor mass in mice within 3 h when conjugated with imaging dyes. E8 nanobody fused with toxin PE38 showed excellent anti-tumor effect and remarkably improved the mice survival in cell-derived (CDX) and patient-derived xenograft (PDX) models. The immunotoxin also enhanced the anti-tumor effect of clinical drug 5-Fluorouracil. CONCLUSIONS The study presents a novel imaging and drug delivery strategy by targeting CDH17. CDH17 nanobody-based immunotoxin is potentially a promising therapeutic modality for clinical translation against gastric cancer.
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Affiliation(s)
- Jingbo Ma
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.,College of Traditional Chinese Medicine, Tianjin University of Traditional Chinese Medicine, Tianjin, 300193, P. R. China
| | - Xiaolong Xu
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China
| | - Chunjin Fu
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China
| | - Peng Xia
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.,Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, P. R. China
| | - Ming Tian
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.,Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, 430072, Hubei, P. R. China
| | - Liuhai Zheng
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China
| | - Kun Chen
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China
| | - Xiaolian Liu
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, P. R. China
| | - Yilei Li
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, P. R. China
| | - Le Yu
- Clinical Pharmacy Center, Nanfang Hospital, Southern Medical University, Guangzhou, 510515, Guangdong, P. R. China.,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, P.R. China
| | - Qinchang Zhu
- College of Pharmacy, Shenzhen Technology University, Shenzhen, 518118, P.R. China
| | - Yangyang Yu
- Health Science Center, Shenzhen University, Shenzhen, 518055, Guangdong, P. R. China
| | - Rongrong Fan
- Deapartment of Biosciences and Nutrition, Karolinska Institute, 14157, Stockholm, Sweden
| | - Haibo Jiang
- Department of Chemistry, The University of Hong Kong, Pok Fu Lam, Hong Kong, P. R. China
| | - Zhifen Li
- School of Chemistry and Chemical Engineering, Shanxi Datong University, Xing Yun Street, Pingcheng District, Datong, 037009, Shanxi, P. R. China
| | - Chuanbin Yang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China
| | - Chengchao Xu
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China
| | - Ying Long
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.
| | - Jigang Wang
- Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China. .,Guangdong Provincial Key Laboratory of New Drug Screening, School of Pharmaceutical Sciences, Southern Medical University, Guangzhou, 510515, Guangdong, P.R. China. .,Artemisinin Research Center, and Institute of Chinese Materia Medica, China Academy of Chinese Medical Sciences, Beijing, 100700, P. R. China.
| | - Zhijie Li
- Department of Hyperbaric Medicine, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China. .,Department of Geriatrics, Shenzhen People's Hospital (The Second Clinical Medical College, Jinan University, The First Affiliated Hospital, Southern University of Science and Technology), Shenzhen, 518020, Guangdong, P. R. China.
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14
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Sattar RSA, Verma R, Nimisha, Kumar A, Dar GM, Apurva, Sharma AK, Kumari I, Ahmad E, Ali A, Mahajan B, Saluja SS. Diagnostic and prognostic biomarkers in colorectal cancer and the potential role of exosomes in drug delivery. Cell Signal 2022; 99:110413. [PMID: 35907519 DOI: 10.1016/j.cellsig.2022.110413] [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: 04/14/2022] [Revised: 07/13/2022] [Accepted: 07/15/2022] [Indexed: 11/03/2022]
Abstract
Colorectal cancer (CRC) is the third most common cancer with the second most frequent cause of death worldwide. One fourth to one fifth of the CRC cases are detected at advance stage. Early detection of colorectal cancer might help in decreasing mortality and morbidity worldwide. CRC being a heterogeneous disease, new non-invasive approaches are needed to complement and improve the screening and management of CRC. Reliable and early detectable biomarkers would improve diagnosis, prognosis, therapeutic responses, and will enable the prediction of drug response and recurrence risk. Over the past decades molecular research has demonstrated the potentials of CTCs, ctDNAs, circulating mRNAs, ncRNAs, and exosomes as tumor biomarkers. Non-invasive screening approaches using fecal samples for identification of altered gut microbes in CRC is also gaining attention. Exosomes can be potential candidates that can be employed in the drug delivery system. Further, the integration of in vitro, in vivo and in silico models that involve CRC biomarkers will help to understand the interactions occurring at the cellular level. This review summarizes recent update on CRC biomarkers and their application along with the nanoparticles followed by the application of organoid culture in CRC.
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Affiliation(s)
- Real Sumayya Abdul Sattar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Renu Verma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Nimisha
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Arun Kumar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ghulam Mehdi Dar
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Apurva
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Abhay Kumar Sharma
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Indu Kumari
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Ejaj Ahmad
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Asgar Ali
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Bhawna Mahajan
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of Biochemistry, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India
| | - Sundeep Singh Saluja
- Central Molecular Laboratory, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India; Department of GI Surgery, Govind Ballabh Pant Institute of Postgraduate Medical Education and Research (GIPMER), New Delhi, India.
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15
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Feng Z, He X, Zhang X, Wu Y, Xing B, Knowles A, Shan Q, Miller S, Hojnacki T, Ma J, Katona BW, Gade TPF, Siegel DL, Schrader J, Metz DC, June CH, Hua X. Potent suppression of neuroendocrine tumors and gastrointestinal cancers by CDH17CAR T cells without toxicity to normal tissues. NATURE CANCER 2022; 3:581-594. [PMID: 35314826 DOI: 10.1038/s43018-022-00344-7] [Citation(s) in RCA: 61] [Impact Index Per Article: 20.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Received: 05/21/2021] [Accepted: 02/09/2022] [Indexed: 12/15/2022]
Abstract
Gastrointestinal cancers (GICs) and neuroendocrine tumors (NETs) are often refractory to therapy after metastasis. Adoptive cell therapy using chimeric antigen receptor (CAR) T cells, though remarkably efficacious for treating leukemia, is yet to be developed for solid tumors such as GICs and NETs. Here we isolated a llama-derived nanobody, VHH1, and found that it bound cell surface adhesion protein CDH17 upregulated in GICs and NETs. VHH1-CAR T cells (CDH17CARTs) killed both human and mouse tumor cells in a CDH17-dependent manner. CDH17CARTs eradicated CDH17-expressing NETs and gastric, pancreatic and colorectal cancers in either tumor xenograft or autochthonous mouse models. Notably, CDH17CARTs do not attack normal intestinal epithelial cells, which also express CDH17, to cause toxicity, likely because CDH17 is localized only at the tight junction between normal intestinal epithelial cells. Thus, CDH17 represents a class of previously unappreciated tumor-associated antigens that is 'masked' in healthy tissues from attack by CAR T cells for developing safer cancer immunotherapy.
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Affiliation(s)
- Zijie Feng
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Xin He
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Xuyao Zhang
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Yuan Wu
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Bowen Xing
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Alison Knowles
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Qiaonan Shan
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Samuel Miller
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Taylor Hojnacki
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jian Ma
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Bryson W Katona
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Terence P F Gade
- Department of Radiology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Don L Siegel
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Jörg Schrader
- Department of Medicine, University Medical Center Hamburg-Eppendorf, Hamburg, Germany
| | - David C Metz
- Division of Gastroenterology and Hepatology, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Carl H June
- Center for Cellular Immunotherapies, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
- Department of Pathology and Laboratory Medicine, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA
| | - Xianxin Hua
- Department of Cancer Biology, Abramson Family Cancer Research Institute, Perelman School of Medicine at the University of Pennsylvania, Philadelphia, PA, USA.
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16
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Furumoto H, Kato T, Wakiyama H, Furusawa A, Choyke PL, Kobayashi H. Endoscopic Applications of Near-Infrared Photoimmunotherapy (NIR-PIT) in Cancers of the Digestive and Respiratory Tracts. Biomedicines 2022; 10:846. [PMID: 35453596 PMCID: PMC9027987 DOI: 10.3390/biomedicines10040846] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/24/2022] [Revised: 03/24/2022] [Accepted: 03/25/2022] [Indexed: 12/11/2022] Open
Abstract
Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed and promising therapy that specifically destroys target cells by irradiating antibody-photo-absorber conjugates (APCs) with NIR light. APCs bind to target molecules on the cell surface, and when exposed to NIR light, cause disruption of the cell membrane due to the ligand release reaction and dye aggregation. This leads to rapid cell swelling, blebbing, and rupture, which leads to immunogenic cell death (ICD). ICD activates host antitumor immunity, which assists in killing still viable cancer cells in the treated lesion but is also capable of producing responses in untreated lesions. In September 2020, an APC and laser system were conditionally approved for clinical use in unresectable advanced head and neck cancer in Japan, and are now routine in appropriate patients. However, most tumors have been relatively accessible in the oral cavity or neck. Endoscopes offer the opportunity to deliver light deeper within hollow organs of the body. In recent years, the application of endoscopic therapy as an alternative to surgery for the treatment of cancer has expanded, providing significant benefits to inoperable patients. In this review, we will discuss the potential applications of endoscopic NIR-PIT, especially in thoracic and gastrointestinal cancers.
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Affiliation(s)
| | | | | | | | | | - Hisataka Kobayashi
- Molecular Imaging Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892, USA; (H.F.); (T.K.); (H.W.); (A.F.); (P.L.C.)
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17
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Shen T, Zhao J, Zhao M, Taggart MW, Ramalingam P, Gong Y, Wu Y, Liu H, Zhang J, Resetkova E, Wang WL, Ding Q, Huo L, Yoon E. Unusual Staining of Immunohistochemical Markers PAX8 and CDX2 in Breast Carcinoma: A Potential Diagnostic Pitfall. Hum Pathol 2022; 125:35-47. [DOI: 10.1016/j.humpath.2022.04.007] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 03/07/2022] [Revised: 04/04/2022] [Accepted: 04/05/2022] [Indexed: 11/16/2022]
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18
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Choi HB, Pyo JS, Son S, Kim K, Kang G. Diagnostic and Prognostic Roles of CDX2 Immunohistochemical Expression in Colorectal Cancers. Diagnostics (Basel) 2022; 12:diagnostics12030757. [PMID: 35328309 PMCID: PMC8947721 DOI: 10.3390/diagnostics12030757] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/08/2022] [Revised: 03/16/2022] [Accepted: 03/18/2022] [Indexed: 02/05/2023] Open
Abstract
The study is aimed to evaluate the diagnostic and prognostic role of the immunohistochemical expression of the Caudal-type homeobox transcription factor 2 (CDX2) in colorectal cancers (CRCs) through a meta-analysis. By searching relevant databases, 38 articles were eligible to be included in this study. We extracted the information for CDX2 expression rates and the correlation between CDX2 expression and clinicopathological characteristics. The estimated rates of CDX2 expression were 0.882 [95% confidence interval (CI) 0.774−0.861] and 0.893 (95% CI 0.820−0.938) in primary and metastatic CRCs, respectively. Furthermore, based on their histologic subtype, CDX2 expression rates of adenocarcinoma and medullary carcinoma were 0.886 (95% CI 0.837−0.923) and 0.436 (95% CI 0.269−0.618), respectively. There was a significant difference in CDX2 expression rates between adenocarcinoma and medullary carcinoma in the meta-regression test (p < 0.001). In addition, CDX2 expression was significantly lower in CRCs with the BRAFV600E mutation than in CRCs without mutation. Patients with CDX2 expression had better overall and cancer-specific survival rates than those without CDX2 expression. Thus, CDX2 is a useful diagnostic and prognostic marker CRCs.
