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Dubey DB, Agarwal P, Singh AK, Maurya MK, Bhalla S, Gupta V, Anand A, Gupta S, Sonkar AA. CD24 and tumor budding as a prognostic variable in carcinoma gall bladder: A pilot study. J Cancer Res Ther 2025; 21:124-130. [PMID: 40214364 DOI: 10.4103/jcrt.jcrt_1986_23] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2023] [Accepted: 09/23/2024] [Indexed: 05/03/2025]
Abstract
BACKGROUND CD24 is a small heavily glycosylated glycosylphosphotidylinositol-linked cell surface protein that is expressed in a variety of hematological and solid tumors. It is majorly involved in tumor development, proliferation, invasion, metastasis, and prevention of tumor cell death via various major and minor signalling pathways although it can also inhibit invasiveness via degrading BART mRNA. AIM AND OBJECTIVE We aimed to evaluate CD24 expression in gall bladder carcinoma (GBC), via immunohistochemical (IHC) staining on paraffin-embedded histological tissue along with assessment of tumor budding. MATERIAL AND METHODS 87 patients were enrolled and CD24 IHC staining was evaluated using four degrees of positivity (negative, mild, moderate, and strong). The expression was then correlated with various clinicopathological parameters. Interpretation was tumor budding was done on the H and E slide. Hotspots were chosen and the total number of buds was reported in an area measuring 0.785 mm2 corresponding to 20× fields in the microscope. RESULTS CD24 positive expression was found in 77.5% of cases. Its positive expression correlated inversely with tumor stage, necrosis, and lymph vascular invasion establishing its usefulness as a prognostic marker. Tumor budding correlated with poor tumor differentiation and higher tumor grade and poorly differentiated cancer with higher budding responded well to chemotherapy. CONCLUSION Our study supports the importance of CD24 and tumor budding as prognostic markers and thus its usefulness in risk stratification in GBC. CD 24 positive subgroup of GBC cases may benefit from anti-CD24 mAb therapy and we also recommend that tumor budding may be included in the morphological synoptic reporting in gall bladder cancer.
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Affiliation(s)
- Devanshi Brajesh Dubey
- Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Preeti Agarwal
- Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Ajay Kumar Singh
- Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Malti Kumar Maurya
- Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Shalini Bhalla
- Department of Pathology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Vishal Gupta
- Department of Gastroenetrology, AIIMS Bhopal, Madhya Pradesh, India
| | - Akshay Anand
- Department of Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Sameer Gupta
- Department of Surgical Oncology, King George's Medical University, Lucknow, Uttar Pradesh, India
| | - Abhinav Arun Sonkar
- Department of Surgery, King George's Medical University, Lucknow, Uttar Pradesh, India
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2
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Pateras IS, Igea A, Nikas IP, Leventakou D, Koufopoulos NI, Ieronimaki AI, Bergonzini A, Ryu HS, Chatzigeorgiou A, Frisan T, Kittas C, Panayiotides IG. Diagnostic Challenges during Inflammation and Cancer: Current Biomarkers and Future Perspectives in Navigating through the Minefield of Reactive versus Dysplastic and Cancerous Lesions in the Digestive System. Int J Mol Sci 2024; 25:1251. [PMID: 38279253 PMCID: PMC10816510 DOI: 10.3390/ijms25021251] [Citation(s) in RCA: 3] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/19/2023] [Revised: 01/12/2024] [Accepted: 01/16/2024] [Indexed: 01/28/2024] Open
Abstract
In the setting of pronounced inflammation, changes in the epithelium may overlap with neoplasia, often rendering it impossible to establish a diagnosis with certainty in daily clinical practice. Here, we discuss the underlying molecular mechanisms driving tissue response during persistent inflammatory signaling along with the potential association with cancer in the gastrointestinal tract, pancreas, extrahepatic bile ducts, and liver. We highlight the histopathological challenges encountered in the diagnosis of chronic inflammation in routine practice and pinpoint tissue-based biomarkers that could complement morphology to differentiate reactive from dysplastic or cancerous lesions. We refer to the advantages and limitations of existing biomarkers employing immunohistochemistry and point to promising new markers, including the generation of novel antibodies targeting mutant proteins, miRNAs, and array assays. Advancements in experimental models, including mouse and 3D models, have improved our understanding of tissue response. The integration of digital pathology along with artificial intelligence may also complement routine visual inspections. Navigating through tissue responses in various chronic inflammatory contexts will help us develop novel and reliable biomarkers that will improve diagnostic decisions and ultimately patient treatment.
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Affiliation(s)
- Ioannis S. Pateras
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Ana Igea
- Instituto de Investigación Sanitaria de Santiago de Compostela (IDIS), 15706 Santiago de Compostela, Spain;
- Mobile Genomes, Centre for Research in Molecular Medicine and Chronic Diseases (CiMUS), University of Santiago de Compostela (USC), 15706 Santiago de Compostela, Spain
| | - Ilias P. Nikas
- Medical School, University of Cyprus, 2029 Nicosia, Cyprus
| | - Danai Leventakou
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Nektarios I. Koufopoulos
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Argyro Ioanna Ieronimaki
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
| | - Anna Bergonzini
- Center for Infectious Medicine, Department of Medicine Huddinge, Karolinska Institutet, Karolinska University Hospital, Alfred Nobels Allé 8, 141 52 Stockholm, Sweden;
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Han Suk Ryu
- Department of Pathology, Seoul National University Hospital, Seoul 03080, Republic of Korea;
| | - Antonios Chatzigeorgiou
- Department of Physiology, Medical School, National and Kapodistrian University of Athens, 115 27 Athens, Greece;
| | - Teresa Frisan
- Department of Molecular Biology and Umeå Centre for Microbial Research (UCMR), Umeå University, 901 87 Umeå, Sweden;
| | - Christos Kittas
- Department of Histopathology, Biomedicine Group of Health Company, 156 26 Athens, Greece;
| | - Ioannis G. Panayiotides
- 2nd Department of Pathology, “Attikon” University Hospital, Medical School, National and Kapodistrian University of Athens, 124 62 Athens, Greece; (D.L.); (N.I.K.); (A.I.I.); (I.G.P.)
