Mesothelin Explained

Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene.^{[1] [2]}

Function

Mesothelin is a 40 kDa protein that is expressed in mesothelial cells.^[3] The protein was first identified by its reactivity with monoclonal antibody K1.^[4] 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.^{[5] [6]} A knockout mouse line that lacks mesothelin reproduces and develops normally.^[7]

Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma, lung adenocarcinoma,^[8] and cholangiocarcinoma.^[9] 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.^[10] 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.^[11]

Medical applications

Mesothelin is a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura,^[12] 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.^{[5] [13]} A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials.^[14] Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.^[15] 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.^[16]

Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.^[17] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).^[18] 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).^[19] Circulating mesothelin is reported in nearly all pancreatic cancers,^[20] 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.^[21] 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.^[22]

Human monoclonal antibodies HN1 and SD1 targeting mesothelin have been isolated by phage display.^{[23] [24]} 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.^[25] The rabbit antibodies have been "humanized" by Ho and Zhang using human immunoglobulin germline framework sequences for CDR grafting based on computational structure modeling.^[26] The CAR-T cells derived from the humanized YP218 antibody (hYP218) effectively inhibit the growth of human xenograft tumors in mice.^{[27] [28]}

Further reading

• Alvarez H, Rojas PL, Yong KT, Ding H, Xu G, Prasad PN, Wang J, Canto M, Eshleman JR, Montgomery EA, Maitra A . 6 . 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 . December 2008 . 18691948 . 2606904 . 10.1016/j.nano.2008.06.006 .
• Cristaudo A, Foddis R, Bonotti A, Simonini S, Vivaldi A, Guglielmi G, Bruno R, Landi D, Gemignani F, Landi S . 6 . 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 . April 2010 . 19858537 . 10.1136/oem.2009.049205 . 207017988 .
• Pu RT, Pang Y, Michael CW . 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 . January 2008 . 18064689 . 10.1002/dc.20747 . 10096707 . free . 2027.42/57547 . free .
• Inami K, Kajino K, Abe M, Hagiwara Y, Maeda M, Suyama M, Watanabe S, Hino O . 6 . Secretion of N-ERC/mesothelin and expression of C-ERC/mesothelin in human pancreatic ductal carcinoma . Oncology Reports . 20 . 6 . 1375–1380 . December 2008 . 19020717 . 10.3892/or_00000155 . free .
• Roe OD, Creaney J, Lundgren S, Larsson E, Sandeck H, Boffetta P, Nilsen TI, Robinson B, Kjaerheim K . 6 . Mesothelin-related predictive and prognostic factors in malignant mesothelioma: a nested case-control study . Lung Cancer . 61 . 2 . 235–243 . August 2008 . 18281122 . 10.1016/j.lungcan.2007.12.025 .
• Johnson MD, Vito F, O'Connell MJ . Mesothelin expression in the leptomeninges and meningiomas . The Journal of Histochemistry and Cytochemistry . 56 . 6 . 579–585 . June 2008 . 18347077 . 2386771 . 10.1369/jhc.2008.950477 .