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Affiliation(s)
- Hong Bae Choi
- Department of Surgery, Daehang Hospital, Seoul 06699, Korea
| | - Jung-Soo Pyo
- Department of Pathology, Uijeongbu Eulji Medical Center, Eulji University School of Medicine, Uijeongbu-si 11759, Korea
| | - Soomin Son
- Division of Molecular Life and Chemical Sciences, College of Natural Sciences, Ewha Woman's University, Seoul 03760, Korea
| | | | - Guhyun Kang
- Department of Pathology, Daehang Hospital, Seoul 06699, Korea
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19
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Novel Diagnostic Biomarkers in Colorectal Cancer. Int J Mol Sci 2022; 23:ijms23020852. [PMID: 35055034 PMCID: PMC8776048 DOI: 10.3390/ijms23020852] [Citation(s) in RCA: 124] [Impact Index Per Article: 41.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2021] [Revised: 12/27/2021] [Accepted: 01/03/2022] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is still a leading cause of cancer death worldwide. Less than half of cases are diagnosed when the cancer is locally advanced. CRC is a heterogenous disease associated with a number of genetic or somatic mutations. Diagnostic markers are used for risk stratification and early detection, which might prolong overall survival. Nowadays, the widespread use of semi-invasive endoscopic methods and feacal blood tests characterised by suboptimal accuracy of diagnostic results has led to the detection of cases at later stages. New molecular noninvasive tests based on the detection of CRC alterations seem to be more sensitive and specific then the current methods. Therefore, research aiming at identifying molecular markers, such as DNA, RNA and proteins, would improve survival rates and contribute to the development of personalized medicine. The identification of “ideal” diagnostic biomarkers, having high sensitivity and specificity, being safe, cheap and easy to measure, remains a challenge. The purpose of this review is to discuss recent advances in novel diagnostic biomarkers for tumor tissue, blood and stool samples in CRC patients.
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20
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Rai A, Fang H, Claridge B, Simpson RJ, Greening DW. Proteomic dissection of large extracellular vesicle surfaceome unravels interactive surface platform. J Extracell Vesicles 2021; 10:e12164. [PMID: 34817906 PMCID: PMC8612312 DOI: 10.1002/jev2.12164] [Citation(s) in RCA: 75] [Impact Index Per Article: 18.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/30/2021] [Revised: 09/20/2021] [Accepted: 10/13/2021] [Indexed: 12/17/2022] Open
Abstract
The extracellular vesicle (EV) surface proteome (surfaceome) acts as a fundamental signalling gateway by bridging intra- and extracellular signalling networks, dictates EVs' capacity to communicate and interact with their environment, and is a source of potential disease biomarkers and therapeutic targets. However, our understanding of surface protein composition of large EVs (L-EVs, 100-800 nm, mean 310 nm, ATP5F1A, ATP5F1B, DHX9, GOT2, HSPA5, HSPD1, MDH2, STOML2), a major EV-subtype that are distinct from small EVs (S-EVs, 30-150 nm, mean 110 nm, CD44, CD63, CD81, CD82, CD9, PDCD6IP, SDCBP, TSG101) remains limited. Using a membrane impermeant derivative of biotin to capture surface proteins coupled to mass spectrometry analysis, we show that out of 4143 proteins identified in density-gradient purified L-EVs (1.07-1.11 g/mL, from multiple cancer cell lines), 961 proteins are surface accessible. The surface molecular diversity of L-EVs include (i) bona fide plasma membrane anchored proteins (cluster of differentiation, transporters, receptors and GPI anchored proteins implicated in cell-cell and cell-ECM interactions); and (ii) membrane surface-associated proteins (that are released by divalent ion chelator EDTA) implicated in actin cytoskeleton regulation, junction organization, glycolysis and platelet activation. Ligand-receptor analysis of L-EV surfaceome (e.g., ITGAV/ITGB1) uncovered interactome spanning 172 experimentally verified cognate binding partners (e.g., ANGPTL3, PLG, and VTN) with highest tissue enrichment for liver. Assessment of biotin inaccessible L-EV proteome revealed enrichment for proteins belonging to COPI/II-coated ER/Golgi-derived vesicles and mitochondria. Additionally, despite common surface proteins identified in L-EVs and S-EVs, our data reveals surfaceome heterogeneity between the two EV-subtype. Collectively, our study provides critical insights into diverse proteins operating at the interactive platform of L-EVs and molecular leads for future studies seeking to decipher L-EV heterogeneity and function.
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Affiliation(s)
- Alin Rai
- Molecular ProteomicsBaker Heart and Diabetes InstituteMelbourneVictoria3004Australia
- Central Clinical SchoolMonash UniversityMelbourneVictoria3004Australia
- Baker Department of Cardiometabolic HealthUniversity of MelbourneMelbourneVictoria3052Australia
| | - Haoyun Fang
- Molecular ProteomicsBaker Heart and Diabetes InstituteMelbourneVictoria3004Australia
| | - Bethany Claridge
- Molecular ProteomicsBaker Heart and Diabetes InstituteMelbourneVictoria3004Australia
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVictoria3086Australia
| | - Richard J. Simpson
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVictoria3086Australia
| | - David W Greening
- Molecular ProteomicsBaker Heart and Diabetes InstituteMelbourneVictoria3004Australia
- Central Clinical SchoolMonash UniversityMelbourneVictoria3004Australia
- Baker Department of Cardiometabolic HealthUniversity of MelbourneMelbourneVictoria3052Australia
- Department of Biochemistry and Genetics, La Trobe Institute for Molecular ScienceLa Trobe UniversityMelbourneVictoria3086Australia
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21
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Asaka S, Nakajima T, Ida K, Asaka R, Kobayashi C, Ito M, Miyamoto T, Uehara T, Ota H. Clinicopathological and prognostic significance of immunophenotypic characterization of endocervical adenocarcinoma using CLDN18, CDH17, and PAX8 in association with HPV status. Virchows Arch 2021; 480:269-280. [PMID: 34581850 DOI: 10.1007/s00428-021-03207-1] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/05/2021] [Revised: 08/16/2021] [Accepted: 09/13/2021] [Indexed: 12/26/2022]
Abstract
In 2020, the WHO published a new system for classifying invasive endocervical adenocarcinoma based on histological features and high-risk human papillomavirus (HPV) infection. However, immunophenotypes of each histological subtype require further investigation. We immunohistochemically analyzed 66 invasive endocervical adenocarcinomas using three cell-lineage-specific markers: claudin 18 (CLDN18) for gastric, cadherin 17 (CDH17) for intestinal, and PAX8 for Müllerian epithelial cells. We identified five immunophenotypes of endocervical adenocarcinoma: gastric (21%); intestinal (14%); gastrointestinal (11%); Müllerian (35%); and not otherwise specified (NOS) (20%). Adenocarcinomas with gastric immunophenotype, characterized by aging (p = 0.0050), infrequent HPV infection (p < 0.0001), concurrent lobular endocervical glandular hyperplasia (p = 0.0060), lymphovascular invasion (p = 0.0073), advanced clinical stage (p = 0.0001), and the poorest progression-free (p < 0.0001) and overall (p = 0.0023) survivals, were morphologically compatible with gastric-type adenocarcinoma of the WHO 2020 classification. Conversely, most adenocarcinomas with Müllerian (91%) and intestinal (89%) immunophenotypes were HPV associated and morphologically compatible with usual- or intestinal-type adenocarcinomas of the WHO 2020 classification. The morphology of adenocarcinomas with gastrointestinal immunophenotype was intermediate or mixed between those of gastric and intestinal immunophenotypes; 57% were HPV associated. Adenocarcinomas with NOS immunophenotype were mainly HPV associated (85%) and histologically poorly differentiated. Multivariate analysis revealed that gastric (p = 0.008), intestinal + gastrointestinal (p = 0.0103), and NOS (p = 0.009) immunophenotypes were independent predictors of progression-free survival. Immunophenotypes characterized by CLDN18, CDH17, and PAX8 exhibited clinicopathological relevance and may improve the diagnostic accuracy and prognostic value of conventional histological classification.
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Affiliation(s)
- Shiho Asaka
- Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan. .,Department of Diagnostic Pathology, Shinshu University Hospital, Matsumoto, Japan.
| | - Tomoyuki Nakajima
- Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Koichi Ida
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Ryoichi Asaka
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Chinatsu Kobayashi
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| | - Masayuki Ito
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, Matsumoto, Japan
| | - Tsutomu Miyamoto
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, Matsumoto, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.,Department of Diagnostic Pathology, Shinshu University Hospital, Matsumoto, Japan
| | - Hiroyoshi Ota
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, Matsumoto, Japan
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22
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Ma H, Xiao W, Wang M, Shi X. CDH17+/CDX2+ Can be Helpful in Providing Support for Small Intestinal Origin Versus Pancreatic or Biliary Origin. Appl Immunohistochem Mol Morphol 2021; 29:541-545. [PMID: 33958523 DOI: 10.1097/pai.0000000000000913] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/19/2020] [Accepted: 12/28/2020] [Indexed: 11/26/2022]
Abstract
Because of the distinct and complex anatomy of the ampullary region, the exact origin of the periampullary tumors was often difficult to ascertain. In this study, we evaluated 78 patient samples, including 26 small intestinal adenocarcinomas, 35 pancreatic ductal adenocarcinomas, and 17 cholangiocarcinomas by immunohistochemical detection of cadherin-17 (CDH17), CDX2, CK20, and CK19 protein expression. The result showed that CDH17 and CDX2 expression was higher in small intestinal adenocarcinoma (73.1% and 65.4%) than in pancreatic (14.3% and 2.9%) and bile duct (41.2% and 23.5%) cancers, respectively. CK20 expression was low in 78 tumor tissues, but relatively high in small intestinal adenocarcinoma (42.3%). CK19 showed a strong positive expression in all 78 adenocarcinoma tissues. The CDH17-high/CDX2-high pattern was predominantly expressed in small intestinal cancer tissues (75%), whereas the CDH17-low/CDX2-low pattern was observed in pancreatic cancers (63.8%) and bile duct cancers (20.9%). The study concluded that CDH17-high/CDX2-high adenocarcinomas more likely originated from small intestine versus pancreas or bile duct, whereas CDH17-low/CDX2-low ones are more likely of pancreatic origin. The combined use of CDH17 and CDX2 could be helpful in providing support for the histologic origin of periampullary adenocarcinoma.