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Faraj Tabrizi P, Peters I, Schimansky I, Dubrowinskaja N, Reese C, Tezval H, Kuczyk MA, Serth J. Alteration of Cadherin 3 Expression and DNA Methylation in Association with Aggressive Renal Cell Carcinoma. Int J Mol Sci 2023; 24:16476. [PMID: 38003666 PMCID: PMC10670999 DOI: 10.3390/ijms242216476] [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: 09/28/2023] [Revised: 11/03/2023] [Accepted: 11/10/2023] [Indexed: 11/26/2023] Open
Abstract
Cadherins (calcium-dependent adhesion proteins) are important in cellular adhesion and may play a role in the development and progression of renal cell carcinoma (RCC). This study investigated changes in cadherin 3 (CDH3; P-cadherin) mRNA expression, DNA methylation, and protein expression in RCC and compared the results with the histopathological and clinical characteristics of patients. The possible contribution of CDH3 to tumor cell invasiveness was tested in a functional assay using siRNA-based suppression of CDH3 expression and subsequent real-time impedance analysis using a Matrigel invasion model. Our analyses revealed a tumor-specific loss of CDH3 mRNA expression, CDH3 DNA hypermethylation, and loss of distal tubular and collecting duct CDH3 protein expression in RCC. A relatively higher methylation level in tumors was associated with a loss of cell differentiation and higher clinical stage. siRNA-induced suppression of CDH3 expression modulated the invasion characteristics of tumor cells in the impedance-based real-time cellular analysis. Our results indicate that loss of CDH3 expression is common in RCC and may contribute to the pathogenesis of a subset of RCC. Further studies to reveal the mechanisms of loss of expression and its effects on the invasive behavior of renal tumor cells are required.
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Affiliation(s)
- Pouriya Faraj Tabrizi
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Inga Peters
- Department of Urology, Krankenhaus Nordwest, 60488 Frankfurt, Germany
| | - Inga Schimansky
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Natalia Dubrowinskaja
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Christel Reese
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Hossein Tezval
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Markus Antonius Kuczyk
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
| | - Jürgen Serth
- Department of Urology and Urological Oncology, Hannover Medical School, 30625 Hannover, Germany
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4
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Affo S, Nair A, Brundu F, Ravichandra A, Bhattacharjee S, Matsuda M, Chin L, Filliol A, Wen W, Song X, Decker A, Worley J, Caviglia JM, Yu L, Yin D, Saito Y, Savage T, Wells RG, Mack M, Zender L, Arpaia N, Remotti HE, Rabadan R, Sims P, Leblond AL, Weber A, Riener MO, Stockwell BR, Gaublomme J, Llovet JM, Kalluri R, Michalopoulos GK, Seki E, Sia D, Chen X, Califano A, Schwabe RF. Promotion of cholangiocarcinoma growth by diverse cancer-associated fibroblast subpopulations. Cancer Cell 2021; 39:866-882.e11. [PMID: 33930309 PMCID: PMC8241235 DOI: 10.1016/j.ccell.2021.03.012] [Citation(s) in RCA: 215] [Impact Index Per Article: 53.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/30/2020] [Revised: 01/26/2021] [Accepted: 03/29/2021] [Indexed: 12/15/2022]
Abstract
Cancer-associated fibroblasts (CAF) are a poorly characterized cell population in the context of liver cancer. Our study investigates CAF functions in intrahepatic cholangiocarcinoma (ICC), a highly desmoplastic liver tumor. Genetic tracing, single-cell RNA sequencing, and ligand-receptor analyses uncovered hepatic stellate cells (HSC) as the main source of CAF and HSC-derived CAF as the dominant population interacting with tumor cells. In mice, CAF promotes ICC progression, as revealed by HSC-selective CAF depletion. In patients, a high panCAF signature is associated with decreased survival and increased recurrence. Single-cell RNA sequencing segregates CAF into inflammatory and growth factor-enriched (iCAF) and myofibroblastic (myCAF) subpopulations, displaying distinct ligand-receptor interactions. myCAF-expressed hyaluronan synthase 2, but not type I collagen, promotes ICC. iCAF-expressed hepatocyte growth factor enhances ICC growth via tumor-expressed MET, thus directly linking CAF to tumor cells. In summary, our data demonstrate promotion of desmoplastic ICC growth by therapeutically targetable CAF subtype-specific mediators, but not by type I collagen.
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Affiliation(s)
- Silvia Affo
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Ajay Nair
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Francesco Brundu
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | | | | | - Michitaka Matsuda
- Department of Medicine, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90024, USA
| | - LiKang Chin
- Department of Medicine, Penn Physical Sciences in Oncology Center PSOC@Penn, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Aveline Filliol
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Wen Wen
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Xinhua Song
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94158, USA
| | - Aubrianna Decker
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Jeremy Worley
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | | | - Lexing Yu
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Deqi Yin
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Yoshinobu Saito
- Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Thomas Savage
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Rebecca G Wells
- Department of Medicine, Penn Physical Sciences in Oncology Center PSOC@Penn, University of Pennsylvania, Philadelphia, PA 19104, USA
| | - Matthias Mack
- Department of Nephrology, University Hospital Regensburg, 93053 Regensburg, Germany
| | - Lars Zender
- Department of Medical Oncology and Pneumology, University Hospital Tuebingen, 72076 Tuebingen, Germany; German Cancer Research Consortium (DKTK), German Cancer Research Center (DKFZ), 69120 Heidelberg, Germany; iFIT Cluster of Excellence EXC 2180, University of Tuebingen, 72076 Tuebingen, Germany
| | - Nicholas Arpaia
- Department of Microbiology and Immunology, Vagelos College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA
| | - Helen E Remotti
- Department of Pathology & Cell Biology, Columbia University, New York, NY 10032, USA
| | - Raul Rabadan
- Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA
| | - Peter Sims
- Department of Systems Biology, Columbia University, New York, NY 10032, USA
| | - Anne-Laure Leblond
- Department for Pathology and Molecular Pathology, Zürich University Hospital, 8091 Zürich, Switzerland
| | - Achim Weber
- Department for Pathology and Molecular Pathology, Zürich University Hospital, 8091 Zürich, Switzerland
| | - Marc-Oliver Riener
- Department for Pathology and Molecular Pathology, Zürich University Hospital, 8091 Zürich, Switzerland
| | - Brent R Stockwell
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA; Department of Chemistry, Columbia University, New York, NY 10027, USA
| | - Jellert Gaublomme
- Department of Biological Sciences, Columbia University, New York, NY 10027, USA
| | - Josep M Llovet
- Liver Cancer Translational Research Laboratory, Institut d'Investigacions Biomèdiques August Pi i Sunyer, Hospital Clínic, Universitat de Barcelona, 08036 Barcelona, Spain; Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA; Institució Catalana de Recerca i Estudis Avançats, Barcelona, Spain
| | - Raghu Kalluri
- Department of Cancer Biology, Metastasis Research Center, University of Texas MD Anderson Cancer Center, Houston, TX 77030, USA
| | | | - Ekihiro Seki
- Department of Medicine, Division of Digestive and Liver Diseases, Cedars-Sinai Medical Center, Los Angeles, CA 90024, USA
| | - Daniela Sia
- Mount Sinai Liver Cancer Program, Divisions of Liver Diseases, Tisch Cancer Institute, Icahn School of Medicine at Mount Sinai, New York, NY 10029, USA
| | - Xin Chen
- Department of Bioengineering and Therapeutic Sciences and Liver Center, University of California, San Francisco, CA 94158, USA
| | - Andrea Califano
- Department of Medicine, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University Irving Medical Center, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Department of Systems Biology, Columbia University, New York, NY 10032, USA; Department of Biomedical Informatics, Columbia University, New York, NY 10032, USA; Department of Biochemistry & Molecular Biophysics, Columbia University, New York, NY 10032, USA
| | - Robert F Schwabe
- Department of Medicine, Columbia University, New York, NY 10032, USA; Herbert Irving Comprehensive Cancer Center, Columbia University, New York, NY 10032, USA; Institute of Human Nutrition, Columbia University, New York, NY 10032, USA.
