Mesothelin Is Overexpressed in Pancreaticobiliary Adenocarcinomas But Not in Normal Pancreas and Chronic Pancreatitis

Laboratory of Molecular Biology, National Cancer Institute, National Institutes of Health, Bethesda, MD 20892-4264, USA.
American Journal of Clinical Pathology (Impact Factor: 2.51). 01/2006; 124(6):838-45. DOI: 10.1309/F1B64CL7H8VJKEAF
Source: PubMed


Mesothelin, a cell surface glycoprotein present on normal mesothelial cells, has been reported to be expressed in pancreatic adenocarcinomas. We conducted this study to fully characterize mesothelin expression in surgically resected, formalin-fixed, paraffin-embedded tissue specimens of 18 pancreatic adenocarcinomas, 9 adenocarcinomas of the ampulla of Vater, 12 adenocarcinomas of the common bile duct, and 17 cases of chronic pancreatitis. Mesothelin immunostaining was performed using the antimesothelin monoclonal antibody 5B2. All 18 cases (100%) of pancreatic adenocarcinomas showed mesothelin expression, as did 8 (89%) of 9 cases of ampullar adenocarcinoma and all 12 cases (100%) of common bile duct adenocarcinoma. In all cases of pancreaticobiliary adenocarcinoma, the adjacent normal pancreas did not stain for mesothelin. Of 17 specimens of chronic pancreatitis, 16 were negative for mesothelin expression, and 1 case showed weak mesothelin staining of fewer than 5% of normal pancreatic ducts. Our results demonstrated mesothelin expression in the majority of pancreaticobiliary adenocarcinomas and no expression in normal pancreatic tissues and in chronic pancreatitis.

