Mesothelin

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Mesothelin
Available structures
PDB Ortholog search: PDBe, RCSB
Identifiers
SymbolsMSLN; MPF; SMRP
External IDsOMIM: 601051 MGI: 1888992 HomoloGene: 4249 GeneCards: MSLN Gene
Orthologs
SpeciesHumanMouse
Entrez1023256047
EnsemblENSG00000102854ENSMUSG00000063011
UniProtQ13421Q61468
RefSeq (mRNA)NM_001177355NM_018857
RefSeq (protein)NP_001170826NP_061345
Location (UCSC)Chr 16:
0.69 – 0.82 Mb		Chr 17:
25.75 – 25.75 Mb
PubMed search
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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 present on normal mesothelial cells and overexpressed in several human tumors, including mesothelioma and ovarian and pancreatic adenocarcinoma. The protein was first identified by its reactivity with monoclonal antibody K1.[3] 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.[4]

Medical applications

Mesothelin is a tumour differentiation antigen that is normally present on the mesothelial cells lining the pleura, peritoneum and pericardium.[5] 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.[4][5]

Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays.[6] Assays for blood-bourne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed.[7] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%).[8] 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).[9] Circulating mesothelin is reported in nearly all pancreatic cancers,[10] 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.[11] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used (compare Sharon et al[11] and Iwahori et al[9] with Hassan et al[8]) and thus that normal levels must be determined anew when new assays are introduced.

Jack Andraka, an American teenage prodigy, claimed to have developed a cheap and quick test for pancreatic, ovarian and lung cancer based on detecting mesothelin using nanotechnology.[12] Although claims were made that the new test was "over 400 times more sensitive than the current gold standard of detection",[13] a conventional commercial test for soluble mesothelin [14] has a sensitivity of less than 10 ng/ml, and an assay for a mesothelin property, metakaryotype potentiating factor, has a similar high sensitivity.[11] The middle 50% of normal persons have a level as high as 80 ng/ml (2 nmol/L, 40Kdalton for soluble mesothelin); 25% of normal persons had a yet higher level when using the same assay. This level, according to a refutation published by Sharon et al [11] in the same year as the Intel award, produces the difficulty in distinguishing normal persons from pancreatic cancer patients, in that the serum levels of mesothelin overlap greatly between normal and cancer patients. Pancreatic cancer patients representing multiple stages of disease did not have serum mesothelin levels higher than was normal.

References

  1. ↑ Kojima T, Oh-eda M, Hattori K, Taniguchi Y, Tamura M, Ochi N, Yamaguchi N (September 1995). "Molecular cloning and expression of megakaryocyte potentiating factor cDNA". J. Biol. Chem. 270 (37): 21984–90. doi:10.1074/jbc.270.37.21984. PMID 7665620. 
  2. ↑ Chang K, Pastan I (January 1996). "Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers". Proc. Natl. Acad. Sci. U.S.A. 93 (1): 136–40. doi:10.1073/pnas.93.1.136. PMC 40193. PMID 8552591. 
  3. ↑ 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 Res 52 (1): 181–6. PMID 1727378. 
  4. ↑ 4.0 4.1 Hassan R, Bera T, Pastan I (June 2004). "Mesothelin: a new target for immunotherapy". Clin. Cancer Res. 10 (12 Pt 1): 3937–42. doi:10.1158/1078-0432.CCR-03-0801. PMID 15217923. 
  5. ↑ 5.0 5.1 Hassan R, Ho M (January 2008). "Mesothelin targeted cancer immunotherapy". Eur. J. Cancer 44 (1): 46–53. doi:10.1016/j.ejca.2007.08.028. PMC 2265108. PMID 17945478. 
  6. ↑ Scholler N, Fu N, Yang Y, Ye Z, Goodman GE, Hellström KE, Hellström I (September 1999). "Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma". Proc. Natl. Acad. Sci. U.S.A. 96 (20): 11531–6. Bibcode:1999PNAS...9611531S. doi:10.1073/pnas.96.20.11531. PMC 18068. PMID 10500211. 
  7. ↑ Maeda M, Hino O (2006). "Blood tests for asbestos-related mesothelioma". Oncology 71 (1–2): 26–31. doi:10.1159/000100446. PMID 17344668. 
  8. ↑ 8.0 8.1 Hassan 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. PMID 16428485. 
  9. ↑ 9.0 9.1 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. PMID 18394747. 
  10. ↑ 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 (November 2009). "Circulating mesothelin protein and cellular antimesothelin immunity in patients with pancreatic cancer". Clin. Cancer Res. 15 (21): 6511–8. doi:10.1158/1078-0432.CCR-09-0565. PMC 2782601. PMID 19843662. 
  11. ↑ 11.0 11.1 11.2 11.3 Sharon 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. PMID 22149739. 
  12. ↑ "Amazing Kids! of the Month – April 2013 – Jack Andraka". Amazing Kids Magazine. 
  13. ↑ For A World Without Cancer : Jack Andraka at TEDxOrangeCoast
  14. ↑ MESOMARK(TM), Fujirebio Diagnostics, Inc.

Further reading

External links

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