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5
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Kaszak I, Witkowska-Piłaszewicz O, Niewiadomska Z, Dworecka-Kaszak B, Ngosa Toka F, Jurka P. Role of Cadherins in Cancer-A Review. Int J Mol Sci 2020; 21:E7624. [PMID: 33076339 PMCID: PMC7589192 DOI: 10.3390/ijms21207624] [Citation(s) in RCA: 208] [Impact Index Per Article: 41.6] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/17/2020] [Revised: 10/10/2020] [Accepted: 10/12/2020] [Indexed: 02/06/2023] Open
Abstract
Cadherins play an important role in tissue homeostasis, as they are responsible for cell-cell adhesion during embryogenesis, tissue morphogenesis, differentiation and carcinogenesis. Cadherins are inseparably connected with catenins, forming cadherin-catenin complexes, which are crucial for cell-to-cell adherence. Any dysfunction or destabilization of cadherin-catenin complex may result in tumor progression. Epithelial mesenchymal transition (EMT) is a mechanism in which epithelial cadherin (E-cadherin) expression is lost during tumor progression. However, during tumorigenesis, many processes take place, and downregulation of E-cadherin, nuclear β-catenin and p120 catenin (p120) signaling are among the most critical. Additional signaling pathways, such as Receptor tyrosine kinase (RTK), Rho GTPases, phosphoinositide 3-kinase (PI3K) and Hippo affect cadherin cell-cell adhesion and also contribute to tumor progression and metastasis. Many signaling pathways may be activated during tumorigenesis; thus, cadherin-targeting drugs seem to limit the progression of malignant tumor. This review discusses the role of cadherins in selected signaling mechanisms involved in tumor growth. The clinical importance of cadherin will be discussed in cases of human and animal cancers.
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Affiliation(s)
- Ilona Kaszak
- Department of Small Animal Diseases, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
| | - Olga Witkowska-Piłaszewicz
- Department of Pathology and Veterinary Diagnostics, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland
| | - Zuzanna Niewiadomska
- Carnivore Reproduction Study Center, Ecole Nationale Veterinaire d’Alfort, 94700 Maison Alfort, France;
| | - Bożena Dworecka-Kaszak
- Department of Preclinical Sciences, Institute of Veterinary Medicine; Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
| | - Felix Ngosa Toka
- Center for Integrative Mammalian Research, Ross University School of Veterinary Medicine, BOX 334 Basseterre, Saint Kitts and Nevis, West Indies;
| | - Piotr Jurka
- Department of Small Animal Diseases, Institute of Veterinary Medicine, Warsaw University of Life Sciences, 02-787 Warsaw, Poland;
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Sun J, Feng D, Xi H, Luo J, Zhou Z, Liu Q, Chen Y, Shao Q. CD24 blunts the sensitivity of retinoblastoma to vincristine by modulating autophagy. Mol Oncol 2020; 14:1740-1759. [PMID: 32394616 PMCID: PMC7400807 DOI: 10.1002/1878-0261.12708] [Citation(s) in RCA: 24] [Impact Index Per Article: 4.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/19/2020] [Revised: 04/25/2020] [Accepted: 05/05/2020] [Indexed: 12/14/2022] Open
Abstract
Retinoblastoma (RB) is the most common childhood malignant intraocular tumor. The clinical efficacy of vincristine (VCR) in the treatment of RB is severely limited by drug resistance. Here, we found that CD24, a GPI-anchored protein, was overexpressed in human RB tissues and RB cell lines, and was associated with the sensitivity of RB cells in response to VCR therapy. We demonstrated that CD24 plays a critical role in impairing RB sensitivity to VCR via regulating autophagy. Mechanistically, CD24 recruits PTEN to the lipid raft domain and regulates the PTEN/AKT/mTORC1 pathway to activate autophagy. Lipid raft localization was essential for CD24 recruitment function. Collectively, our findings revealed a novel role of CD24 in regulating RB sensitivity to VCR and showed that CD24 is a potential target for improving chemotherapeutic sensitivity and RB patient outcomes.
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Affiliation(s)
- Jie Sun
- Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Dongju Feng
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, China
| | - Huiyu Xi
- Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China.,Department of Ophthalmology, Xuzhou First People's Hospital of Xuzhou Medical University, Xuzhou Eye Research Institute, Xuzhou, China
| | - Jiajing Luo
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, China
| | - Zewei Zhou
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, China
| | - Qinghuai Liu
- Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
| | - Yun Chen
- Department of Immunology, Key Laboratory of Immune Microenvironment and Disease, Nanjing Medical University, Nanjing, China.,Jiangsu Key Lab of Cancer Biomarkers, Prevention and Treatment, Collaborative Innovation Center for Cancer Personalized Medicine, Nanjing Medical University, Nanjing, China
| | - Qing Shao
- Department of Ophthalmology, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China
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Tomita H, Kanayama T, Niwa A, Noguchi K, Tanaka T, Hara A. The Stem Cells in Liver Cancers and the Controversies. STEM CELLS AND CANCER IN HEPATOLOGY 2018:273-287. [DOI: 10.1016/b978-0-12-812301-0.00013-x] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 01/03/2025]
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Reid MD, Lewis MM, Willingham FF, Adsay NV. The Evolving Role of Pathology in New Developments, Classification, Terminology, and Diagnosis of Pancreatobiliary Neoplasms. Arch Pathol Lab Med 2017; 141:366-380. [PMID: 28055239 DOI: 10.5858/arpa.2016-0262-sa] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/06/2022]
Abstract
Pancreatobiliary tract lesions are increasingly being discovered because of more sensitive imaging modalities. Magnetic resonance imaging has identified incidental pancreatic cysts in 13.5% of patients of progressively increasing age. Pancreatobiliary tissue is more accessible through endoscopic ultrasound and magnetic resonance imaging-guided biopsy procedures, and is now an integral part of pathologists' routine practice. Accordingly, several new tumor categories have been recently recognized, including intraductal tubulopapillary neoplasm, a new addition to tumoral intraepithelial neoplasms. Other entities have been reclassified, including the recent transition to 2-tiered grading of preinvasive neoplasms, as well as new perspectives on the distinctive biologic behavior of oncocytic intraductal papillary mucinous neoplasms (IPMNs) compared with other IPMN subtypes. This has led to proposals for revised staging of virtually every segment of the pancreatobiliary tree, with theranostic markers becoming an integral part of workup. Ki-67 is now an integral part of the classification of neuroendocrine tumors, with new definitions of "high-grade neuroendocrine carcinoma." Although bile duct brushings have opened new avenues for diagnosis, their sensitivity remains low and often requires concomitant fluorescent in situ hybridization to better define ambiguous cases. Various molecular pathways have been elucidated for pancreatic cysts, including KRAS for ductal neoplasia, GNAS for intestinal IPMNs, RNF3 for mucinous cysts, and VHL for serous cystic neoplasms, all key players in diagnostic workup. Integration of these updates into our understanding of pancreatobiliary disease requires active engagement of pathologists for appropriate specimen triage, judicious interpretation of results, and incorporation into reporting and staging. They also provide exciting opportunities for targeted therapy.