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Affiliation(s)
| | | | | | - Xiaohai Shi
- Gastrointestinal Surgery, Beilun People's Hospital, Ningbo, Zhejiang Province, China
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23
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Kmeid M, Lukose G, Hodge K, Cho D, Kim KA, Lee H. Aberrant expression of SATB2, CDX2, CDH17 and CK20 in hepatocellular carcinoma: a pathological, clinical and outcome study. Histopathology 2021; 79:768-778. [PMID: 34036629 DOI: 10.1111/his.14420] [Citation(s) in RCA: 9] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/20/2021] [Revised: 05/08/2021] [Accepted: 05/23/2021] [Indexed: 12/11/2022]
Abstract
AIMS Data regarding expression of intestinal markers in hepatocellular carcinoma (HCC) are limited. We determined the clinicopathological associations of cytokeratin (CK)19, a progenitor liver epithelial cell marker as well as biliary epithelial marker, and intestinal immunohistochemical markers expression in HCC and assessed their prognostic value. METHODS AND RESULTS Tissue sections and/or tissue microarrays (TMAs) from 202 known HCCs were immunostained using CK19, CK20, CDH17, CDX2 and SATB2 antibodies. Haematoxylin and eosin (H&E)-stained slides were reviewed for tumour grading. Clinical and oncological outcomes were retrieved. Associations of staining with clinicopathological features and survival outcomes were evaluated. CK19, CK20, CDH17, CDX2 and SATB2 were positive in 12.8, 5.4, 10.3, 8.6 and 59.9%, respectively. All but SATB2 were strongly associated with higher tumour grade and AFP levels > 400 ng/ml (P < 0.05). CK19-positive HCC were more likely to express CDX2 (P = 0.001), CDH17 (P < 0.001) and/or CK20 (P = 0.012). CK20, CDX2 and CDH17 co-expression was seen in five cases (2.5%). CK19 and SATB2 positivity, tumour size ≥ 5 cm, background cirrhosis, AFP > 400 ng/ml and having no treatment were associated with decreased overall survival by log-rank test and univariable proportional hazards regression. However, in a multivariable model, CK19 and SATB2 positivity were not independent predictors of decreased survival while their association with known poor prognosticators in HCC was evident. CONCLUSIONS HCC can express markers of intestinal differentiation. This phenotypical aberrancy correlates with variable clinicopathological parameters, some of which are independent predictors of poor survival.
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Affiliation(s)
- Michel Kmeid
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | | | | | - Daniel Cho
- Schenectady Pathology Associates, Ellis Hospital, Schenectady, NY, USA
| | - Kelly-Ann Kim
- Department of Pathology, Albany Medical Center, Albany, NY, USA
| | - Hwajeong Lee
- Department of Pathology, Albany Medical Center, Albany, NY, USA
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24
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Kato T, Wakiyama H, Furusawa A, Choyke PL, Kobayashi H. Near Infrared Photoimmunotherapy; A Review of Targets for Cancer Therapy. Cancers (Basel) 2021; 13:cancers13112535. [PMID: 34064074 PMCID: PMC8196790 DOI: 10.3390/cancers13112535] [Citation(s) in RCA: 43] [Impact Index Per Article: 10.8] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/16/2021] [Revised: 05/12/2021] [Accepted: 05/18/2021] [Indexed: 12/15/2022] Open
Abstract
Simple Summary Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies. Abstract Near-infrared photoimmunotherapy (NIR-PIT) is a newly developed cancer treatment that uses an antibody-photoabsorber (IRDye700DX) conjugate (APC) that is activated by NIR light irradiation. In September 2020, the first APC and laser system were conditionally approved for clinical use in Japan. A major benefit of NIR-PIT is that only APC-bound cancer cells that are exposed to NIR light are killed by NIR-PIT; thus, minimal damage occurs in adjacent normal cells. These early trials have demonstrated that in addition to direct cell killing, there is a significant therapeutic host immune response that greatly contributes to the success of the therapy. Although the first clinical use of NIR-PIT targeted epidermal growth factor receptor (EGFR), many other targets are suitable for NIR-PIT. NIR-PIT has now been applied to many cancers expressing various cell-surface target proteins using monoclonal antibodies designed to bind to them. Moreover, NIR-PIT is not limited to tumor antigens but can also be used to kill specific host cells that create immune-permissive environments in which tumors grow. Moreover, multiple targets can be treated simultaneously with NIR-PIT using a cocktail of APCs. NIR-PIT can be used in combination with other therapies, such as immune checkpoint inhibitors, to enhance the therapeutic effect. Thus, NIR-PIT has great potential to treat a wide variety of cancers by targeting appropriate tumor cells, immune cells, or both, and can be augmented by other immunotherapies.
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25
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Park JW, Jeong JM, Cho KS, Cho SY, Cheon JH, Choi DH, Park SJ, Kim HK. MiR-30a and miR-200c differentiate cholangiocarcinomas from gastrointestinal cancer liver metastases. PLoS One 2021; 16:e0250083. [PMID: 33852640 PMCID: PMC8046207 DOI: 10.1371/journal.pone.0250083] [Citation(s) in RCA: 3] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Accepted: 03/30/2021] [Indexed: 11/19/2022] Open
Abstract
Prior studies have demonstrated the utility of microRNA assays for predicting some cancer tissue origins, but these assays need to be further optimized for predicting the tissue origins of adenocarcinomas of the liver. We performed microRNA profiling on 195 frozen primary tumor samples using 14 types of tumors that were either adenocarcinomas or differentiated from adenocarcinomas. The 1-nearest neighbor method predicted tissue-of-origin in 33 samples of a test set, with an accuracy of 93.9% at feature selection p values ranging from 10-4 to 10-10. According to binary decision tree analyses, the overexpression of miR-30a and the underexpression of miR-200 family members (miR-200c and miR-141) differentiated intrahepatic cholangiocarcinomas from extrahepatic adenocarcinomas. When binary decision tree analyses were performed using the test set, the prediction accuracy was 84.8%. The overexpression of miR-30a and the reduced expressions of miR-200c, miR-141, and miR-425 could distinguish intrahepatic cholangiocarcinomas from liver metastases from the gastrointestinal tract.
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Affiliation(s)
- Jun Won Park
- National Cancer Center of Korea, Goyang, Republic of Korea
- Department of Biomedical Convergence, Kangwon National University, Kangwon, Republic of Korea
| | - Jong Min Jeong
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Kye Soo Cho
- National Cancer Center of Korea, Goyang, Republic of Korea
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Soo Young Cho
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Jae Hee Cheon
- Department of Internal Medicine and Institute of Gastroenterology, Yonsei University College of Medicine, Seoul, Republic of Korea
| | - Dong Ho Choi
- Departments of Surgery, Hanyang University School of Medicine, Seoul, Republic of Korea
| | - Sang Jae Park
- National Cancer Center of Korea, Goyang, Republic of Korea
| | - Hark Kyun Kim
- National Cancer Center of Korea, Goyang, Republic of Korea
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26
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Quality control and evaluation of Inonotus obliquus using HPLC method with novel marker compounds. J Anal Sci Technol 2020. [DOI: 10.1186/s40543-020-00249-z] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/23/2023] Open
Abstract
AbstractCurrent quality control ofInonotus obliquusrequires chromogen complex content limit of 10% in accordance with the State Pharmacopoeia of the Union of Soviet Socialist Republics. However, this causes ambiguous results, impeding precise quality control. To improve ambiguous quality control criteria, this study developed a new HPLC method using two novel marker compounds (inotodiol and 3β-hydroxylanosta-8,24-dien-21-al) to control the quality control ofI. obliquus. The HPLC analysis was carried out in a C18 column with an isocratic elution of 95% acetonitrile at 210 nm. The developed method validated in terms of linearity, precision, accuracy, and recovery. The content criteria were established by the linear regression method and relative standard deviation method. As the results of the quantitative monitoring, 1.165 mg/g of inotodiol and 1.717 mg/g of 3β-hydroxylanosta-8,24-dien-21-al, calculated by the relative standard deviation method, were suggested new quality criteria. A new HPLC method was developed to improve current quality control ofI. obliquusand new lower content criteria were proposed as a result of quantitative monitoring.Graphical abstract
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Massalha H, Bahar Halpern K, Abu‐Gazala S, Jana T, Massasa EE, Moor AE, Buchauer L, Rozenberg M, Pikarsky E, Amit I, Zamir G, Itzkovitz S. A single cell atlas of the human liver tumor microenvironment. Mol Syst Biol 2020; 16:e9682. [PMID: 33332768 PMCID: PMC7746227 DOI: 10.15252/msb.20209682] [Citation(s) in RCA: 115] [Impact Index Per Article: 23.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/01/2020] [Revised: 11/11/2020] [Accepted: 11/18/2020] [Indexed: 02/06/2023] Open
Abstract
Malignant cell growth is fueled by interactions between tumor cells and the stromal cells composing the tumor microenvironment. The human liver is a major site of tumors and metastases, but molecular identities and intercellular interactions of different cell types have not been resolved in these pathologies. Here, we apply single cell RNA-sequencing and spatial analysis of malignant and adjacent non-malignant liver tissues from five patients with cholangiocarcinoma or liver metastases. We find that stromal cells exhibit recurring, patient-independent expression programs, and reconstruct a ligand-receptor map that highlights recurring tumor-stroma interactions. By combining transcriptomics of laser-capture microdissected regions, we reconstruct a zonation atlas of hepatocytes in the non-malignant sites and characterize the spatial distribution of each cell type across the tumor microenvironment. Our analysis provides a resource for understanding human liver malignancies and may expose potential points of interventions.