• Schneider J, Hoffmann H, Dienemann H, Herth FJ, Meister M, Muley T . 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 . November 2008 . 18978568 . 10.1097/JTO.0b013e318187491c . 5183602 . free .
• Pass HI, Wali A, Tang N, Ivanova A, Ivanov S, Harbut M, Carbone M, Allard J . 6 . Soluble mesothelin-related peptide level elevation in mesothelioma serum and pleural effusions . The Annals of Thoracic Surgery . 85 . 1 . 265–72; discussion 272 . January 2008 . 18154821 . 10.1016/j.athoracsur.2007.07.042 . free .
• Sapede C, Gauvrit A, Barbieux I, Padieu M, Cellerin L, Sagan C, Scherpereel A, Dabouis G, Grégoire M . 6 . Aberrant splicing and protease involvement in mesothelin release from epithelioid mesothelioma cells . Cancer Science . 99 . 3 . 590–594 . March 2008 . 18167128 . 10.1111/j.1349-7006.2007.00715.x . 205233632 . free . 11158685 .
• Li M, Bharadwaj U, Zhang R, Zhang S, Mu H, Fisher WE, Brunicardi FC, Chen C, Yao Q . 6 . Mesothelin is a malignant factor and therapeutic vaccine target for pancreatic cancer . Molecular Cancer Therapeutics . 7 . 2 . 286–296 . February 2008 . 18281514 . 2929838 . 10.1158/1535-7163.MCT-07-0483 .
• Uehara N, Matsuoka Y, Tsubura A . 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 . February 2008 . 18245228 . 10.1158/1541-7786.MCR-07-0254 . free .
• 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 . 6 . Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin . Lung Cancer . 62 . 1 . 45–54 . October 2008 . 18394747 . 10.1016/j.lungcan.2008.02.012 .
• Creaney J, Yeoman D, Demelker Y, Segal A, Musk AW, Skates SJ, Robinson BW . 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 . August 2008 . 18670302 . 10.1097/JTO.0b013e318180477b . 12405738 . free .
• 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 . 6 . 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 . March 2008 . 18316566 . 10.1158/1078-0432.CCR-07-1613 . free .
• Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M . A binding domain on mesothelin for CA125/MUC16 . The Journal of Biological Chemistry . 284 . 6 . 3739–3749 . February 2009 . 19075018 . 2635045 . 10.1074/jbc.M806776200 . free .
• Chang MC, Chen CA, Hsieh CY, Lee CN, Su YN, Hu YH, Cheng WF . Mesothelin inhibits paclitaxel-induced apoptosis through the PI3K pathway . The Biochemical Journal . 424 . 3 . 449–458 . December 2009 . 19747165 . 10.1042/BJ20082196 .
• Cheng WF, Huang CY, Chang MC, Hu YH, Chiang YC, Chen YL, Hsieh CY, Chen CA . 6 . High mesothelin correlates with chemoresistance and poor survival in epithelial ovarian carcinoma . British Journal of Cancer . 100 . 7 . 1144–1153 . April 2009 . 19293794 . 2669998 . 10.1038/sj.bjc.6604964 .
• Book: Hellstrom I, Hellstrom KE . SMRP and HE4 as Biomarkers for Ovarian Carcinoma when Used Alone and in Combination with CA125 and/Or Each Other . Ovarian Cancer . 622 . 15–21 . 2008 . 18546615 . 10.1007/978-0-387-68969-2_2 . Advances in Experimental Medicine and Biology . 978-0-387-68966-1 . registration . https://archive.org/details/ovariancancersta00geor/page/15 .
• Bharadwaj U, Li M, Chen C, Yao Q . 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 . November 2008 . 19010822 . 2929833 . 10.1158/1541-7786.MCR-08-0095 .