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Affiliation(s)
| | | | | | - N Volkan Adsay
- From the Departments of Pathology (Drs Reid, Lewis, and Adsay) and Digestive Diseases (Dr Willingham), Emory University School of Medicine, Atlanta, Georgia
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9
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Sukharamwala P, Hennessey D, Wood T, Singh S, Ryan C, Rosemurgy A. Molecular profiles in foregut oncology. Cancer Genet 2016; 209:537-553. [PMID: 27887938 DOI: 10.1016/j.cancergen.2016.09.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/30/2015] [Revised: 09/30/2015] [Accepted: 09/19/2016] [Indexed: 02/07/2023]
Abstract
Oncology is and will continue to evolve resulting from a better understanding of the biology and intrinsic genetic profile of each cancer. Tumor biomarkers and targeted therapies are the new face of precision medicine, so it is essential for all physicians caring for cancer patients to understand and assist patients in understanding the role and importance of such markers and strategies to target them. This review was initiated in an attempt to identify, characterize, and discuss literature supporting clinically relevant molecular markers and interventions. The efficacy of targeting specific markers will be examined with data from clinical trials focusing on treatments for esophageal, gastric, liver, gallbladder, biliary tract, and pancreatic cancers.
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Affiliation(s)
| | - Daniel Hennessey
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Thomas Wood
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Shelly Singh
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Carrie Ryan
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA
| | - Alexander Rosemurgy
- Florida Hospital Tampa, 3000 Medical Park Drive Suite 310, Tampa, FL 33613, USA.
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10
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Qiang Y, Chen Z. Epithelial mesenchymal transition related molecular markers and invasion and metastasis of cholangiocarcinoma. Shijie Huaren Xiaohua Zazhi 2015; 23:4051-4059. [DOI: 10.11569/wcjd.v23.i25.4051] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.1] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 02/06/2023] Open
Abstract
Tumor metastasis is a major cause of death in patients with solid tumors. Epithelial mesenchymal transition (EMT) is a process in which the epithelial cells are transformed into the stroma cells. This process is accompanied by changes in gene expression and cell phenotype, which are often activated during tumor invasion and metastasis. Cholangiocarcinoma is a kind of malignancy originating from the bile duct epithelium, and its main biological characteristics are early invasion, metastasis and recurrence. The research of cholangiocarcinoma metastasis could provide a theoretical basis for the development of new treatment strategies to manage this malignancy. This paper reviews the roles of EMT related molecular markers metastasis in the invasion and metastasis of cholangiocarcinoma.
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11
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Keira Y, Takasawa A, Murata M, Nojima M, Takasawa K, Ogino J, Higashiura Y, Sasaki A, Kimura Y, Mizuguchi T, Tanaka S, Hirata K, Sawada N, Hasegawa T. An immunohistochemical marker panel including claudin-18, maspin, and p53 improves diagnostic accuracy of bile duct neoplasms in surgical and presurgical biopsy specimens. Virchows Arch 2015; 466:265-277. [PMID: 25503275 DOI: 10.1007/s00428-014-1705-4] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2014] [Revised: 10/06/2014] [Accepted: 12/02/2014] [Indexed: 12/14/2022]
Abstract
Biliary tract cancers have an extremely poor outcome, and specific diagnostic markers and effective treatments are needed urgently. In this study, we assessed the capacity of panel of immunohistochemical markers including claudin-18, maspin, and p53 to distinguish biliary tract carcinoma and biliary intraepithelial neoplasia (BilIN) from non-neoplastic epithelium. We performed a retrospective study of 66 biliary tract cancer specimens and 63 specimens with non-neoplastic lesions. Of the surgical specimens, 96.7 % with adenocarcinoma/BilIN were detected as neoplastic, and all 63 specimens histologically diagnosed as non-neoplastic lesion were detected as non-neoplastic with high sensitivity (91.1 %) and specificity (100 %). Of presurgical endobiliary forceps biopsy specimens, all with adenocarcinoma/BilIN and only 1 of the 19 with a non-neoplastic lesion were distinguished as neoplastic with high sensitivity (100 %) and specificity (94.7 %). Moreover, this panel provided good separation of neoplasm from malignancy-undetermined atypical epithelium (18/21, 85.7 %). This panel achieves a more reliable distinction of biliary tract cancers and BilINs from non-neoplastic epithelia in both surgical and biopsy specimens than immunohistochemical analysis with single antibodies and is useful in supporting a diagnosis of adenocarcinoma and BilIN.
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Affiliation(s)
- Yoshiko Keira
- Departments of Surgical Pathology, Sapporo Medical University School of Medicine, Sapporo, Japan
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12
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Lin F, Chen ZE, Wang HL. Utility of immunohistochemistry in the pancreatobiliary tract. Arch Pathol Lab Med 2015; 139:24-38. [PMID: 25549142 DOI: 10.5858/arpa.2014-0072-ra] [Citation(s) in RCA: 39] [Impact Index Per Article: 3.9] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/14/2022]
Abstract
CONTEXT Immunohistochemistry has become a useful ancillary study in the identification and classification of pancreatic neoplasms. The diagnostic accuracy has been significantly improved because of the continuous discoveries of tumor-associated biomarkers and the development of effective immunohistochemical panels. OBJECTIVES To identify and classify pancreatic neoplasms by immunohistochemistry. DATA SOURCES Literature review and authors' research data and personal practice experience were used. CONCLUSIONS To better guide therapeutic decisions and predict the prognostic outcome, it is crucial to make an accurate diagnosis of a pancreatic neoplasm. Application of appropriate immunohistochemical panels enables pathologists to differentiate pancreaticobiliary adenocarcinomas from reactive conditions and to identify rare types of pancreatic neoplasms. Knowing the utilities and pitfalls of each tumor-associated biomarker is essential to avoiding a potential diagnostic error because an absolutely cancer-specific biomarker does not exist. This article reviews frequently used tumor-associated biomarkers, provides lists of effective immunohistochemical panels, and recommends a diagnostic algorithm as a standard approach to pancreatic neoplasms.
