Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.
Function
Mesothelin is a 40 kDa protein that is expressed in mesothelial cells. The protein was first identified by its reactivity with monoclonal antibody K1. Subsequent cloning studies showed that the mesothelin gene encodes a precursor protein that is processed to yield mesothelin which is attached to the cell membrane by a glycophosphatidylinositol linkage and a 31-kDa shed fragment named megakaryocyte-potentiating factor (MPF). Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known. A knockout mouse line that lacks mesothelin reproduces and develops normally.
Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma, lung adenocarcinoma, and cholangiocarcinoma. Mesothelin binds MUC16 (also known as CA125), indicating that the interaction of mesothelin and MUC16 may contribute to the implantation and peritoneal spread of tumors by cell adhesion. The region (residues 296-359) consisting of 64 amino acids at the N-terminus of cell surface mesothelin has been identified as the functional binding domain (named IAB) for MUC16/CA125, suggesting the mechanism of mesothelin acting as a MUC16/CA125 functional partner in cancer development.
A protein structure model of human mesothelin and the binding sites of MUC16 (CA125) and antibodies
Medical applications
Mesothelin is a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura,peritoneum and pericardium. Since mesothelin is overexpressed in several cancers and is immunogenic, the protein could be exploited as tumor marker or as the antigenic target of a therapeutic cancer vaccine. A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials.
Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays. Soluble mesothelin is identified as the extracellular domain of membrane-bound mesothelin shed from tumor cells according to the mass spectrometry analysis of soluble mesothelin purified from cell culture supernatant.
Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed. Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%). Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer (sensitivity 74% and 59%, specificity 90% and 86%, respectively for MPF and mesothelin assays). Circulating mesothelin is reported in nearly all pancreatic cancers, however the levels in healthy persons often exceed 80 ng/mL (using 40 kD molecular weight as the conversion factor) and to widely overlap the values in the pancreatic cancer patients. It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used and thus that normal levels must be determined anew when new assays are introduced. Increase of mesothelin-specific antibodies were also detected in the sera of about 40% of patients with mesothelioma and 42% with ovarian cancer, indicating an antibody response to mesothelin was correlated with high expression of mesothelin on tumor cells.
Human monoclonal antibodies HN1 and SD1 targeting mesothelin have been isolated by phage display. Mitchell Ho and Ira Pastan at the U.S. National Institutes of Health (NIH) generated rabbit monoclonal antibodies targeting rare and poorly immunogenic epitopes of mesothelin, including the C terminus recognized by the YP218 antibody. The rabbit antibodies have been humanized by protein engineering and computational structure modeling. The CAR T cells derived from the humanized YP218 antibody (hYP218) effectively inhibit the growth of human xenograft tumors in mice.
Further reading
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Alvarez H, Rojas PL, Yong KT, Ding H, Xu G, Prasad PN, et al. (December 2008). "Mesothelin is a specific biomarker of invasive cancer in the Barrett-associated adenocarcinoma progression model: translational implications for diagnosis and therapy". Nanomedicine. 4 (4): 295–301. doi:10.1016/j.nano.2008.06.006. PMC 2606904. PMID 18691948.
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Cristaudo A, Foddis R, Bonotti A, Simonini S, Vivaldi A, Guglielmi G, et al. (April 2010). "Polymorphisms in the putative micro-RNA-binding sites of mesothelin gene are associated with serum levels of mesothelin-related protein". Occupational and Environmental Medicine. 67 (4): 233–236. doi:10.1136/oem.2009.049205. PMID 19858537. S2CID 207017988.
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Pu RT, Pang Y, Michael CW (January 2008). "Utility of WT-1, p63, MOC31, mesothelin, and cytokeratin (K903 and CK5/6) immunostains in differentiating adenocarcinoma, squamous cell carcinoma, and malignant mesothelioma in effusions". Diagnostic Cytopathology. 36 (1): 20–25. doi:10.1002/dc.20747. hdl:2027.42/57547. PMID 18064689. S2CID 10096707.
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Inami K, Kajino K, Abe M, Hagiwara Y, Maeda M, Suyama M, et al. (December 2008). "Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma". Oncology Reports. 20 (6): 1375–1380. doi:10.3892/or_00000155. PMID 19020717.
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Johnson MD, Vito F, O'Connell MJ (June 2008). "Mesothelin expression in the leptomeninges and meningiomas". The Journal of Histochemistry and Cytochemistry. 56 (6): 579–585. doi:10.1369/jhc.2008.950477. PMC 2386771. PMID 18347077.