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Affiliation(s)
- Hassan Massalha
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Keren Bahar Halpern
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Samir Abu‐Gazala
- Department of General SurgeryHadassah Hebrew University Medical CenterJerusalemIsrael
- Transplant DivisionDepartment of SurgeryHospital of the University of PennsylvaniaPhiladelphiaPAUSA
| | - Tamar Jana
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Efi E Massasa
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Andreas E Moor
- Department of Biosystems Science and EngineeringETH ZürichBaselSwitzerland
| | - Lisa Buchauer
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Milena Rozenberg
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
| | - Eli Pikarsky
- The Lautenberg Center for ImmunologyInstitute for Medical Research Israel‐CanadaHebrew University Medical SchoolJerusalemIsrael
| | - Ido Amit
- Department of ImmunologyWeizmann Institute of ScienceRehovotIsrael
| | - Gideon Zamir
- Department of General SurgeryHadassah Hebrew University Medical CenterJerusalemIsrael
| | - Shalev Itzkovitz
- Department of Molecular Cell BiologyWeizmann Institute of ScienceRehovotIsrael
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Wan X, Zhang H, Zhang Y, Peng Y. Metastases to the Breast from Extramammary Nonhematological Malignancies: Case Series. Int J Gen Med 2020; 13:1105-1114. [PMID: 33209053 PMCID: PMC7670084 DOI: 10.2147/ijgm.s276602] [Citation(s) in RCA: 10] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/11/2020] [Accepted: 10/21/2020] [Indexed: 02/05/2023] Open
Abstract
Objective This article aims to provide a better understanding of ultrasonography and immunohistochemistry of secondary nonhematological tumors of breast. Methods The study reviewed the ultrasound findings and immunohistochemical features of nonhematological metastatic breast tumor cases found in patients of West China Hospital, Sichuan University from 2007 to 2019. Each case was categorized as secondary breast malignancy using histopathological results. Results Fourteen cases were identified from West China Hospital database. Ten cases originated in the lung, 2 cases in the stomach, 1 case in the ovary and 1 case of neuroendocrine carcinomas. Fourteen masses were evaluated. Ultrasound findings showed that tumors were hypoechoic (14/14), irregular (13/14), indistinct margin (13/14), along a long axis parallel to the skin (11/14), lacked vascularity via color doppler flow imaging (9/14). Eight cases showed no posterior features. Calcification was found in 1 case of lung adenocarcinoma that had metastasized to the breast. Abnormal axillary lymph nodes were detected in 5 cases. Immunohistochemical analysis showed that estrogen receptor (ER) and progesterone receptor (PR) were both negative in 11 cases, including gastric and lung cancer metastasis. One case of ovarian metastasis was positive for ER and negative for PR. Six patients were positive for cytokeratin 7 (CK7) and negative for cytokeratin 20 (CK20), including lung and ovarian carcinoma metastasis. Thyroid transcription factor-1 (TTF-1) was positive in 9 of 10 pulmonary carcinoma metastases. The patient of ovarian metastasis was positive for Wilms' tumour 1 (WT-1) and carbohydrate antigen 125 (CA125). Two cases from gastric metastasis were positive for caudal-type homeobox 2 (CDX2). Conclusion Although breast ultrasound is not useful in distinguishing metastases from primary breast cancer, it is helpful in diagnosing breast lesions as oncological diseases and provide evidence for further examination of patients. Immunohistochemistry plays an important role in distinguishing secondary breast cancer from primary, especially in patients without tumor history.
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Affiliation(s)
- Xue Wan
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Heqing Zhang
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Yahan Zhang
- Department of Pathology, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
| | - Yulan Peng
- Department of Ultrasound, West China Hospital of Sichuan University, Chengdu, Sichuan 610041, People's Republic of China
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García-Martínez JM, Wang S, Weishaeupl C, Wernitznig A, Chetta P, Pinto C, Ho J, Dutcher D, Gorman PN, Kroe-Barrett R, Rinnenthal J, Giragossian C, Impagnatiello MA, Tirapu I, Hilberg F, Kraut N, Pearson M, Kuenkele KP. Selective Tumor Cell Apoptosis and Tumor Regression in CDH17-Positive Colorectal Cancer Models using BI 905711, a Novel Liver-Sparing TRAILR2 Agonist. Mol Cancer Ther 2020; 20:96-108. [PMID: 33037135 DOI: 10.1158/1535-7163.mct-20-0253] [Citation(s) in RCA: 17] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/31/2020] [Revised: 08/12/2020] [Accepted: 09/30/2020] [Indexed: 11/16/2022]
Abstract
Activation of TRAILR2 has emerged as an important therapeutic concept in cancer treatment. TRAILR2 agonistic molecules have only had limited clinical success, to date, due either to lack of efficacy or hepatotoxicity. BI 905711 is a novel tetravalent bispecific antibody targeting both TRAILR2 and CDH17 and represents a novel liver-sparing TRAILR2 agonist specifically designed to overcome the disadvantages of previous strategies. Here, we show that BI 905711 effectively triggered apoptosis in a broad panel of CDH17-positive colorectal cancer tumor cells in vitro. Efficient induction of apoptosis was dependent on the presence of CDH17, as exemplified by the greater than 1,000-fold drop in potency in CDH17-negative cells. BI 905711 demonstrated single-agent tumor regressions in CDH17-positive colorectal cancer xenografts, an effect that was further enhanced upon combination with irinotecan. Antitumor efficacy correlated with induction of caspase activation, as measured in both the tumor and plasma. Effective tumor growth inhibition was further demonstrated across a series of different colorectal cancer PDX models. BI 905711 induced apoptosis in both a cis (same cell) as well as trans (adjacent cell) fashion, translating into significant antitumor activity even in xenograft models with heterogeneous CDH17 expression. In summary, we demonstrate that BI 905711 has potent and selective antitumor activity in CDH17-positive colorectal cancer models both in vitro and in vivo. The high prevalence of over 95% CDH17-positive tumors in patients with colorectal cancer, the molecule preclinical efficacy together with its potential for a favorable safety profile, support the ongoing BI 905711 phase I trial in colorectal cancer and additional CDH17-positive cancer types (NCT04137289).
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Affiliation(s)
| | - Shirley Wang
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | | | | | - Paolo Chetta
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Catarina Pinto
- Boehringer Ingelheim Cancer Immunology and Immune Modulation, Vienna, Austria
| | - Jason Ho
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Darrin Dutcher
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Philip N Gorman
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Rachel Kroe-Barrett
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | - Joerg Rinnenthal
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Craig Giragossian
- Boehringer Ingelheim Biotherapeutics Discovery Research, Ridgefield, Connecticut
| | | | - Iñigo Tirapu
- Boehringer Ingelheim Cancer Immunology and Immune Modulation, Vienna, Austria
| | - Frank Hilberg
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Norbert Kraut
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
| | - Mark Pearson
- Boehringer Ingelheim Cancer Research Therapeutic Area, Vienna, Austria
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Immunoaffinity enrichment LC-MS/MS quantitation of CDH17 in tissues. Bioanalysis 2020; 12:1439-1447. [PMID: 33006478 DOI: 10.4155/bio-2020-0162] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/17/2022] Open
Abstract
Aim: There is little information in the literature regarding assays for measuring CDH17 in tissues. Numerous studies indicate overexpression of CDH17 in a variety of diseases including hepatocellular carcinoma, colorectal and gastric cancer. Here we present an immunoaffinity enrichment LC-MS/MS approach for analysis of CDH17 in human tissues, plasma and serum as well as preclinical models. Results: CDH17 levels were measured in colon and ileum tissues from healthy donors and inflamed tissues from patients with Ulcerative Colitus or Crohn's disease. Applicability of the immunocapture LC-MS/MS approach is demonstrated for colon tissues from non-diseased mouse and cynomolgus monkey. Conclusion: The analytical approaches discussed here are suitable for quantitation of CDH17 in various tissues to enable both preclinical and clinical assessment.
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Lum YL, Luk JM, Staunton DE, Ng DKP, Fong WP. Cadherin-17 Targeted Near-Infrared Photoimmunotherapy for Treatment of Gastrointestinal Cancer. Mol Pharm 2020; 17:3941-3951. [PMID: 32931292 DOI: 10.1021/acs.molpharmaceut.0c00700] [Citation(s) in RCA: 19] [Impact Index Per Article: 3.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/20/2023]
Abstract
In cancer photodynamic therapy (PDT), a photosensitizer taken up by cancer cells can generate reactive oxygen species upon near-infrared light activation to induce cancer cell death. To increase PDT potency and decrease its adverse effect, one approach is to conjugate the photosensitizer with an antibody that specifically targets cancer cells. In the present study, IR700, a hydrophilic phthalocyanine photosensitizer, was conjugated to the humanized monoclonal antibody ARB102, which binds specifically cadherin-17 (CDH17 aka CA17), a cell surface marker highly expressed in gastrointestinal cancer to produce ARB102-IR700. Photoimmunotherapy (PIT) of gastrointestinal cancer cell lines was conducted by ARB102-IR700 treatment and near-infrared light irradiation. The results showed that ARB102-IR700 PIT could induce cell death in CDH17-positive cancer cells with high potency. In a co-culture model, CDH17-negative and CDH17-overexpressing SW480 cells were labeled with distinct fluorescent dyes and cultured together prior to PIT treatment. The results confirmed that ARB102-IR700 PIT could kill CDH17-positive cells specifically, while leaving the adjacent CDH17-negative cells unaffected. An in vivo efficacy study was conducted using a pancreatic adenocarcinoma AsPC-1 xenograft tumor model in nude mice. Fluorescence scanning indicated that ARB102-IR700 accumulated specifically in the tumor sites. To perform PIT, at 24 and 48 h postinjection, mice were irradiated with a 680 nm laser at the tumor site to activate the photosensitizer. It was shown that ARB102-IR700 PIT could inhibit tumor growth significantly. In summary, this study demonstrated that the novel ARB102-IR700 is a promising agent for PIT in gastrointestinal cancers.
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Affiliation(s)
- Yick-Liang Lum
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - John M Luk
- Arbele Limited, Shatin N.T., Hong Kong, China
| | | | - Dennis K P Ng
- Department of Chemistry, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
| | - Wing-Ping Fong
- School of Life Sciences, The Chinese University of Hong Kong, Shatin, N.T., Hong Kong, China
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Abouelkhair MB, Mabrouk SH, Zaki SSA, Nada OH, Hakim SA. The Diagnostic Value of Cadherin 17 and CDX2 Expression as Immunohistochemical Markers in Colorectal Adenocarcinoma. J Gastrointest Cancer 2020; 52:960-969. [PMID: 32929682 DOI: 10.1007/s12029-020-00513-w] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 09/06/2020] [Indexed: 11/30/2022]
Abstract
BACKGROUND Colorectal cancer is a major cause of morbidity and mortality throughout the world. Although the diagnosis of colorectal cancer is straightforward in primary site, yet it may represent a diagnostic problem in metastatic tumor of unknown primary origin. Hence, immunohistochemical analysis in combination with morphologic assessment and correlation with clinical data becomes crucial, because it is important to specify the primary site of metastasis since some specific tumor types may respond well to targeted molecular therapies. Therefore, establishment of reliable diagnostic markers that confirm or rule out colorectal origin is mandatory. AIM To study the expression of cadherin 17 and CDX2 in colorectal carcinoma and to evaluate their diagnostic roles in identifying metastatic colonic from non-colonic adenocarcinomas in cancer of unknown primary site. DESIGN AND METHODS This retrospective study included 65 cases of adenocarcinomas: 35 cases of colorectal adenocarcinoma (primary or metastatic) and 30 cases of non-colorectal adenocarcinoma. They were retrieved from the archives of Pathology Department of Ain Shams University and Ain Shams University Specialized Hospitals during the period from 2010 to 2015. Immunohistochemical study was performed using cadherin 17 and CDX2 antibodies. RESULTS The sensitivity and specificity of CDX2 and cadherin 17 are 97.1% and 53.3% and 100% and 50% in detecting colonic adenocarcinoma respectively. The PPV, NPV, and overall accuracy of CDX2 versus cadherin 17 were 70.8%, 94.1%, and 76.9% versus 70%, 100%, and 76.9% respectively. CONCLUSION Cadherin 17 is a more sensitive marker than CDX2 in diagnosis of carcinoma of unknown primary site especially when colorectal carcinoma is suspected.