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Affiliation(s)
- Fan Lin
- From the Department of Laboratory Medicine, Geisinger Medical Center, Danville, Pennsylvania (Drs Lin and Chen); and the Department of Pathology, University of California, Los Angeles (Dr Wang)
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13
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Westbom CM, Shukla A, MacPherson MB, Yasewicz EC, Miller JM, Beuschel SL, Steele C, Pass HI, Vacek PM, Shukla A. CREB-induced inflammation is important for malignant mesothelioma growth. THE AMERICAN JOURNAL OF PATHOLOGY 2014; 184:2816-27. [PMID: 25111229 DOI: 10.1016/j.ajpath.2014.06.008] [Citation(s) in RCA: 23] [Impact Index Per Article: 2.1] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 05/15/2014] [Accepted: 06/05/2014] [Indexed: 12/25/2022]
Abstract
Malignant mesothelioma (MM) is an aggressive tumor with no treatment regimen. Previously we have demonstrated that cyclic AMP response element binding protein (CREB) is constitutively activated in MM tumor cells and tissues and plays an important role in MM pathogenesis. To understand the role of CREB in MM tumor growth, we generated CREB-inhibited MM cell lines and performed in vitro and in vivo experiments. In vitro experiments demonstrated that CREB inhibition results in significant attenuation of proliferation and drug resistance of MM cells. CREB-silenced MM cells were then injected into severe combined immunodeficiency mice, and tumor growth in s.c. and i.p. models of MM was followed. We observed significant inhibition in MM tumor growth in both s.c. and i.p. models and the presence of a chemotherapeutic drug, doxorubicin, further inhibited MM tumor growth in the i.p. model. Peritoneal lavage fluids from CREB-inhibited tumor-bearing mice showed a significantly reduced total cell number, differential cell counts, and pro-inflammatory cytokines and chemokines (IL-6, IL-8, regulated on activation normal T cell expressed and secreted, monocyte chemotactic protein-1, and vascular endothelial growth factor). In vitro studies showed that asbestos-induced inflammasome/inflammation activation in mesothelial cells was CREB dependent, further supporting the role of CREB in inflammation-induced MM pathogenesis. In conclusion, our data demonstrate the involvement of CREB in the regulation of MM pathogenesis by regulation of inflammation.
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Affiliation(s)
- Catherine M Westbom
- Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont
| | - Anurag Shukla
- Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont
| | | | - Elizabeth C Yasewicz
- Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont
| | - Jill M Miller
- Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont
| | - Stacie L Beuschel
- Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont
| | - Chad Steele
- Department of Medicine, University of Alabama at Birmingham School of Medicine, Birmingham, Alabama
| | - Harvey I Pass
- Langone Medical Center, NYU School of Medicine, New York, New York
| | - Pamela M Vacek
- Department of Medical Biostatistics, College of Medicine, University of Vermont, Burlington, Vermont
| | - Arti Shukla
- Department of Pathology, College of Medicine, University of Vermont, Burlington, Vermont.
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14
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Wiggers JK, Ruys AT, Groot Koerkamp B, Beuers U, ten Kate FJ, van Gulik TM. Differences in immunohistochemical biomarkers between intra- and extrahepatic cholangiocarcinoma: a systematic review and meta-analysis. J Gastroenterol Hepatol 2014; 29:1582-94. [PMID: 24787096 DOI: 10.1111/jgh.12620] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Accepted: 03/05/2014] [Indexed: 12/15/2022]
Abstract
BACKGROUND AND AIM Cholangiocarcinomas of different locations differ in growth patterns, symptoms, treatment response, and survival. Still, they are regarded in many studies as a uniform malignancy. Because intra- (iCCA) and extrahepatic (eCCA) cholangiocarcinoma display such differences, we performed a systematic review and meta-analysis to analyze differences in the immunohistochemical profile of these tumors. METHODS In February 2014, we searched the two main medical literature databases MEDLINE and EMBASE. We extracted risk ratios and 95% confidence intervals from the identified studies and performed random-effects model meta-analyses in accordance with PRISMA and REMARK guidelines. RESULTS A total of 54 cohort studies, including 4458 patients and studying 102 individual markers met the inclusion criteria. Of the 57 markers that were evaluated in more than 30 iCCA and eCCA patients, 18 showed a statistically significant difference in expression between iCCA and eCCA. Biomarkers expressed differently between iCCA and eCCA included potential targets of therapy: EGFR, c-erbB-2 and VEGF-A. Several markers showed no statistical difference but large 95% confidence intervals, suggesting insufficient sample size. CONCLUSIONS This systematic review shows differences in marker expression between iCCA and eCCA. Consequently, patients with iCCA and eCCA may benefit from different treatment strategies.
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Affiliation(s)
- Jimme K Wiggers
- Department of Surgery, Academic Medical Center, Amsterdam, The Netherlands
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15
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Yi S, Yang ZL, Miao X, Zou Q, Li J, Liang L, Zeng G, Chen S. N-cadherin and P-cadherin are biomarkers for invasion, metastasis, and poor prognosis of gallbladder carcinomas. Pathol Res Pract 2014; 210:363-8. [PMID: 24636838 DOI: 10.1016/j.prp.2014.01.014] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/29/2013] [Revised: 12/22/2013] [Accepted: 01/30/2014] [Indexed: 12/29/2022]
Abstract
Gallbladder cancer (GBC) is a rare, but highly aggressive cancer. The most common type of gallbladder cancer is adenocarcinoma (AC), while squamous cell/adenosquamous carcinoma (SC/ASC) is a rare type of gallbladder cancer. The clinicopathologic and biological characteristics of SC/ASC have not been well documented. In this study, the protein expression of N-cadherin and P-cadherin in 46 SC/ASCs and 80 ACs was measured using immunohistochemistry. We demonstrated that positive N-cadherin and P-cadherin expression were significantly associated with large tumor size, invasion, and lymph node metastasis of both SC/ASC and AC. In contrast, positive N-cadherin and P-cadherin expression were significantly associated with differentiation and TNM stage in only AC. Univariate Kaplan-Meier analysis showed that positive N-cadherin and P-cadherin expression, differentiation, tumor size, TNM stage, invasion, lymph node metastasis, and surgical curability were significantly associated with overall survival in both SC/ASC and AC patients. Multivariate Cox regression analysis showed that positive N-cadherin and P-cadherin expression are independent poor-prognostic factors in both SC/ASC and AC patients. Our study suggested that positive N-cadherin and P-cadherin expression closely correlated with clinicopathological and biological behaviors, and poor-prognosis of gallbladder cancer.
