MSLN (Mesothelin)


Mesothelin (MSLN) is a 40-kDa plasma membrane-bound glycoprotein whose normal biologic role is unclear.1,2

  • Expression in normal human tissues is limited to mesothelial cells lining the pleura, pericardium, and peritoneum.1,2
  • Knockout mice have no distinguishable phenotype.3

Implications in cancer

Overexpression of MSLN induces malignant transformation and aggressiveness by promoting cancer cell proliferation, contributing to local invasion and metastasis, and conferring resistance to apoptosis induced by cytotoxic agents.4-7

Upregulated MSLN plays a key role in controlling epithelial-to-mesenchymal transition (EMT) and inducing stem cell properties in human lung cancer and mesothelioma cells.4

Oncogenic Expression

MSLN is expressed at a high level in almost all mesothelioma and many other solid tumors.8,9

  • 90% to 100% of mesotheliomas10,11
  • 85% to 100% of pancreatic cancers12-14
  • 38% to 69% of lung adenocarcinoma7,11
  • 60% to 67% of triple-negative breast cancers5,15
  • 75% to 100% of nonmucinous ovarian carcinomas12

MSLN expression is more prevalent in aggressive histologic subtypes of lung (KRAS+ tumors),7 breast (triple-negative),5 and esophageal cancers (high-grade dysplasia and adenocarcinoma).16

  1. Chang K, Pastan I. Molecular cloning of mesothelin, a differentiation antigen present on mesothelium, mesotheliomas, and ovarian cancers. Proc Natl Acad Sci USA. 1996;93:136-140.
  2. Hassan R, Thomas A, Alewine C, Le DT, Jaffee EM, Pastan I. Mesothelin Immunotherapy for Cancer: Ready for Prime Time? J Clin Oncol. 2016;34(34):4171-4179.
  3. Bera TK, Pastan I. Mesothelin is not required for normal mouse development or reproduction. Mol Cell Biol. 2000;20(8):2902-2906.
  4. He X, Wang L, Riedel H, Wang K, Yang Y, Dinu CZ, Rojanasakul Y. Mesothelin promotes epithelial-to-mesenchymal transition and tumorigenicity of human lung cancer and mesothelioma cells. Mol Cancer. 2017;16(1):63.
  5. Tozbikian G, Brogi E, Kadota K, et al. Mesothelin expression in triple negative breast carcinomas correlates significantly with basal-like phenotype, distant metastases and decreased survival. PLoS One. 2014;9:e114900.
  6. Bharadwaj U, Marin-Muller C, Li M, Chen C, Yao Q. Mesothelin confers pancreatic cancer cell resistance to TNF-alpha-induced apoptosis through Akt/PI3K/NF-kappaB activation and IL-6/Mcl-1 overexpression. Mol Cancer. 2011;10:106.
  7. Kachala SS, Bograd AJ, Villena-Vargas J, et al. Mesothelin overexpression is a marker of tumor aggressiveness and is associated with reduced recurrence-free and overall survival in early-stage lung adenocarcinoma. Clin Cancer Res. 2014;20:1020-1028.
  8. Morello A, Sadelain M, Adusumilli PS. Mesothelin-targeted CARs: driving T cells to solid tumors. Cancer Discov. 2016;6:133-146.
  9. Lamberts LE, de Groot DJ, Bense RD, de Vries EG, Fehrmann RS. Functional genomic mRNA profiling of a large cancer data base demonstrates mesothelin overexpression in a broad range of tumor types. Oncotarget. 2015;6(29):28164-28172.
  10. Servais EL, Colovos C, Rodriguez L, et al. Mesothelin overexpression promotes mesothelioma cell invasion and MMP-9 secretion in an orthotopic mouse model and in epithelioid pleural mesothelioma patients. Clin Cancer Res. 2012;18:2478-2489.
  11. Ordóñez NG. The immunohistochemical diagnosis of mesothelioma: a comparative study of epithelioid mesothelioma and lung adenocarcinoma. Am J Surg Pathol. 2003;27(8):1031-1051.
  12. Ordóñez NG. Application of mesothelin immunostaining in tumor diagnosis. Am J Surg Pathol. 2003;27(11):1418-1428.
  13. Hassan R, Laszik ZG, Lerner M, Raffeld M, Postier R, Brackett D. Mesothelin is overexpressed in pancreaticobiliary adenocarcinomas but not in normal pancreas and chronic pancreatitis. Am J Clin Pathol. 2005;124(6):838-845.
  14. Argani P, Iacobuzio-Donahue C, Ryu B, et al. Mesothelin is overexpressed in the vast majority of ductal adenocarcinomas of the pancreas: identification of a new pancreatic cancer marker by serial analysis of gene expression (SAGE). Clin Cancer Res. 2001;7(12):3862-3868.
  15. Tchou J, Wang LC, Selven B, et al. Mesothelin, a novel immunotherapy target for triple negative breast cancer. Breast Cancer Res Treat. 2012;133(2):799-804.
  16. Rizk NP, Servais EL, Tang LH, et al. Tissue and serum mesothelin are potential markers of neoplastic progression in Barrett's associated esophageal adenocarcinoma. Cancer Epidemiol Biomarkers Prev. 2012;21:482-486.

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