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Affiliation(s)
- Mariam B Abouelkhair
- Department of Pathology, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, 11561, Egypt
| | - Shadia H Mabrouk
- Department of Pathology, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, 11561, Egypt
| | - Sahar S A Zaki
- Department of Pathology, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, 11561, Egypt
| | - Ola H Nada
- Department of Pathology, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, 11561, Egypt
| | - Sarah A Hakim
- Department of Pathology, Faculty of Medicine, Ain Shams University, Abbasseya Square, Cairo, 11561, Egypt.
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A panel of intestinal differentiation markers (CDX2, GPA33, and LI-cadherin) identifies gastric cancer patients with favourable prognosis. Gastric Cancer 2020; 23:811-823. [PMID: 32215766 DOI: 10.1007/s10120-020-01064-6] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 01/04/2020] [Accepted: 03/12/2020] [Indexed: 02/07/2023]
Abstract
BACKGROUND Gastric cancer is the fifth most common cancer and the third cause of global cancer mortality. CDX2 is an intestinal differentiation marker with prognostic value in gastric cancer and transcriptionally regulates the expression of glycoprotein A33 (GPA33) and liver intestine cadherin (LI-cadherin). METHODS This study evaluated the clinical significance of the combined expression of CDX2 and its targets GPA33 and LI-cadherin in gastric cancer by fluorescence-based multiplex immunohistochemistry together with digital image analysis and chromogenic immunohistochemistry in 329 gastric cancer samples arranged in tissue microarrays. Additionally, publicly available RNA-seq expression data from 354 gastric cancer samples from the TCGA database were used to validate the immunohistochemistry results. RESULTS Expression of the three markers (CDX2, GPA33, and LI-cadherin) was strongly correlated, defining an intestinal differentiation panel. Low or negative protein expression of the intestinal differentiation panel identified patients with particularly poor overall survival, irrespective of the methodology used, and was validated in the independent series at the RNA-seq level. CONCLUSIONS Expression of the intestinal differentiation panel (CDX2, GPA33, and LI-cadherin) defines a set of biomarkers with a strong biological rationale and favourable impact for prognostication of gastric cancer patients.
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Lee AHS, Hodi Z, Soomro I, Sovani V, Abbas A, Rakha E, Ellis IO. Histological clues to the diagnosis of metastasis to the breast from extramammary malignancies. Histopathology 2020; 77:303-313. [PMID: 32396659 DOI: 10.1111/his.14141] [Citation(s) in RCA: 14] [Impact Index Per Article: 2.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/29/2020] [Accepted: 05/07/2020] [Indexed: 12/30/2022]
Abstract
AIMS The aims of this study were to review the histological features useful for the identification of metastases to the breast and to investigate the impression that this diagnosis has become more common. METHODS AND RESULTS The histological features of metastases to the breast from 2008 to 2018 were reviewed. Seventy-four biopsies from 66 patients were identified: 1% compared with primary carcinoma of the breast. Non-haematological metastases comprised 0.75% compared with 0.3% in a series from 1996 to 2005. The most common tumour types were pulmonary carcinoma (22), lymphoma (15), melanoma (13), gastrointestinal carcinoma (eight) and serous papillary carcinoma (four). In 73% there were histological features that were not typical of primary mammary carcinoma. Some metastases were histologically similar to breast cancer and the history was essential to making the correct diagnosis. Useful histological clues included small-cell morphology for pulmonary carcinoma, glands containing necrosis for gastrointestinal carcinoma, intranuclear inclusions, marked pleomorphism and spindle cells for melanoma, clear cells for renal carcinoma, papillary architecture for serous papillary carcinoma and sheets of centroblasts or nodules of centroblasts and centrocytes for lymphoma. Useful immunohistochemical markers included TTF-1 for pulmonary carcinoma, S100, melan-A and HMB45 for melanoma, CK20 and CDX2 for colorectal carcinoma, PAX8 and WT1 for serous papillary carcinoma and lymphoid markers for lymphomas, in addition to the absence of expression of mammary markers ER, GATA3 and GCDFP-15. CONCLUSION The majority of metastases to the breast have histological clues to the diagnosis. Immunohistochemistry is helpful. This diagnosis is being made more frequently.
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Affiliation(s)
- Andrew H S Lee
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | - Zsolt Hodi
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | - Irshad Soomro
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | - Vishakha Sovani
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | - Areeg Abbas
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | - Emad Rakha
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
| | - Ian O Ellis
- Department of Histopathology, Nottingham University Hospitals, City Hospital Campus, Nottingham, UK
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LI-cadherin and CDX2: Useful Markers in Metastatic Gastrointestinal Adenocarcinoma Cells in Serous Cavity Effusion. Appl Immunohistochem Mol Morphol 2020; 27:e75-e80. [PMID: 30095466 DOI: 10.1097/pai.0000000000000694] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022]
Abstract
OBJECTIVE The aim of this study was to investigate the expression and significance of liver-intestine cadherin (LI-cadherin) and CDX2 (caudal-type homeobox transcription factor 2) in cytology specimens of metastatic gastrointestinal adenocarcinoma in serous cavity effusion. MATERIALS AND METHODS The serous cavity effusion samples that were suspected of tumor metastasis in the last 5 years were made into paraffin-imbedded cell blocks, a total of 180 cases, including 97 cases of pleural effusion, 78 cases of ascites, and 5 cases of pericardial effusion. The expressions of LI-cadherin and CDX2 were detected by immunohistochemical staining in cell blocks and primary tumor tissues; thereafter, the specificity and sensitivity were analyzed. RESULTS The positive expressions of LI-cadherin and CDX2 in 63 cases of gastrointestinal adenocarcinoma cells were 65.1% (41/63), 61.9% (39/63), respectively. Of 11 cases of pancreaticobiliary duct cancers, only one case (9.09%) was weakly positive for LI-cadherin and CDX2 expressions, and 107 cases of non-digestive tract cancers were all negative. In 57 matched-pair samples of cell blocks and primary gastrointestinal adenocarcinoma tissues, the positive expressions of LI-cadherin and CDX2 were 64.9% (37/57), 61.4% (35/57), respectively, in cells, and 82.5% (47/57), and 77.2% (44/57), respectively, in tissues. Positive correlation was observed between the expressions of LI-cadherin and CDX2 in metastatic gastrointestinal adenocarcinoma cells (P<0.05). Both LI-cadherin and CDX2 expressions demonstrated positive correlation in cells with paired cancer tissues (P<0.05). The positive expression reached 80.7% with at least one positive marker in the total cell samples through combined detection of LI-cadherin and CDX2, increased by 15.8% and 19.3% compared with using either of the markers alone. CONCLUSIONS Combined use of LI-cadherin and CDX2 can improve the accuracy in the diagnosis of metastatic adenocarcinoma cells in serous cavity effusion and provide some bases of histologic origin because of their high sensitivity and specificity.
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An Algorithmic Immunohistochemical Approach to Define Tumor Type and Assign Site of Origin. Adv Anat Pathol 2020; 27:114-163. [PMID: 32205473 DOI: 10.1097/pap.0000000000000256] [Citation(s) in RCA: 50] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/17/2022]
Abstract
Immunohistochemistry represents an indispensable complement to an epidemiology and morphology-driven approach to tumor diagnosis and site of origin assignment. This review reflects the state of my current practice, based on 15-years' experience in Pathology and a deep-dive into the literature, always striving to be better equipped to answer the age old questions, "What is it, and where is it from?" The tables and figures in this manuscript are the ones I "pull up on the computer" when I am teaching at the microscope and turn to myself when I am (frequently) stuck. This field is so exciting because I firmly believe that, through the application of next-generation immunohistochemistry, we can provide better answers than ever before. Specific topics covered in this review include (1) broad tumor classification and associated screening markers; (2) the role of cancer epidemiology in determining pretest probability; (3) broad-spectrum epithelial markers; (4) noncanonical expression of broad tumor class screening markers; (5) a morphologic pattern-based approach to poorly to undifferentiated malignant neoplasms; (6) a morphologic and immunohistochemical approach to define 4 main carcinoma types; (7) CK7/CK20 coordinate expression; (8) added value of semiquantitative immunohistochemical stain assessment; algorithmic immunohistochemical approaches to (9) "garden variety" adenocarcinomas presenting in the liver, (10) large polygonal cell adenocarcinomas, (11) the distinction of primary surface ovarian epithelial tumors with mucinous features from metastasis, (12) tumors presenting at alternative anatomic sites, (13) squamous cell carcinoma versus urothelial carcinoma, and neuroendocrine neoplasms, including (14) the distinction of pheochromocytoma/paraganglioma from well-differentiated neuroendocrine tumor, site of origin assignment in (15) well-differentiated neuroendocrine tumor and (16) poorly differentiated neuroendocrine carcinoma, and (17) the distinction of well-differentiated neuroendocrine tumor G3 from poorly differentiated neuroendocrine carcinoma; it concludes with (18) a discussion of diagnostic considerations in the broad-spectrum keratin/CD45/S-100-"triple-negative" neoplasm.
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Oh HH, Joo YE. Novel biomarkers for the diagnosis and prognosis of colorectal cancer. Intest Res 2020; 18:168-183. [PMID: 31766836 PMCID: PMC7206347 DOI: 10.5217/ir.2019.00080] [Citation(s) in RCA: 70] [Impact Index Per Article: 14.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/05/2019] [Revised: 09/05/2019] [Accepted: 10/24/2019] [Indexed: 02/06/2023] Open
Abstract
Colorectal cancer (CRC) is among the most common malignancies and remains a major cause of cancer-related death worldwide. Despite recent advances in surgical and multimodal therapies, the overall survival of advanced CRC patients remains very low. Cancer progression, including invasion and metastasis, is a major cause of death among CRC patients. The underlying mechanisms of action resulting in cancer progression are beginning to unravel. The reported molecular and biochemical mechanisms that might contribute to the phenotypic changes in favor of carcinogenesis include apoptosis inhibition, enhanced tumor cell proliferation, increased invasiveness, cell adhesion perturbations, angiogenesis promotion, and immune surveillance inhibition. These events may contribute to the development and progression of cancer. A biomarker is a molecule that can be detected in tissue, blood, or stool samples to allow the identification of pathological conditions such as cancer. Thus, it would be beneficial to identify reliable and practical molecular biomarkers that aid in the diagnostic and therapeutic processes of CRC. Recent research has targeted the development of biomarkers that aid in the early diagnosis and prognostic stratification of CRC. Despite that, the identification of diagnostic, prognostic, and/or predictive biomarkers remains challenging, and previously identified biomarkers might be insufficient to be clinically applicable or offer high patient acceptability. Here, we discuss recent advances in the development of molecular biomarkers for their potential usefulness in early and less-invasive diagnosis, treatment, and follow-up of CRC.