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Affiliation(s)
- Shengen Yi
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China
| | - Zhu-Lin Yang
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China.
| | - Xiongying Miao
- Research Laboratory of Hepatobiliary Diseases, Second Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China
| | - Qiong Zou
- Department of Pathology, Third Xiangya Hospital, Central South University, Changsha, Hunan 410011, PR China
| | - Jinghe Li
- Department of Pathology, Basic Medical Science College, Central South University, Changsha, Hunan 410011, PR China
| | - Lufeng Liang
- Department of Hepatobiliary and Pancreatic Surgery, Hunan Provincial People's Hospital, Changsha, Hunan 410007, PR China
| | - Guixiang Zeng
- Department of Pathology, Loudi Central Hospital, Loudi, Hunan 417011, PR China
| | - Senlin Chen
- Department of Pathology, Hunan Provincial Tumor Hospital, Changsha, Hunan 410013, PR China
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16
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Ito T, Sakurai-Yageta M, Goto A, Pairojkul C, Yongvanit P, Murakami Y. Genomic and transcriptional alterations of cholangiocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2014; 21:380-7. [PMID: 24532422 DOI: 10.1002/jhbp.67] [Citation(s) in RCA: 20] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
Cholangiocarcinoma (CCA) is one of the representative cancers refractory to any therapeutic approach. The incidence of CCA is highest in the northeastern part of Thailand, where chronic inflammation caused by liver fluke (Opisthorchis viverrini: Ov) infection is a major etiologic factor. The incidence of CCA is also increasing in other countries, including Japan. Here, we overview the genetic and transcriptional alterations of CCA with and without association with Ov infection. CCA with Ov shows enhanced expression of the genes involved in xenobiotic metabolism and chronic inflammatory responses, including cytokine signaling, whereas CCA without Ov shows enhanced expression of growth factor signaling, such as HER2. Exome and the following prevalence sequencing identified mutations of the BAP1, ARID1A, IDH1 and IDH2 genes in CCA, in addition to the high incidence of known mutations in the TP53, KRAS2 SMAD4, and CDKN2A genes, suggesting the role of chromatin modulators in CCA pathogenesis. CCA with Ov shows significantly higher incidence of the TP53 gene mutation, whereas CCA without Ov showed significantly more frequent mutations of the BAP1, IDH1 and IDH2 genes. However, CCAs with Ov and without Ov share a similar mutation spectrum dominated by C : G > T : A transitions mainly at CpG dinucleotides, suggesting that CCA shares etiologic factors with pancreatic ductal carcinoma but not with hepatocellular carcinoma. Comprehensive analyses of the genetic and transcriptional alterations of CCA with and without Ov infection would provide useful information for the prevention, early diagnosis, and treatment of CCA.
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Affiliation(s)
- Takeshi Ito
- Division of Molecular Pathology, Institute of Medical Science, The University of Tokyo, 4-6-1 Shirokanedai, Minato-ku, Tokyo, 108-8639, Japan.
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Recent advances in cancer stem cell research for cholangiocarcinoma. JOURNAL OF HEPATO-BILIARY-PANCREATIC SCIENCES 2013; 19:606-13. [PMID: 22907641 DOI: 10.1007/s00534-012-0542-6] [Citation(s) in RCA: 41] [Impact Index Per Article: 3.4] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/07/2023]
Abstract
Cancer stem cells have been identified as cells with the capacity to self-renew and differentiate into multiple lineages of human malignancies. Cholangiocarcinoma is one of the most difficult intra-abdominal malignancies that can be treated using a surgical approach. Chemotherapy in addition to surgery is necessary to improve patient survival. However, its clinical benefit is limited, and, to date, no other effective anticancer drug is available for this disease. Several reports have shown the existence of cholangiocarcinoma stem cells. Cell surface antigens such as CD133, CD24, EpCAM, CD44, and others have been used to isolate cholangiocarcinoma stem cells. In general, enhanced expression of these markers in resected specimens of cholangiocarcinoma was associated with malignant potential. Distinct and specific pathways are expected to be present in cancer stem cells compared to other cancer cells that have no stem cell properties. To date, reports showing possible signaling pathways in cholangiocarcinoma stem cells are limited. More research is anticipated. Targeting therapies for surface molecular markers or specific signaling pathways of cholangiocarcinoma stem cells may be important in order to change the clinical outcome of patients with this disease. However, no clinical trial has been performed so far. This review will focus on the markers and signaling pathways used to define cholangiocarcinoma stem cells. A novel therapeutic approach of targeting cholangiocarcinoma stem cells will also be discussed.