Notes and References

1. Kojima T, Oh-eda M, Hattori K, Taniguchi Y, Tamura M, Ochi N, Yamaguchi N . Molecular cloning and expression of megakaryocyte potentiating factor cDNA . The Journal of Biological Chemistry . 270 . 37 . 21984–21990 . September 1995 . 7665620 . 10.1074/jbc.270.37.21984 . free .
2. Chang K, Pastan I . Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers . Proceedings of the National Academy of Sciences of the United States of America . 93 . 1 . 136–140 . January 1996 . 8552591 . 40193 . 10.1073/pnas.93.1.136 . free . 1996PNAS...93..136C .
3. Hassan R, Ho M . Mesothelin targeted cancer immunotherapy . European Journal of Cancer . 44 . 1 . 46–53 . January 2008 . 17945478 . 2265108 . 10.1016/j.ejca.2007.08.028 .
4. Chang K, Pai LH, Batra JK, Pastan I, Willingham MC . Characterization of the antigen (CAK1) recognized by monoclonal antibody K1 present on ovarian cancers and normal mesothelium . Cancer Research . 52 . 1 . 181–186 . January 1992 . 1727378 .
5. Hassan R, Bera T, Pastan I . Mesothelin: a new target for immunotherapy . Clinical Cancer Research . 10 . 12 Pt 1 . 3937–3942 . June 2004 . 15217923 . 10.1158/1078-0432.CCR-03-0801 . free .
6. Ho M . Advances in liver cancer antibody therapies: a focus on glypican-3 and mesothelin . BioDrugs . 25 . 5 . 275–284 . October 2011 . 21942912 . 3198870 . 10.2165/11595360-000000000-00000 .
7. Bera TK, Pastan I . Mesothelin is not required for normal mouse development or reproduction . Molecular and Cellular Biology . 20 . 8 . 2902–2906 . April 2000 . 10733593 . 85523 . 10.1128/MCB.20.8.2902-2906.2000 .
8. Ho M, Bera TK, Willingham MC, Onda M, Hassan R, FitzGerald D, Pastan I . Mesothelin expression in human lung cancer . Clinical Cancer Research . 13 . 5 . 1571–1575 . March 2007 . 17332303 . 10.1158/1078-0432.CCR-06-2161 . free .
9. Yu L, Feng M, Kim H, Phung Y, Kleiner DE, Gores GJ, Qian M, Wang XW, Ho M . 6 . Mesothelin as a potential therapeutic target in human cholangiocarcinoma . Journal of Cancer . 1 . 141–149 . October 2010 . 20922056 . 2948219 . 10.7150/jca.1.141 .
10. Rump A, Morikawa Y, Tanaka M, Minami S, Umesaki N, Takeuchi M, Miyajima A . Binding of ovarian cancer antigen CA125/MUC16 to mesothelin mediates cell adhesion . The Journal of Biological Chemistry . 279 . 10 . 9190–9198 . March 2004 . 14676194 . 10.1074/jbc.M312372200 . free .
11. Kaneko O, Gong L, Zhang J, Hansen JK, Hassan R, Lee B, Ho M . A binding domain on mesothelin for CA125/MUC16 . The Journal of Biological Chemistry . 284 . 6 . 3739–3749 . February 2009 . 19075018 . 2635045 . 10.1074/jbc.M806776200 . free .
12. Grosso F, Mannucci M, Ugo F, Ferro P, Cassinari M, Vigani A, De Angelis AM, Delfanti S, Lia M, Guaschino R, Barbero S, Roncella S, Giannoni U, Bertolotti M, Pistillo MP, Fontana V . 6 . Pilot Study to Evaluate Serum Soluble Mesothelin-Related Peptide (SMRP) as Marker for Clinical Monitoring of Pleural Mesothelioma (PM): Correlation with Modified RECIST Score . Diagnostics . 11 . 11 . 2015 . October 2021 . 34829362 . 8623660 . 10.3390/diagnostics11112015 . free .
13. Hassan R, Ho M . Mesothelin targeted cancer immunotherapy . European Journal of Cancer . 44 . 1 . 46–53 . January 2008 . 17945478 . 2265108 . 10.1016/j.ejca.2007.08.028 .
14. Morello A, Sadelain M, Adusumilli PS . Mesothelin-Targeted CARs: Driving T Cells to Solid Tumors . Cancer Discovery . 6 . 2 . 133–146 . February 2016 . 26503962 . 4744527 . 10.1158/2159-8290.CD-15-0583 .
15. Scholler N, Fu N, Yang Y, Ye Z, Goodman GE, Hellström KE, Hellström I . Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma . Proceedings of the National Academy of Sciences of the United States of America . 96 . 20 . 11531–11536 . September 1999 . 10500211 . 18068 . 10.1073/pnas.96.20.11531 . free . 1999PNAS...9611531S .