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Affiliation(s)
- Hyung-Hoon Oh
- Department of Internal Medicine, 3rd Fleet Medical Corps, Republic of Korea Navy, Yeongam, Korea
| | - Young-Eun Joo
- Department of Internal Medicine, Chonnam National University Medical School, Gwangju, Korea
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Asaka S, Nakajima T, Kugo K, Kashiwagi R, Yazaki N, Miyamoto T, Uehara T, Ota H. Immunophenotype analysis using CLDN18, CDH17, and PAX8 for the subcategorization of endocervical adenocarcinomas in situ: gastric-type, intestinal-type, gastrointestinal-type, and Müllerian-type. Virchows Arch 2020; 476:499-510. [PMID: 31932920 DOI: 10.1007/s00428-019-02739-x] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/18/2019] [Revised: 12/10/2019] [Accepted: 12/22/2019] [Indexed: 12/16/2022]
Abstract
A classification system for invasive endocervical adenocarcinoma (ECA) focusing on high-risk human papillomavirus (HPV) detection has been recently developed. However, precursor lesions of each ECA subtype and immunohistochemical markers that effectively subcategorize ECAs with gastric and intestinal differentiation have not been fully described. Here, we aimed to subcategorize endocervical adenocarcinoma in situ (AIS) by immunophenotype and to characterize the histopathology of each AIS subtype. We immunohistochemically analyzed 36 AIS and 25 lobular endocervical glandular hyperplasia (LEGH) samples using three cell lineage-specific markers (CLDN18, gastric epithelial cells; CDH17, intestinal epithelial cells; and PAX8, Müllerian epithelial cells). The AISs were immunophenotypically classified as gastric-type (G-AIS; n = 2), intestinal-type (I-AIS; n = 10), gastrointestinal-type (GI-AIS; n = 3), Müllerian-type (M-AIS; n = 18), and AIS, not otherwise specified (AIS-NOS; n = 3). All 25 LEGHs were categorized as gastric-type. G-AIS had pale eosinophilic or clear cytoplasm with a small amount of apical mucin and fewer mitotic bodies. I-AIS comprised various numbers of goblet cell-type tumor cells. GI-AIS showed intermediate or mixed features of G-AIS and I-AIS. M-AIS, as with the usual-type ECA, was typically characterized by mucin depletion; however, several lesions had abundant cytoplasmic mucin. High-risk HPV was detected in most AISs but was negative in 100% (2/2) of G-AIS, 10% (1/10) of I-AIS, and 6% (1/18) of M-AIS lesions. In summary, the AIS subtypes defined by immunophenotype had distinct histopathological and etiological characteristics. Thus, immunophenotyping with CLDN18, CDH17, and PAX8 might improve the diagnostic accuracy of histopathological classifications of ECAs.
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Affiliation(s)
- Shiho Asaka
- Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
- Department of Diagnostic Pathology, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan.
| | - Tomoyuki Nakajima
- Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Kaori Kugo
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Risako Kashiwagi
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Nozomi Yazaki
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Tsutomu Miyamoto
- Department of Obstetrics and Gynecology, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Takeshi Uehara
- Department of Laboratory Medicine, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
- Department of Diagnostic Pathology, Shinshu University Hospital, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
| | - Hiroyoshi Ota
- Department of Clinical Laboratory Sciences, Shinshu University School of Medicine, 3-1-1 Asahi, Matsumoto, Nagano, 390-8621, Japan
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Lv Y, Lin SY, Hu FF, Ye Z, Zhang Q, Wang Y, Guo AY. Landscape of cancer diagnostic biomarkers from specifically expressed genes. Brief Bioinform 2019; 21:2175-2184. [PMID: 31814027 DOI: 10.1093/bib/bbz131] [Citation(s) in RCA: 41] [Impact Index Per Article: 6.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/02/2019] [Revised: 08/25/2019] [Accepted: 09/08/2019] [Indexed: 12/31/2022] Open
Abstract
Although there has been great progress in cancer treatment, cancer remains a serious health threat to humans because of the lack of biomarkers for diagnosis, especially for early-stage diagnosis. In this study, we comprehensively surveyed the specifically expressed genes (SEGs) using the SEGtool based on the big data of gene expression from the The Cancer Genome Atlas (TCGA) and the Genotype-Tissue Expression (GTEx) projects. In 15 solid tumors, we identified 233 cancer-specific SEGs (cSEGs), which were specifically expressed in only one cancer and showed great potential to be diagnostic biomarkers. Among them, three cSEGs (OGDH, MUDENG and ACO2) had a sample frequency >80% in kidney cancer, suggesting their high sensitivity. Furthermore, we identified 254 cSEGs as early-stage diagnostic biomarkers across 17 cancers. A two-gene combination strategy was applied to improve the sensitivity of diagnostic biomarkers, and hundreds of two-gene combinations were identified with high frequency. We also observed that 13 SEGs were targets of various drugs and nearly half of these drugs may be repurposed to treat cancers with SEGs as their targets. Several SEGs were regulated by specific transcription factors in the corresponding cancer, and 39 cSEGs were prognosis-related genes in 7 cancers. This work provides a survey of cancer biomarkers for diagnosis and early diagnosis and new insights to drug repurposing. These biomarkers may have great potential in cancer research and application.
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Affiliation(s)
- Yao Lv
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China
| | - Sheng-Yan Lin
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China
| | - Fei-Fei Hu
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China
| | - Zheng Ye
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China.,Tianjin Key Laboratory of Medical Epigenetics, Key Laboratory of Breast Cancer Prevention and Therapy (Ministry of Education), Tianjin Key Laboratory of Spine and Spinal Cord, Department of Biochemistry and Molecular Biology, Tianjin Medical University, Tianjin 300070, P. R. China
| | - Qiong Zhang
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China
| | - Yan Wang
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China
| | - An-Yuan Guo
- Department of Bioinformatics and Systems Biology, Key Laboratory of Molecular Biophysics of the Ministry of Education, Hubei Bioinformatics and Molecular Imaging Key Laboratory, College of Life Science and Technology, Huazhong University of Science and Technology, Wuhan, Hubei, 430074, P. R. China
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Fujiwara K, Tsuji AB, Sudo H, Sugyo A, Akiba H, Iwanari H, Kusano-Arai O, Tsumoto K, Momose T, Hamakubo T, Higashi T. 111In-labeled anti-cadherin17 antibody D2101 has potential as a noninvasive imaging probe for diagnosing gastric cancer and lymph-node metastasis. Ann Nucl Med 2019; 34:13-23. [PMID: 31605356 PMCID: PMC6970965 DOI: 10.1007/s12149-019-01408-y] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/02/2019] [Accepted: 09/30/2019] [Indexed: 12/16/2022]
Abstract
OBJECTIVE Cadherin-17 (CDH17) is a transmembrane protein that mediates cell-cell adhesion and is frequently expressed in adenocarcinomas, including gastric cancer. CDH17 may be an effective diagnostic marker for the staging of gastric cancer. Here, we developed an 111In-labeled anti-CDH17 monoclonal antibody (Mab) as an imaging tracer and performed biodistribution and single-photon emission computed tomography (SPECT)/computed tomography (CT) imaging studies using mice with CDH17-positive gastric cancer xenografts. CDH17 expression in gastric cancer specimens was also analyzed. METHODS The cross-reactivity and affinity of our anti-CDH17 Mab D2101 was evaluated by surface plasmon resonance analysis and cell enzyme-linked immunosorbent assay, respectively. Biodistribution and SPECT/CT studies of 111In-labeled D2101 (111In-D2101) were performed. CDH17 expression in gastric cancer specimens was evaluated by immunohistochemistry. RESULTS Surface plasmon resonance analysis revealed that D2101 specifically recognizes human CDH17, but not murine CDH17. The affinity of D2101 slightly decreased as a result of the radiolabeling procedures. The biodistribution study revealed high uptake of 111In-D2101 in tumors (maximum, 39.2 ± 9.5% ID/g at 96 h postinjection), but low uptake in normal organs, including the stomach. Temporal SPECT/CT imaging with 111In-D2101 visualized tumors with a high degree of tumor-to-nontumor contrast. Immunohistochemical analysis revealed that, compared with HER2, which is a potential marker of N-stage, CDH17 had a higher frequency of positivity in specimens of primary and metastatic gastric cancer. CONCLUSION Our 111In-anti-CDH17 Mab D2101 depicted CDH17-positive gastric cancer xenografts in vivo and has the potential to be an imaging probe for the diagnosis of primary lesions and lymph-node metastasis in gastric cancer.
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Affiliation(s)
- Kentaro Fujiwara
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
| | - Atsushi B Tsuji
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan.
| | - Hitomi Sudo
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
| | - Aya Sugyo
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
| | - Hiroki Akiba
- Laboratory of Pharmacokinetic Optimization, Center for Drug Design Research, National Institutes of Biomedical Innovation, Health and Nutrition, Osaka, Japan
| | - Hiroko Iwanari
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Osamu Kusano-Arai
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Institute of Immunology Co., Ltd., Tokyo, Japan
| | - Kouhei Tsumoto
- Department of Bioengineering, School of Engineering, The University of Tokyo, Tokyo, Japan
| | - Toshimitsu Momose
- Department of Radiology, Faculty of Medicine, International University of Health and Welfare, Chiba, Japan
| | - Takao Hamakubo
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan.,Department of Protein-Protein Interaction Research, Institute for Advanced Medical Sciences, Nippon Medical School, Tokyo, Japan
| | - Tatsuya Higashi
- Department of Molecular Imaging and Theranostics, National Institute of Radiological Sciences, National Institutes for Quantum and Radiological Science and Technology (QST-NIRS), 4-9-1 Anagawa, Inage, 263-8555, Chiba, Japan
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Serafín V, Valverde A, Garranzo-Asensio M, Barderas R, Campuzano S, Yáñez-Sedeño P, Pingarrón JM. Simultaneous amperometric immunosensing of the metastasis-related biomarkers IL-13Rα2 and CDH-17 by using grafted screen-printed electrodes and a composite prepared from quantum dots and carbon nanotubes for signal amplification. Mikrochim Acta 2019; 186:411. [DOI: 10.1007/s00604-019-3531-5] [Citation(s) in RCA: 34] [Impact Index Per Article: 5.7] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/01/2019] [Accepted: 05/19/2019] [Indexed: 02/07/2023]
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Brettfeld SM, Ramos BD, Berry RS, Martin DR, Hanson JA. SATB2 Versus CDX2: A Battle Royale for Diagnostic Supremacy in Mucinous Tumors. Arch Pathol Lab Med 2019; 143:1119-1125. [PMID: 30838879 DOI: 10.5858/arpa.2018-0337-oa] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT.— Metastatic mucinous tumors present a diagnostic challenge for pathologists as tumor histomorphology is often nonspecific and optimal immunoprofiles are still under investigation. OBJECTIVE.— To present a head-to-head comparison of special AT-rich sequence-binding protein 2 (SATB2) and caudal type homeobox 2 (CDX2) expression in a diverse array of primary mucinous tumors. DESIGN.— SATB2 and CDX2 immunohistochemical stains were performed on whole sections from 44 mucinous colorectal carcinomas and 175 noncolorectal mucinous tumors. A nuclear scoring system measuring intensity (0-3+) and percentage staining (0 = <5%, 1 = 5%-49%, 2 = ≥50%) was implemented, producing an additive histologic score (H-score). RESULTS.— SATB2 demonstrated acceptable accuracy at low to moderate expression levels (H-scores of 1-4). With these H-score cutoffs, overall accuracy was greater than 90%. In contrast, CDX2's accuracy rivaled that of SATB2 only at an H-score of 5 (89.0%), as its specificity suffered at lower expression levels (<70.0% at H-scores of 1-4). Using a moderate H-score cutoff of 3 or higher, significant differences for both sensitivity and specificity were identified between SATB2 and CDX2 (P = .01 for sensitivity and P < .001 for specificity), though these stains were near equivalent when each was interpreted as positive at its respective optimal H-score (SATB2 ≥ 3 and CDX2 = 5). CONCLUSIONS.— SATB2 is a more accurate marker of colorectal origin across a variety of expression levels compared with CDX2 when applied to mucinous tumors from a host of primary sites. However, these stains are near equivalent when each is interpreted at its optimal expression level.
