Disease relevance of Msln

• Mesothelin is a glycosylphosphatidylinositol-linked glycoprotein highly expressed in mesothelial cells, mesotheliomas, and ovarian cancer, but the biological function(s) of the protein is not known [1].
• Based on the finding that a soluble form of mesothelin specifically binds to ovarian carcinoma cell line OVCAR-3, we isolated cDNAs encoding a mesothelin-binding protein by expression cloning [2].
• Finally, we show that CA125 and mesothelin are co-expressed in advanced grade ovarian adenocarcinoma [2].
• Taken together, our data indicate that mesothelin is a novel CA125-binding protein and that CA125 might contribute to the metastasis of ovarian cancer to the peritoneum by initiating cell attachment to the mesothelial epithelium via binding to mesothelin [2].
• The biodistribution of 111In-K1 was studied in athymic nude mice bearing 2 s.c. tumors, one expressing a stably transfected plasmid encoding mesothelin and one composed of the parental untransfected A431 epidermoid carcinoma cells which do not express mesothelin [3].

High impact information on Msln

• Soluble member(s) of the mesothelin/megakaryocyte potentiating factor family are detectable in sera from patients with ovarian carcinoma [4].
• OV569 recognizes a protein(s) of 42-45 kDa with the same N-terminal amino acid sequence as the membrane-bound portion of mesothelin and megakaryocyte potentiating factor (MPF) [4].
• A new member of the mesothelin/MPF family was discovered, which has an 82-bp insert in the membrane-associated part, leading to a frameshift of 212 bp, and whose predicted molecular structure indicates that it is soluble [4].
• To directly assess the function of the mesothelin in vivo, we generated mutant mice in which the mesothelin gene was inactivated by replacing it with the neomycin resistance gene [1].
• In adult tissues the mesothelin gene was expressed in lung, heart, spleen, liver, kidney, and testis [1].

Chemical compound and disease context of Msln

• An antimesothelin disulfide-linked Fv (SS1 Fv) was fused to a truncated mutant of Pseudomonas exotoxin A to produce the recombinant immunotoxin SS1(dsFv)-PE38, which has a high binding affinity to mesothelin (Kd = 0.7 nM) [5].

Biological context of Msln

• One gene, Erc (expressed in renal carcinoma) showed sequence homology to the mouse and human megakaryocyte potentiating factor (MPF)/mesothelin gene [6].
• Binding of CA125 to membrane-bound mesothelin mediates heterotypic cell adhesion as anti-mesothelin antibody blocks binding of OVCAR-3 cells expressing CA125 to an endothelial-like cell line expressing mesothelin [2].
• Our results also show low concentrations of an immunotoxin targeting mesothelin is cytotoxic to mesothelin-expressing human tumors by inducing apoptosis [7].
• Moreover, the light chains of the two scFvs selected on cells are very similar to the light chains of two of the scFvs selected by panning on recombinant mesothelin except for a few point mutations [8].

Anatomical context of Msln

• The same or homologous amino acid sequence has not been found in known proteins, demonstrating that MPF is a novel cytokine that has megakaryocyte potentiating activity in the murine assay system [9].
• The monoclonal antibody (MAb) K1 is a murine IgG1 that recognizes mesothelin, a differentiation antigen present on mesothelium which is highly expressed on cancers derived from mesothelium, including most ovarian cancers and epithelioid mesotheliomas [3].
• Then, the immunohistocytochemical analysis and in situ hybridization revealed that MPF-producing cells were identified as lung macrophages [10].
• Several attempts to produce anti-mesothelin hybridomas from spleen cells of mice immunized with recombinant mesothelin were unsuccessful [8].

Associations of Msln with chemical compounds

• Glycopeptidase F digestion, and amino sugar analysis of the factor demonstrated that MPF is a glycoprotein carrying at least one N-linked sugar chain [9].

Analytical, diagnostic and therapeutic context of Msln

• Molecular cloning and expression of megakaryocyte potentiating factor cDNA [11].
• By flow cytometric analysis and immunoprecipitation, we demonstrate that CA125 binds to mesothelin in a specific manner [2].
• The megakaryocyte potentiating factor (MPF) was purified from an HPC-Y5 conditioned medium by a combination of ion-exchange chromatography, gel filtration and reverse-phase HPLC [9].
• Tumor-directed radiation and the immunotoxin SS1P in the treatment of mesothelin-expressing tumor xenografts [12].
• A sandwich ELISA using mAbs to two different epitopes was constructed and used to measure the presence of MPF in the media of various mesothelin-expressing cancer cell lines and in human serum [13].

References