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    • "Cytokeratin- 19 (CK19) served as a marker for ductal epithelial cells, both normal and transformed [22] [23]. Differential overexpression of mesothelin (MSLN) was assumed to mark only malignant ductal epithelium [24] [25]. A desmoplastic reaction is characteristic of both inflammatory and cancerous pancreata. "
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    ABSTRACT: Meaningful profiling of pancreatic cancer samples is particularly challenging due to their complex cellular composition. Beyond tumor cells, surgical biopsies contain desmoplastic stroma with infiltrating inflammatory cells, adjacent normal parenchyma, and "non-pancreatic tissues". The risk of misinterpretation rises when the heterogeneous cancer tissues are sub-divided into smaller fragments for multiple analytic procedures. Pre-analytic histological evaluation is the best option to characterize pancreatic tissue samples. Our aim was to develop a complement or alternative procedure to determine the cellular composition of pancreatic cancerous biopsies, basing on intra-analytic molecular annotation. A standard process for sample stratification at a molecular level does not yet exist. Particularly in the case of retrospective or data depository-based studies, when hematoxylin-eosin stained sections are not available, it supports the correct interpretation of expression profiles. A five-gene transcriptional signature (RNACellStrat) was defined that allows cell type-specific stratification of pancreatic tissues. Testing biopsy material from biobanks with this procedure demonstrated high correspondence of molecular (qRT-PCR and microarray) and histologic (hematoxylin-eosin stain) evaluations. Notably, about a quarter of randomly selected samples (tissue fragments) were exposed as inappropriate for subsequent clinico-pathological interpretation. Via immediate intra-analytical procedure, our RNA-based stratification RNACellStrat increases the accuracy and reliability of the conclusions drawn from diagnostic and prognostic molecular information. Copyright © 2015 IAP and EPC. Published by Elsevier B.V. All rights reserved.
    Pancreatology 06/2015; 29(4). DOI:10.1016/j.pan.2015.05.480 · 2.84 Impact Factor
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    • "The human epidermoid carcinoma cell line A431 was purchased from ATCC (Mananasas, VA) and maintained in the laboratory as recommended. Immunohistochemical staining for MSLN and CA125 was performed by Histoserv, Inc (Germantown, MD) using mouse anti-MSLN 5B2 (Novocastra Reagents from Leica Bioystems, Buffalo Grove, IL) as previously described [17], and mouse anti-CA125 OC125 (Zymed Laboratories) at 1:50 dilution. "
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    ABSTRACT: The mesothelin (MSLN) gene encodes a 71 kilodalton (kDa) precursor protein that is processed into megakaryocytic potentiating factor (MPF), a 31 kDa protein that is secreted from the cell, and mature mesothelin (mMSLN), a 40 kDa cell surface protein. The mMSLN binds to CA125, an interaction that has been implicated in the intra-cavitary spread of mesothelioma and ovarian cancer. To better define the role of MPF and mMSLN, growth of the lung cancer cell line A549 was evaluated in immuno-deficient mice with inactivation of the Msln gene. We observed that Msln–/– mice xenografted with intraperitoneal A549 tumors survive significantly long than tumor-bearing Msln+/+ mice. When tumor-bearing Msln–/– mice are supplemented with recombinant MPF (and to a lesser extent mMSLN), most of this survival advantage is lost. These studies demonstrate that MPF and mMSLN have an important role in the growth of lung cancer cells in vivo and raise the possibility that inactivation of MPF may be a useful treatment for lung and other MSLN expressing cancers.
    PLoS ONE 08/2014; 9(8):e104388. DOI:10.1371/journal.pone.0104388 · 3.23 Impact Factor
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    • "IHC biomarkers have previously been investigated in surgical and cytological cohorts but none is yet routinely used for improving the diagnosis of PBA [35-37,41,44-46]. There are six significant reasons delaying the clinical translation of diagnostic biomarkers in PBA and other cancers. "
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    ABSTRACT: Background Pancreatico-biliary adenocarcinomas (PBA) have a poor prognosis. Diagnosis is usually achieved by imaging and/or endoscopy with confirmatory cytology. Cytological interpretation can be difficult especially in the setting of chronic pancreatitis/cholangitis. Immunohistochemistry (IHC) biomarkers could act as an adjunct to cytology to improve the diagnosis. Thus, we performed a meta-analysis and selected KOC, S100P, mesothelin and MUC1 for further validation in PBA resection specimens. Methods Tissue microarrays containing tumour and normal cores in a ratio of 3:2, from 99 surgically resected PBA patients, were used for IHC. IHC was performed on an automated platform using antibodies against KOC, S100P, mesothelin and MUC1. Tissue cores were scored for staining intensity and proportion of tissue stained using a Histoscore method (range, 0–300). Sensitivity and specificity for individual biomarkers, as well as biomarker panels, were determined with different cut-offs for positivity and compared by summary receiver operating characteristic (ROC) curve. Results The expression of all four biomarkers was high in PBA versus normal ducts, with a mean Histoscore of 150 vs. 0.4 for KOC, 165 vs. 0.3 for S100P, 115 vs. 0.5 for mesothelin and 200 vs. 14 for MUC1 (p < .0001 for all comparisons). Five cut-offs were carefully chosen for sensitivity/specificity analysis. Four of these cut-offs, namely 5%, 10% or 20% positive cells and Histoscore 20 were identified using ROC curve analysis and the fifth cut-off was moderate-strong staining intensity. Using 20% positive cells as a cut-off achieved higher sensitivity/specificity values: KOC 84%/100%; S100P 83%/100%; mesothelin 88%/92%; and MUC1 89%/63%. Analysis of a panel of KOC, S100P and mesothelin achieved 100% sensitivity and 99% specificity if at least 2 biomarkers were positive for 10% cut-off; and 100% sensitivity and specificity for 20% cut-off. Conclusion A biomarker panel of KOC, S100P and mesothelin with at least 2 biomarkers positive was found to be an optimum panel with both 10% and 20% cut-offs in resection specimens from patients with PBA.
    BMC Clinical Pathology 07/2014; 14(1):35. DOI:10.1186/1472-6890-14-35
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