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Schneider J, Hoffmann H, Dienemann H, Herth FJ, Meister M, Muley T (November 2008). "Diagnostic and prognostic value of soluble mesothelin-related proteins in patients with malignant pleural mesothelioma in comparison with benign asbestosis and lung cancer". Journal of Thoracic Oncology. 3 (11): 1317–1324. doi:10.1097/JTO.0b013e318187491c. PMID 18978568. S2CID 5183602.
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Pass HI, Wali A, Tang N, Ivanova A, Ivanov S, Harbut M, et al. (January 2008). "Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions". The Annals of Thoracic Surgery. 85 (1): 265–72, discussion 272. doi:10.1016/j.athoracsur.2007.07.042. PMID 18154821.
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Sapede C, Gauvrit A, Barbieux I, Padieu M, Cellerin L, Sagan C, et al. (March 2008). "Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells". Cancer Science. 99 (3): 590–594. doi:10.1111/j.1349-7006.2007.00715.x. PMID 18167128. S2CID 205233632.
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Li M, Bharadwaj U, Zhang R, Zhang S, Mu H, Fisher WE, et al. (February 2008). "Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer". Molecular Cancer Therapeutics. 7 (2): 286–296. doi:10.1158/1535-7163.MCT-07-0483. PMC 2929838. PMID 18281514.
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Uehara N, Matsuoka Y, Tsubura A (February 2008). "Mesothelin promotes anchorage-independent growth and prevents anoikis via extracellular signal-regulated kinase signaling pathway in human breast cancer cells". Molecular Cancer Research. 6 (2): 186–193. doi:10.1158/1541-7786.MCR-07-0254. PMID 18245228.
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Iwahori K, Osaki T, Serada S, Fujimoto M, Suzuki H, Kishi Y, et al. (October 2008). "Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin". Lung Cancer. 62 (1): 45–54. doi:10.1016/j.lungcan.2008.02.012. PMID 18394747.
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Creaney J, Yeoman D, Demelker Y, Segal A, Musk AW, Skates SJ, Robinson BW (August 2008). "Comparison of osteopontin, megakaryocyte potentiating factor, and mesothelin proteins as markers in the serum of patients with malignant mesothelioma". Journal of Thoracic Oncology. 3 (8): 851–857. doi:10.1097/JTO.0b013e318180477b. PMID 18670302. S2CID 12405738.
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Shiomi K, Hagiwara Y, Sonoue K, Segawa T, Miyashita K, Maeda M, et al. (March 2008). "Sensitive and specific new enzyme-linked immunosorbent assay for N-ERC/mesothelin increases its potential as a useful serum tumor marker for mesothelioma". Clinical Cancer Research. 14 (5): 1431–1437. doi:10.1158/1078-0432.CCR-07-1613. PMID 18316566.
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Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M (February 2009). "A binding domain on mesothelin for CA125/MUC16". The Journal of Biological Chemistry. 284 (6): 3739–3749. doi:10.1074/jbc.M806776200. PMC 2635045. PMID 19075018.
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Chang MC, Chen CA, Hsieh CY, Lee CN, Su YN, Hu YH, Cheng WF (December 2009). "Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway". The Biochemical Journal. 424 (3): 449–458. doi:10.1042/BJ20082196. PMID 19747165.
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Cheng WF, Huang CY, Chang MC, Hu YH, Chiang YC, Chen YL, et al. (April 2009). "High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma". British Journal of Cancer. 100 (7): 1144–1153. doi:10.1038/sj.bjc.6604964. PMC 2669998. PMID 19293794.
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Hellstrom I, Hellstrom KE (2008). "SMRP and HE4 as biomarkers for ovarian carcinoma when used alone and in combination with CA125 and/or each other". Ovarian Cancer. Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. Vol. 622. pp. 15–21. doi:10.1007/978-0-387-68969-2_2. ISBN 978-0-387-68966-1. PMID 18546615.
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Bharadwaj U, Li M, Chen C, Yao Q (November 2008). "Mesothelin-induced pancreatic cancer cell proliferation involves alteration of cyclin E via activation of signal transducer and activator of transcription protein 3". Molecular Cancer Research. 6 (11): 1755–1765. doi:10.1158/1541-7786.MCR-08-0095. PMC 2929833. PMID 19010822.
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