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AbdulMajeed AA, Dalley AJ, Farah CS. Putative cancer stem cell marker expression in oral epithelial dysplasia and squamous cell carcinoma. J Oral Pathol Med 2013; 42:755-60. [PMID: 23614644 DOI: 10.1111/jop.12073] [Citation(s) in RCA: 26] [Impact Index Per Article: 2.2] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Accepted: 04/04/2013] [Indexed: 12/25/2022]
Affiliation(s)
- Ahmad A. AbdulMajeed
- The University of Queensland; UQ Centre for Clinical Research; Herston Qld Australia
- The University of Queensland; School of Dentistry; Brisbane Qld Australia
| | - Andrew J. Dalley
- The University of Queensland; UQ Centre for Clinical Research; Herston Qld Australia
- The University of Queensland; School of Dentistry; Brisbane Qld Australia
| | - Camile S. Farah
- The University of Queensland; UQ Centre for Clinical Research; Herston Qld Australia
- The University of Queensland; School of Dentistry; Brisbane Qld Australia
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Kim K, Min HS, Chie EK, Jang JY, Kim SW, Han SW, Oh DY, Im SA, Kim TY, Bang YJ, Jang JJ, Ha SW. CD24 expression predicts distant metastasis in extrahepatic bile duct cancer. World J Gastroenterol 2013; 19:1438-1443. [PMID: 23539485 PMCID: PMC3602503 DOI: 10.3748/wjg.v19.i9.1438] [Citation(s) in RCA: 10] [Impact Index Per Article: 0.8] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 09/23/2012] [Revised: 12/26/2012] [Accepted: 01/05/2013] [Indexed: 02/06/2023] Open
Abstract
AIM To evaluate the prognostic significance of CD24 expression in patients undergoing adjuvant chemoradiotherapy for extrahepatic bile duct (EHBD) cancer. METHODS Eighty-four patients with EHBD cancer who underwent curative resection followed by adjuvant chemoradiotherapy were enrolled in this study. Postoperative radiotherapy was delivered to the tumor bed and regional lymph nodes up to a median of 40 Gy (range: 40-56 Gy). All patients also received fluoropyrimidine chemotherapy for radiosensitization during radiotherapy. CD24 expression was assessed with immunohistochemical staining on tissue microarray. Clinicopathologic factors as well as CD24 expression were evaluated in multivariate analysis for clinical outcomes including loco-regional recurrence, distant metastasis-free and overall survival. RESULTS CD24 was expressed in 36 patients (42.9%). CD24 expression was associated with distant metastasis, but not with loco-regional recurrence nor with overall survival. The 5-year distant metastasis-free survival rates were 55.1% and 29.0% in patients with negative and positive expression, respectively (P = 0.0100). On multivariate analysis incorporating N stage, histologic differentiation and CD24 expression, N stage was the only significant factor predicting distant metastasis-free survival (P = 0.0089), while CD24 expression had borderline significance (P = 0.0733). In subgroup analysis, CD24 expression was significantly associated with 5-year distant metastasis-free survival in node-positive patients (38.4% with negative expression vs 0% with positive expression, P = 0.0110), but not in node-negative patients (62.0% with negative expression vs 64.0% with positive expression, P = 0.8599). CONCLUSION CD24 expression was a significant predictor of distant metastasis for patients undergoing curative resection followed by adjuvant chemoradiotherapy especially for node-positive EHBD cancer.
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Shi J, Liu H, Wang HL, Prichard JW, Lin F. Diagnostic utility of von Hippel-Lindau gene product, maspin, IMP3, and S100P in adenocarcinoma of the gallbladder. Hum Pathol 2012; 44:503-11. [PMID: 23079206 DOI: 10.1016/j.humpath.2012.06.010] [Citation(s) in RCA: 16] [Impact Index Per Article: 1.2] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 02/17/2012] [Revised: 06/26/2012] [Accepted: 06/27/2012] [Indexed: 12/28/2022]
Abstract
Our recent study demonstrated the up-regulation of maspin, IMP3, and S100P and down-regulation of von Hippel-Lindau gene product (pVHL) in ductal adenocarcinoma of the pancreas. Distinction of adenocarcinoma of the gallbladder from benign/reactive glandular epithelium can be challenging if based on hematoxylin and eosin-stained sections alone. Immunohistochemical stains for pVHL, maspin, IMP3, and S100P were performed on 82 gallbladder specimens, including adenocarcinoma (n = 33) and normal/reactive gallbladder (n = 49). The results demonstrated (1) only 6.0% of adenocarcinoma cases were focally positive for pVHL, and all normal and most reactive cases (85%) were diffusely positive for pVHL; (2) maspin, IMP3, and S100P were positive in 100%, 81.8%, and 75.8% of adenocarcinoma cases, respectively; in contrast, 53.1%, 12.2%, and 30.6% of normal/reactive cases were only focally and weakly positive for maspin, IMP3, and S100P, respectively; and (3) 90.3% of adenocarcinoma cases were pVHL-negative and positive for 2 or more positive markers, whereas none of the benign/reactive cases showed this staining profile. This study demonstrates that the immunostaining profile of pVHL-/IMP3+/maspin+/S100P+ is useful in the distinction of adenocarcinoma of the gallbladder from normal/reactive conditions.
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Affiliation(s)
- Jianhui Shi
- Geisinger Medical Center, Danville, PA 17822, USA
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21
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Sibulesky L, Nguyen J, Patel T. Preneoplastic conditions underlying bile duct cancer. Langenbecks Arch Surg 2012; 397:861-7. [PMID: 22391777 PMCID: PMC3804833 DOI: 10.1007/s00423-012-0943-7] [Citation(s) in RCA: 9] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2012] [Accepted: 02/22/2012] [Indexed: 02/07/2023]
Abstract
BACKGROUND Malignancies arising from the biliary tract can arise from the epithelial lining of the biliary tract and surrounding tissues. Conditions that predispose to malignancy as well as preneoplastic changes in biliary tract epithelia have been identified. In this overview, we discuss preneoplastic conditions of the biliary tract and emphasize their clinical relevance. RESULTS Chronic biliary tract inflammation predisposes to cancer in the biliary tract. Biliary tract carcinogenesis involves a multistep process as a consequence of chronic biliary epithelial injury or inflammation. Reminiscent of other gastrointestinal epithelial malignancies such as gastric, colon, and pancreatic cancer, biliary tract cancers may evolve via multistep progression from epithelial hyperplasia and dysplasia to malignant transformation. The potential role of initiating cells is also becoming recognized. CONCLUSIONS In spite of improved risk factor recognition, and advances in diagnostic tools, the early diagnosis of pre-malignant or malignant biliary tract conditions is extremely challenging, and there is a paucity of evidence on which to base their management. As a result, the role of pre-emptive surgery remains largely undefined.
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Affiliation(s)
- Lena Sibulesky
- Department of Transplantation, Mayo Clinic, 4500 San Pablo Road, Jacksonville, FL 32224, USA
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Clinical value of CD24 expression in retinoblastoma. J Biomed Biotechnol 2012; 2012:158084. [PMID: 22745528 PMCID: PMC3382394 DOI: 10.1155/2012/158084] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/10/2011] [Accepted: 02/06/2012] [Indexed: 01/02/2023] Open
Abstract
Background. The expression of CD24 has been detected in a wide variety of human malignancies. Downregulation of CD24 inhibits proliferation and induces apoptosis in tumor cells, whereas its upregulation increases tumor growth and metastasis. However, no data on CD24 protein levels in retinoblastoma are available, and the mechanism of CD24 involvement in retinoblastoma progress has not been elucidated. The aim of this study was to explore the expression profile of CD24 in the retinoblastoma tumor samples and to correlate with clinicopathological parameters. Methods. Immunohistochemistry was performed for CD24 on the archival paraffin sections of retinoblastoma and correlated with clinicopathological features. Western blotting was performed to confirm immunoreactivity results. Results. CD24 immunoreactivity was observed in 72.0% (36/50) of the retinoblastoma specimens. Among the 35 low-risk tumors, CD24 was expressed in 62.9% (22/35) tumors and among the 15 high-risk tumors, CD24 was expressed in 93.3% (14/15) tumors. High-risk tumors showed significantly increased expression of CD24 compared to tumors with low-risk (P < 0.05). Conclusions. This is the first correlation between CD24 expression and histopathology in human retinoblastoma. Our study showed increased expression of CD24 in high risk tumors compared to low risk tumors. Further functional studies are required to explore the role of CD24 in retinoblastoma.