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Affiliation(s)
- Stefan M Brettfeld
- From the Department of Pathology, University of New Mexico School of Medicine, Albuquerque (Drs Brettfeld, Ramos, Martin, and Hanson); and the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Berry)
| | - Benjamin D Ramos
- From the Department of Pathology, University of New Mexico School of Medicine, Albuquerque (Drs Brettfeld, Ramos, Martin, and Hanson); and the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Berry)
| | - Ryan S Berry
- From the Department of Pathology, University of New Mexico School of Medicine, Albuquerque (Drs Brettfeld, Ramos, Martin, and Hanson); and the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Berry)
| | - David R Martin
- From the Department of Pathology, University of New Mexico School of Medicine, Albuquerque (Drs Brettfeld, Ramos, Martin, and Hanson); and the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Berry)
| | - Joshua A Hanson
- From the Department of Pathology, University of New Mexico School of Medicine, Albuquerque (Drs Brettfeld, Ramos, Martin, and Hanson); and the Department of Pathology, Cleveland Clinic, Cleveland, Ohio (Dr Berry)
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43
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Ma L, Wolkow N, Jakobiec FA. Choroidal Mucinous Metastatic Adenocarcinoma from the Colon: A Diagnostic Challenge. Ocul Oncol Pathol 2019; 5:66-74. [PMID: 30675480 DOI: 10.1159/000487598] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2017] [Revised: 02/06/2018] [Indexed: 01/19/2023] Open
Abstract
An enucleated globe was submitted from an outside hospital to the Ophthalmic Pathology Laboratory for evaluation. There was a minimal amount of accompanying clinical history. Histopathologic examination revealed a mucinous adenocarcinoma of the choroid. The determination of the origin of the tumor proved to be challenging based on the lack of a definitive systemic diagnosis. Initial suspicions that the tumor may represent a breast carcinoma were disproved when immunohistochemical biomarkers for breast carcinoma were negative. Similarly, typical markers of colon adenocarcinoma were not expressed. Positive immunostaining with a newer immunohistochemical marker, SATB2, and defects in DNA mismatch repair helped to confirm that the ocular metastasis was of colonic origin. Further clinical evaluation including imaging studies established that the patient had a primary colonic adenocarcinoma with widespread systemic metastases. The diagnostic utility and biologic significance of these latest immunohistochemical biomarkers for colon cancer are reviewed. Clinicians are encouraged to provide detailed clinical histories with the tissue specimens to enable the discovery of undetected "silent primaries" at the time an ocular metastasis develops and is discovered.
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Affiliation(s)
- Lina Ma
- David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA
| | - Natalie Wolkow
- David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA
| | - Frederick A Jakobiec
- David G. Cogan Laboratory of Ophthalmic Pathology, Massachusetts Eye and Ear Infirmary, Harvard Medical School, Boston, Massachusetts, USA
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Sommer CA, Capilla A, Molina-Estevez FJ, Gianotti-Sommer A, Skvir N, Caballero I, Chowdhury S, Mostoslavsky G. Modeling APC mutagenesis and familial adenomatous polyposis using human iPS cells. PLoS One 2018; 13:e0200657. [PMID: 30024920 PMCID: PMC6053155 DOI: 10.1371/journal.pone.0200657] [Citation(s) in RCA: 31] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2018] [Accepted: 06/30/2018] [Indexed: 01/31/2023] Open
Abstract
Mutations in the gene Adenomatous Polyposis Coli or APC appear in most sporadic cases of colorectal cancer and it is the most frequent mutation causing hereditary Familial Adenomatous Polyposis. The detailed molecular mechanism by which APC mutations predispose to the development of colorectal cancer is not completely understood. This is in part due to the lack of accessibility to appropriate models that recapitulate the early events associated with APC mediated intestinal transformation. We have established a novel platform utilizing human induced Pluripotent Stem cells or iPSC from normal or FAP-specific APC mutant individuals and evaluated the effect of the mutation in the cells before and after differentiation into intestinal organoids. In order to minimize genetic background effects, we also established an isogenic platform using TALEN-mediated gene editing. Comparison of normal and APC mutant iPSC revealed a significant defect in cell identity and polarity due to the presence of APC in heterozygosity as well as chromosomal aberrations including abnormal anaphases and centrosome numbers. Importantly, upon specification into intestinal progeny, APC heterozygosity was responsible for a major change in the transcriptional identity of the cells with dysregulation of key signaling pathways, including metabolic reprogramming, abnormal lipid metabolism and intestinal-specific cadherin expression. In conclusion, we have developed a novel iPSC/intestinal model of APC mutagenesis and provide strong evidence that APC in heterozygosity imparts a clear phenotypic and molecular defect, affecting basic cellular functions and integrity, providing novel insights in the earlier events of APC-mediated tumorigenesis.
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Affiliation(s)
- Cesar A. Sommer
- Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Amalia Capilla
- Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Francisco J. Molina-Estevez
- Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Andreia Gianotti-Sommer
- Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Nicholas Skvir
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Ignacio Caballero
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Sanjib Chowdhury
- Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
| | - Gustavo Mostoslavsky
- Section of Gastroenterology, Department of Medicine, Boston University School of Medicine, Boston, Massachusetts, United States of America
- Center for Regenerative Medicine (CReM), Boston University School of Medicine, Boston, Massachusetts, United States of America
- * E-mail:
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Nikolouzakis TK, Vassilopoulou L, Fragkiadaki P, Sapsakos TM, Papadakis GZ, Spandidos DA, Tsatsakis AM, Tsiaoussis J. Improving diagnosis, prognosis and prediction by using biomarkers in CRC patients (Review). Oncol Rep 2018; 39:2455-2472. [PMID: 29565457 PMCID: PMC5983921 DOI: 10.3892/or.2018.6330] [Citation(s) in RCA: 39] [Impact Index Per Article: 5.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/09/2018] [Accepted: 03/21/2018] [Indexed: 12/17/2022] Open
Abstract
Colorectal cancer (CRC) is among the most common cancers. In fact, it is placed in the third place among the most diagnosed cancer in men, after lung and prostate cancer, and in the second one for the most diagnosed cancer in women, following breast cancer. Moreover, its high mortality rates classifies it among the leading causes of cancer‑related death worldwide. Thus, in order to help clinicians to optimize their practice, it is crucial to introduce more effective tools that will improve not only early diagnosis, but also prediction of the most likely progression of the disease and response to chemotherapy. In that way, they will be able to decrease both morbidity and mortality of their patients. In accordance with that, colon cancer research has described numerous biomarkers for diagnostic, prognostic and predictive purposes that either alone or as part of a panel would help improve patient's clinical management. This review aims to describe the most accepted biomarkers among those proposed for use in CRC divided based on the clinical specimen that is examined (tissue, faeces or blood) along with their restrictions. Lastly, new insight in CRC monitoring will be discussed presenting promising emerging biomarkers (telomerase activity, telomere length and micronuclei frequency).
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Affiliation(s)
| | - Loukia Vassilopoulou
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Persefoni Fragkiadaki
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - Theodoros Mariolis Sapsakos
- Laboratory of Anatomy and Histology, Nursing School, National and Kapodistrian University of Athens, 11527 Athens, Greece
| | - Georgios Z. Papadakis
- Foundation for Research and Technology Hellas (FORTH), Institute of Computer Sciences (ICS), Computational Biomedicine Laboratory (CBML), 71003 Heraklion, Crete, Greece
| | - Demetrios A. Spandidos
- Laboratory of Clinical Virology, Medical School, University of Crete, 71003 Heraklion, Crete, Greece
| | - Aristides M. Tsatsakis
- Laboratory of Forensic Sciences and Toxicology, Medical School, University of Crete, 71409 Heraklion, Crete, Greece
| | - John Tsiaoussis
- Laboratory of Anatomy-Histology-Embryology, Medical School, University of Crete, 71110 Heraklion, Greece
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Matsusaka K, Ushiku T, Urabe M, Fukuyo M, Abe H, Ishikawa S, Seto Y, Aburatani H, Hamakubo T, Kaneda A, Fukayama M. Coupling CDH17 and CLDN18 markers for comprehensive membrane-targeted detection of human gastric cancer. Oncotarget 2018; 7:64168-64181. [PMID: 27580354 PMCID: PMC5325433 DOI: 10.18632/oncotarget.11638] [Citation(s) in RCA: 21] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/22/2016] [Accepted: 08/13/2016] [Indexed: 01/15/2023] Open
Abstract
Patients with gastric cancer typically face gastrectomies even when few or no nodal metastases are reported. Current procedures poorly predict lymphatic metastases; thus, evaluation of target molecules expressed on cancer cell membranes is necessary for in vivo detection. However, marker development is limited by the intratumoral heterogeneity of gastric cancer cells. In this study, multiple gene expression arrays of 42 systemic normal tissue samples and 56 gastric cancer samples were used to investigate two adhesion molecules, cadherin 17 (CDH17) and claudin 18 (CLDN18), which are intestinal and gastric markers, respectively. Expression of CDH17 and CLDN18 was partially redundant, but overlapped in 50 of 56 cases (89.3%). Tissue microarrays constructed using primary lesions and nodal metastases of 106 advanced gastric cancers revealed CDH17 and CLDN18 expression in 98 positive cases of 106 (92%). Hierarchical clustering classified gastric cancers into three subgroups, CDH17(++)/CLDN18(+/-), CDH17(++)/CLDN18(++) or CDH17(+)/CLDN18(+), and CDH17(-)/CLDN18(++/+/-). Whole tissue sections displayed strong, homogeneous staining for CDH17 and CLDN18. Together, these results indicate that CDH17 and CLDN18 are useful target molecules; moreover, their coupling can aid in the comprehensive detection and localization of gastric cancer metastases in vivo to overcome challenges associated with intratumoral heterogeneity.