16. Ho M, Onda M, Wang QC, Hassan R, Pastan I, Lively MO . Mesothelin is shed from tumor cells . Cancer Epidemiology, Biomarkers & Prevention . 15 . 9 . 1751 . September 2006 . 16985043 . 10.1158/1055-9965.EPI-06-0479 . free .
17. Maeda M, Hino O . Blood tests for asbestos-related mesothelioma . Oncology . 71 . 1–2 . 26–31 . 2006 . 17344668 . 10.1159/000100446 . 12953614 .
18. Hassan R, Remaley AT, Sampson ML, Zhang J, Cox DD, Pingpank J, Alexander R, Willingham M, Pastan I, Onda M . 6 . Detection and quantitation of serum mesothelin, a tumor marker for patients with mesothelioma and ovarian cancer . Clinical Cancer Research . 12 . 2 . 447–453 . January 2006 . 16428485 . 10.1158/1078-0432.CCR-05-1477 . free .
19. 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 . 6 . Megakaryocyte potentiating factor as a tumor marker of malignant pleural mesothelioma: evaluation in comparison with mesothelin . Lung Cancer . 62 . 1 . 45–54 . October 2008 . 18394747 . 10.1016/j.lungcan.2008.02.012 .
20. Johnston FM, Tan MC, Tan BR, Porembka MR, Brunt EM, Linehan DC, Simon PO, Plambeck-Suess S, Eberlein TJ, Hellstrom KE, Hellstrom I, Hawkins WG, Goedegebuure P . 6 . Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer . Clinical Cancer Research . 15 . 21 . 6511–6518 . November 2009 . 19843662 . 2782601 . 10.1158/1078-0432.CCR-09-0565 .
21. Sharon E, Zhang J, Hollevoet K, Steinberg SM, Pastan I, Onda M, Gaedcke J, Ghadimi BM, Ried T, Hassan R . 6 . Serum mesothelin and megakaryocyte potentiating factor in pancreatic and biliary cancers . Clinical Chemistry and Laboratory Medicine . 50 . 4 . 721–725 . April 2012 . 22149739 . 6309905 . 10.1515/CCLM.2011.816 .
22. Ho M, Hassan R, Zhang J, Wang QC, Onda M, Bera T, Pastan I . Humoral immune response to mesothelin in mesothelioma and ovarian cancer patients . Clinical Cancer Research . 11 . 10 . 3814–3820 . May 2005 . 15897581 . 10.1158/1078-0432.CCR-04-2304 . 38327063 . free .
23. Ho M, Feng M, Fisher RJ, Rader C, Pastan I . A novel high-affinity human monoclonal antibody to mesothelin . International Journal of Cancer . 128 . 9 . 2020–2030 . May 2011 . 20635390 . 2978266 . 10.1002/ijc.25557 .
24. Tang Z, Feng M, Gao W, Phung Y, Chen W, Chaudhary A, St Croix B, Qian M, Dimitrov DS, Ho M . 6 . A human single-domain antibody elicits potent antitumor activity by targeting an epitope in mesothelin close to the cancer cell surface . Molecular Cancer Therapeutics . 12 . 4 . 416–426 . April 2013 . 23371858 . 3624043 . 10.1158/1535-7163.MCT-12-0731 .
25. Zhang YF, Phung Y, Gao W, Kawa S, Hassan R, Pastan I, Ho M . New high affinity monoclonal antibodies recognize non-overlapping epitopes on mesothelin for monitoring and treating mesothelioma . Scientific Reports . 5 . 9928 . May 2015 . 25996440 . 4440525 . 10.1038/srep09928 . 2015NatSR...5E9928Z .
26. Zhang YF, Ho M . April 2017 . Humanization of rabbit monoclonal antibodies via grafting combined Kabat/IMGT/Paratome complementarity-determining regions: Rationale and examples . mAbs . 9 . 3 . 419–429 . 10.1080/19420862.2017.1289302 . 5384799 . 28165915.
27. Zhang Z, Jiang D, Yang H, He Z, Liu X, Qin W, Li L, Wang C, Li Y, Li H, Xu H, Jin H, Qian Q . 6 . Modified CAR T cells targeting membrane-proximal epitope of mesothelin enhances the antitumor function against large solid tumor . Cell Death & Disease . 10 . 7 . 476 . June 2019 . 31209210 . 6572851 . 10.1038/s41419-019-1711-1 .
28. Tomar S, Zhang J, Khanal M, Hong J, Venugopalan A, Jiang Q, Sengupta M, Miettinen M, Li N, Pastan I, Ho M, Hassan R . 6 . Development of Highly Effective Anti-Mesothelin hYP218 Chimeric Antigen Receptor T Cells With Increased Tumor Infiltration and Persistence for Treating Solid Tumors . Molecular Cancer Therapeutics . 21 . 7 . 1195–1206 . July 2022 . 35499461 . 9256778 . 10.1158/1535-7163.MCT-22-0073 .