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Reduced N-Myc downstream-regulated gene 2 expression is associated with CD24 upregulation and poor prognosis in patients with lung adenocarcinoma. Med Oncol 2012; 29:3162-8. [DOI: 10.1007/s12032-012-0231-y] [Citation(s) in RCA: 13] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2012] [Accepted: 03/21/2012] [Indexed: 01/18/2023]
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Shi Y, Gong HL, Zhou L, Tian J, Wang Y. CD24: a novel cancer biomarker in laryngeal squamous cell carcinoma. ORL J Otorhinolaryngol Relat Spec 2012; 74:78-85. [PMID: 22354323 DOI: 10.1159/000335584] [Citation(s) in RCA: 21] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/01/2011] [Accepted: 11/28/2011] [Indexed: 12/27/2022]
Abstract
PURPOSE To investigate the role of CD24 in tumor invasion and the clinical significance of its expression in laryngeal squamous cell carcinoma (LSCC). PROCEDURES CD24 expression was measured in Hep-2 cell lines and tumor and peritumoral tissues by quantitative real-time PCR and Western blot analysis. The role of CD24 in LSCC was investigated by CD24 depletion using small interfering RNA. Tumor tissue microarrays with samples from 102 LSCC patients were used to detect expression of CD24 and proliferating cell nuclear antigen (PCNA). Prognostic significance was assessed using Kaplan-Meier survival estimates and log-rank tests. RESULTS CD24 was overexpressed in the LSCC cell line and in tumor tissues. Depletion of CD24 caused a notable decrease in cell proliferation, migration and invasiveness in vitro. High CD24 expression was significantly associated with T clinic stage, lymph node metastasis and tumor size (p < 0.05). Patients suffering from LSCC recurrence had higher levels of CD24 protein than those without recurrence (p < 0.0001). The proportion of patients with high PCNA expression was significantly greater among patients with CD24+ LSCC than those with CD24- LSCC (p = 0.000). Univariate and multivariate analyses revealed that CD24 was a significant predictor for overall survival. CONCLUSIONS Overexpression of CD24 in LSCC is associated with invasiveness, metastatic potential and high tumor proliferation status. CD24 may be a promising strategy for the future treatment of LSCC metastasis and recurrence.
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Affiliation(s)
- Yong Shi
- Department of Otolaryngology, Head and Neck Surgery, Fudan University Eye, Ear, Nose and Throat Hospital, Shanghai, China
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Expression and clinicopathological significance of notch signaling and cell-fate genes in biliary tract cancer. Am J Gastroenterol 2012; 107:126-35. [PMID: 21931375 DOI: 10.1038/ajg.2011.305] [Citation(s) in RCA: 24] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 12/11/2022]
Abstract
OBJECTIVES Biliary tract cancer (BTC) is a fatal cancer originating from epithelial cells of the intra- and extra-hepatic biliary duct system and the gallbladder. Genes and pathways regulating stem and progenitor cells as well as cell-fate decisions are increasingly recognized in tumorigenesis. We evaluated the expression of Notch1, Notch2, and HES1 (hairy and enhancer of split 1), as well as the biliary cell-fate regulators SOX9 (SRY (sex determining region Y)-box 9) and HNF1β (hepatocyte nuclear factor 1β), in BTC for correlation with clinicopathological parameters. METHODS Tissue microarrays including normal bile ducts and 111 BTCs consisting of 17 intrahepatic cholangiocarcinomas, 58 extrahepatic cholangiocarcinomas, and 36 gallbladder carcinomas were analyzed using immunohistochemistry. RESULTS Lack of cytoplasmic SOX9 expression was associated with a higher tumor grade (P=0.010) and a significantly reduced overall survival (P=0.002; median 6 months vs. 24 months) in univariate survival analysis, whereas lack of nuclear SOX9 expression was associated with a higher tumor stage (P=0.003). Notch pathway members showed high expression in BTC. However, no correlation was found between cytoplasmic or nuclear Notch1, Notch2, and HES1, as well as HNF1β expression, and any of the clinicopathological parameters. In multivariate analysis, cytoplasmic SOX9 expression was an independent prognostic factor for overall survival (P=0.031, relative risk=0.571). CONCLUSIONS We show strong Notch pathway activation and identify SOX9 as a prognostic marker in BTC. These results substantiate diagnostic and therapeutic approaches targeting developmentally active genes and pathways.
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NDRG2 down-regulation and CD24 up-regulation promote tumor aggravation and poor survival in patients with gallbladder carcinoma. Med Oncol 2011; 29:1879-85. [PMID: 22135002 DOI: 10.1007/s12032-011-0110-y] [Citation(s) in RCA: 22] [Impact Index Per Article: 1.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/19/2011] [Accepted: 11/01/2011] [Indexed: 02/07/2023]
Abstract
Recent studies have demonstrated that N-Myc downstream-regulated gene 2 (NDRG2) may reduce the metastatic potential of breast cancer and hepatocellular carcinoma cells by regulating the expression of CD24, which is expressed in a large variety of solid tumors. The aim of this study was to clarify the clinical value of NDRG2 and CD24 expression in primary gallbladder carcinoma (GBC). One hundred and thirty GBC tissues were evaluated by immunohistochemistry for NDRG2 and CD24 expression. The associations of NDRG2 and CD24 expression with the clinicopathological characteristics and the overall survival of patients with GBC were analyzed. NDRG2 and CD24 were positively expressed in 49/130 (37.69%) and 107/130 (82.31%) of GBC tissues, respectively. In addition, the tumors with the down-regulation of NDRG2 and the up-regulation of CD24 more frequently had lymph node metastasis and lymphovascular invasion. Moreover, the tumors with the down-regulation of NDRG2 and the up-regulation of CD24 tended to show deeper invasion depth and higher TNM stage. There was a negative correlation between NDRG2 expression and CD24 expression in GBC tissues (r = -0.86, P < 0.001). The patients with NDRG2 negative expression correlated with poor prognosis of GBC (P = 0.01), as opposed to CD24 (P = 0.01). The survival rate of the patients with NDRG2-/CD24+ expression was the lowest (P < 0.001), and conjoined expression of NDRG2-/CD24+ was an independent prognostic indicator of GBC (P = 0.003). Our data suggest that NDRG2 down-regulation or CD24 up-regulation is an important feature of GBC. A combined detection of NDRG2/CD24 co-expression may benefit us in prediction of the prognosis in GBC.
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