Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLNgene.[5][6]
Function
Mesothelin is a 40 kDa protein that is expressed in mesothelial cells.[7] The protein was first identified by its reactivity with monoclonal antibody K1.[8] 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.[9] A knockout mouse line that lacks mesothelin reproduces and develops normally.[10]
Mesothelin is over expressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma.[7] The interaction between mesothelin and MUC16 (also known as CA125) may facilitate the implantation and peritoneal spread of tumors by cell adhesion. The region (296-359) consisting of 64 amino acids at the N-terminal of cell surface mesothelin is the functional binding domain for MUC16.[11]
Medical applications
Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium.[12] 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.[9][12] A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials. [13]
Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.[14] Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.[15] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).[16] 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).[17] Circulating mesothelin is reported in nearly all pancreatic cancers,[18] 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.[19] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used[19][17][16] and thus that normal levels must be determined anew when new assays are introduced.
^Chang K, Pai LH, Batra JK, Pastan I, Willingham MC (January 1992). "Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium". Cancer Research. 52 (1): 181–6. PMID1727378.
^ abHassan R, Bera T, Pastan I (June 2004). "Mesothelin: a new target for immunotherapy". Clinical Cancer Research. 10 (12 Pt 1): 3937–42. doi:10.1158/1078-0432.CCR-03-0801. PMID15217923.
^Maeda M, Hino O (2006). "Blood tests for asbestos-related mesothelioma". Oncology. 71 (1–2): 26–31. doi:10.1159/000100446. PMID17344668.
^ abHassan R, Remaley AT, Sampson ML, Zhang J, Cox DD, Pingpank J, Alexander R, Willingham M, Pastan I, Onda M (January 2006). "Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer". Clin. Cancer Res. 12 (2): 447–53. doi:10.1158/1078-0432.CCR-05-1477. PMID16428485.
^ abIwahori K, Osaki T, Serada S, Fujimoto M, Suzuki H, Kishi Y, Yokoyama A, Hamada H, Fujii Y, Yamaguchi K, Hirashima T, Matsui K, Tachibana I, Nakamura Y, Kawase I, Naka T (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. PMID18394747.
^ abSharon E, Zhang J, Hollevoet K, Steinberg SM, Pastan I, Onda M, Gaedcke J, Ghadimi BM, Ried T, Hassan R (April 2012). "Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers". Clin. Chem. Lab. Med. 50 (4): 721–5. doi:10.1515/CCLM.2011.816. PMID22149739.
Cristaudo A, Foddis R, Bonotti A, Simonini S, Vivaldi A, Guglielmi G, Bruno R, Landi D, Gemignani F, Landi S (April 2010). "Polymorphisms in the putative micro-RNA-binding sites of mesothelin gene are associated with serum levels of mesothelin-related protein". Occup Environ Med. 67 (4): 233–6. doi:10.1136/oem.2009.049205. PMID19858537.
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". Diagn. Cytopathol. 36 (1): 20–5. doi:10.1002/dc.20747. PMID18064689.
Inami K, Kajino K, Abe M, Hagiwara Y, Maeda M, Suyama M, Watanabe S, Hino O (December 2008). "Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma". Oncol. Rep. 20 (6): 1375–80. doi:10.3892/or_00000155. PMID19020717.
Roe OD, Creaney J, Lundgren S, Larsson E, Sandeck H, Boffetta P, Nilsen TI, Robinson B, Kjaerheim K (August 2008). "Mesothelin-related predictive and prognostic factors in malignant mesothelioma: a nested case-control study". Lung Cancer. 61 (2): 235–43. doi:10.1016/j.lungcan.2007.12.025. PMID18281122.
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". J Thorac Oncol. 3 (11): 1317–24. doi:10.1097/JTO.0b013e318187491c. PMID18978568.
Pass HI, Wali A, Tang N, Ivanova A, Ivanov S, Harbut M, Carbone M, Allard J (January 2008). "Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions". Ann. Thorac. Surg. 85 (1): 265–72, discussion 272. doi:10.1016/j.athoracsur.2007.07.042. PMID18154821.
Sapede C, Gauvrit A, Barbieux I, Padieu M, Cellerin L, Sagan C, Scherpereel A, Dabouis G, Grégoire M (March 2008). "Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells". Cancer Sci. 99 (3): 590–4. doi:10.1111/j.1349-7006.2007.00715.x. PMID18167128.
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". Mol. Cancer Res. 6 (2): 186–93. doi:10.1158/1541-7786.MCR-07-0254. PMID18245228.
Iwahori K, Osaki T, Serada S, Fujimoto M, Suzuki H, Kishi Y, Yokoyama A, Hamada H, Fujii Y, Yamaguchi K, Hirashima T, Matsui K, Tachibana I, Nakamura Y, Kawase I, Naka T (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. PMID18394747.
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". J Thorac Oncol. 3 (8): 851–7. doi:10.1097/JTO.0b013e318180477b. PMID18670302.
Shiomi K, Hagiwara Y, Sonoue K, Segawa T, Miyashita K, Maeda M, Izumi H, Masuda K, Hirabayashi M, Moroboshi T, Yoshiyama T, Ishida A, Natori Y, Inoue A, Kobayashi M, Sakao Y, Miyamoto H, Takahashi K, Hino O (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". Clin. Cancer Res. 14 (5): 1431–7. doi:10.1158/1078-0432.CCR-07-1613. PMID18316566.
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". Biochem. J. 424 (3): 449–58. doi:10.1042/BJ20082196. PMID19747165.
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". Adv. Exp. Med. Biol. Advances in Experimental Medicine and Biology. 622: 15–21. doi:10.1007/978-0-387-68969-2_2. ISBN978-0-387-68966-1. PMID18546615.