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Affiliation(s)
- Keisuke Matsusaka
- Division of Diagnostic Pathology, The University of Tokyo Hospital, Tokyo, Japan.,Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Tetsuo Ushiku
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masayuki Urabe
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.,Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Masaki Fukuyo
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan
| | - Hiroyuki Abe
- Division of Diagnostic Pathology, The University of Tokyo Hospital, Tokyo, Japan
| | - Shumpei Ishikawa
- Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan.,Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Yasuyuki Seto
- Department of Gastrointestinal Surgery, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
| | - Hiroyuki Aburatani
- Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Takao Hamakubo
- Department of Quantitative Biology and Medicine, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Atsushi Kaneda
- Department of Molecular Oncology, Graduate School of Medicine, Chiba University, Chiba, Japan.,Genome Science Division, Research Center for Advanced Science and Technology, The University of Tokyo, Tokyo, Japan
| | - Masashi Fukayama
- Division of Diagnostic Pathology, The University of Tokyo Hospital, Tokyo, Japan.,Department of Pathology, Graduate School of Medicine, The University of Tokyo, Tokyo, Japan
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Atak A, Khurana S, Gollapalli K, Reddy PJ, Levy R, Ben-Salmon S, Hollander D, Donyo M, Heit A, Hotz-Wagenblatt A, Biran H, Sharan R, Rane S, Shelar A, Ast G, Srivastava S. Quantitative mass spectrometry analysis reveals a panel of nine proteins as diagnostic markers for colon adenocarcinomas. Oncotarget 2018; 9:13530-13544. [PMID: 29568375 PMCID: PMC5862596 DOI: 10.18632/oncotarget.24418] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Accepted: 01/30/2018] [Indexed: 01/21/2023] Open
Abstract
Adenocarcinomas are cancers originating from the gland forming cells of the colon and rectal lining, and are known to be the most common type of colorectal cancers. The current diagnosis strategies for colorectal cancers include biopsy, laboratory tests, and colonoscopy which are time consuming. Identification of protein biomarkers could aid in the detection of colon adenocarcinomas (CACs). In this study, tissue proteome of colon adenocarcinomas (n = 11) was compared with the matched control specimens (n = 11) using isobaric tags for relative and absolute quantitation (iTRAQ) based liquid chromatography-mass spectrometry (LC-MS/MS) approach. A list of 285 significantly altered proteins was identified in colon adenocarcinomas as compared to its matched controls, which are associated with growth and malignancy of the tumors. Protein interaction analysis revealed the association of altered proteins in colon adenocarcinomas with various transcription factors and their targets. A panel of nine proteins was validated using multiple reaction monitoring (MRM). Additionally, S100A9 was also validated using immunoblotting. The identified panel of proteins may serve as potential biomarkers and thereby aid in the detection of colon adenocarcinomas.
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Affiliation(s)
- Apurva Atak
- Proteomics Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Samiksha Khurana
- Proteomics Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Kishore Gollapalli
- Proteomics Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Panga Jaipal Reddy
- Proteomics Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
| | - Roei Levy
- Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel
| | - Stav Ben-Salmon
- Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel
| | - Dror Hollander
- Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel
| | - Maya Donyo
- Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel
| | - Anke Heit
- Bioinformatics Group, Genomics and Proteomics Core Facility (GPCF), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Agnes Hotz-Wagenblatt
- Bioinformatics Group, Genomics and Proteomics Core Facility (GPCF), German Cancer Research Center (DKFZ), Heidelberg 69120, Germany
| | - Hadas Biran
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
| | - Roded Sharan
- Blavatnik School of Computer Science, Tel Aviv University, Tel Aviv 69978, Israel
| | - Shailendra Rane
- Shimadzu Analytical (India) Pvt. Ltd, 1A/B, Rushabh Chambers, Makwana Road, Marol, Andheri (E), Mumbai 400059, India
| | - Ashutosh Shelar
- Shimadzu Analytical (India) Pvt. Ltd, 1A/B, Rushabh Chambers, Makwana Road, Marol, Andheri (E), Mumbai 400059, India
| | - Gil Ast
- Department of Human Molecular Genetics and Biochemistry, Sackler Medical School, Tel Aviv University, Tel Aviv 69978, Israel
| | - Sanjeeva Srivastava
- Proteomics Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Bombay, Powai, Mumbai 400076, India
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Wang HL, Kim CJ, Koo J, Zhou W, Choi EK, Arcega R, Chen ZE, Wang H, Zhang L, Lin F. Practical Immunohistochemistry in Neoplastic Pathology of the Gastrointestinal Tract, Liver, Biliary Tract, and Pancreas. Arch Pathol Lab Med 2017; 141:1155-1180. [PMID: 28854347 DOI: 10.5858/arpa.2016-0489-ra] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/29/2022]
Abstract
CONTEXT - Immunomarkers with diagnostic, therapeutic, or prognostic values have been increasingly used to maximize the benefits of clinical management of patients with neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. OBJECTIVES - To review the characteristics of immunomarkers that are commonly used in surgical pathology practice for neoplasms of the gastrointestinal tract, liver, biliary tract, and pancreas, and to summarize the clinical usefulness of immunomarkers that have been discovered in recent years in these fields. DATA SOURCES - Data sources include literature review, authors' research data, and personal practice experience. CONCLUSIONS - Immunohistochemistry is an indispensable tool for the accurate diagnosis of neoplastic diseases of the gastrointestinal tract, liver, biliary tract, and pancreas. Useful immunomarkers are available to help distinguish malignant neoplasms from benign conditions, determine organ origins, and subclassify neoplasms that are morphologically and biologically heterogeneous. Specific immunomarkers are also available to help guide patient treatment and assess disease aggressiveness, which are keys to the success of personalized medicine. Pathologists will continue to play a critical role in the discovery, validation, and application of new biomarkers, which will ultimately improve patient care.
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Bian T, Zhao J, Feng J, Zhang Q, Qian L, Liu J, Jiang D, Liu Y, Zhang J. Combination of cadherin-17 and SATB homeobox 2 serves as potential optimal makers for the differential diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal adenocarcinoma. Oncotarget 2017; 8:63442-63452. [PMID: 28969003 PMCID: PMC5609935 DOI: 10.18632/oncotarget.18828] [Citation(s) in RCA: 28] [Impact Index Per Article: 3.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/06/2017] [Accepted: 06/02/2017] [Indexed: 12/24/2022] Open
Abstract
Background Pulmonary enteric adenocarcinoma (PEAC), a rare type of non-small cell lung cancer, has similar histological and immunohistochemical morphology to colorectal adenocarcinoma. Cadherin-17 (CDH17) and SATB homeobox 2 (SATB2) immunoexpression have recently been demonstrated in colorectal adenocarcinoma. In this study, we evaluated the value of CDH17 and SATB2 in the diagnosis of pulmonary enteric adenocarcinoma and metastatic colorectal adenocarcinoma. Methods A total of 13 PEAC cases and 27 metastatic colorectal adenocarcinoma cases were enrolled in our cohort study. We analyzed the expressions of CK7, CK20, CDX-2, villin, cadherin-17 (CDH17), and SATB homeobox 2 (SATB2) using immunohistochemistry. Staining intensity and percentage of positive-staining cells were recorded. Sensitivity and specificity values for immunostains, individually and in combination, were computed and compared. Results Combining CDH17 and SATB2 resulted in high sensitivity (76.92%) and specificity (100%). In our study, the use of CK7+, napsin A+, TTF-1+, napsin A+TTF-1+ in combination with CDH17-/SATB2- had a higher area under the curve compared to the combination CDH17-/SATB2-. However, no significant differences were observed between the combination CDH17-/SATB2- and other combinations (P>0.05). Conclusions In combination, CDH17 and SATB2 serve as potential optimal markers for the differential diagnosis of PEAC and metastatic colorectal adenocarcinoma.
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Affiliation(s)
- Tingting Bian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Jinli Zhao
- Department of Radiology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Jia Feng
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Qing Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Li Qian
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Jian Liu
- Department of Chemotherapy, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Daishan Jiang
- Department of Emergency Medicine, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Yifei Liu
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
| | - Jianguo Zhang
- Department of Pathology, Affiliated Hospital of Nantong University, Nantong, Jiangsu, P.R. China
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Altree-Tacha D, Tyrrell J, Haas T. CDH17 Is a More Sensitive Marker for Gastric Adenocarcinoma Than CK20 and CDX2. Arch Pathol Lab Med 2017; 141:144-150. [PMID: 28029907 DOI: 10.5858/arpa.2015-0404-oa] [Citation(s) in RCA: 24] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
CONTEXT -CDH17, which is expressed in the intestinal epithelium, is a novel oncogene involved in tumor invasion and metastasis. A panel consisting of cytokeratin (CK) 7, CD20, and CDX2 antibodies is typically used to diagnose gastrointestinal adenocarcinomas. However, studies have shown that CDH17 is a highly specific marker for gastrointestinal adenocarcinoma and may be important in clinical diagnosis. OBJECTIVE -To evaluate the sensitivity and specificity of CDH17, CK20, and CDX2 antibodies in neoplastic tissues, with emphasis on colon, stomach, and esophageal gastrointestinal lineage. DESIGN -Immunohistochemistry was performed with CDH17, CK20, and CDX2 antibodies on formalin-fixed, paraffin-embedded tissue microarrays from normal (n = 26) and neoplastic (n = 884) tissues. RESULTS -CDH17 immunostaining was positive in 97.3% (145 of 149) of colon adenocarcinomas, whereas CK20 and CDX2 stained positively in 88.6% (132 of 149) and 93.3% (139 of 149), respectively. In metastatic colon cancers, CDH17, CK20, and CDX2 positive staining was observed in 90.6% (29 of 32), 59.4% (19 of 32), and 81.3% (26 of 32) of cases, respectively. In stomach adenocarcinomas, CDH17 positively stained 64.0% (112 of 175) of tissues, compared to CK20 and CDX2, where staining was observed in only 24.6% (43 of 175) and 46.9% (82 of 175), respectively. In esophageal adenocarcinomas, CDH17, CK20, and CDX2 stained 38.7% (12 of 31), 25.8% (8 of 31), and 29% (9 of 31) of specimens, respectively. Low or no expression was observed in other neoplastic tissues, except pancreatic cancers, where CDH17 displayed higher expression than CK20 and CDX2. CONCLUSIONS -CDH17 is a specific and more sensitive marker in the gastrointestinal tract than CK20 and CDX2. CDH17 may be especially valuable when gastrointestinal tumors are suspected in cancers of unknown primary.
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Affiliation(s)
| | | | - Thomas Haas
- From Chief Scientific Officer (Dr Altree-Tacha) and the Department of Research and Development (Dr Tyrrell), Biocare Medical, Concord, California; and the Department of Pathology, Mercy Health System, Janesville, Wisconsin (Dr Haas)
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