Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLNgene.
Function
Mesothelin is a 40kDa protein that is expressed in mesothelial cells. The protein was first identified by its reactivity with monoclonal antibody K1. 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. Although it has been proposed that mesothelin may be involved in cell adhesion, its biological function is not known. A knockout mouse line that lacks mesothelin reproduces and develops normally. Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma, lung adenocarcinoma, and cholangiocarcinoma. Mesothelin binds MUC16, indicating that the interaction of mesothelin and MUC16 may contribute to the implantation and peritoneal spread of tumors by cell adhesion. The region consisting of 64 amino acids at the N-terminus of cell surface mesothelin has been identified as the functional binding domain for MUC16/CA125, suggesting the mechanism of mesothelin acting as a MUC16/CA125 functional partner in cancer development.
Medical applications
Mesothelin is a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura, 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. A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials. Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays. 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. Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed. Elevated serum mesothelin was found in most patients with mesothelioma and ovarian cancer. Blood MPF and mesothelin levels were correlated, with modest accuracy for malignant pleural mesothelioma and lung cancer. Circulating mesothelin is reported in nearly all pancreatic cancers, however the levels in healthy persons often exceed 80 ng/mL and to widely overlap the values in the pancreatic cancer patients. 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. Human monoclonal antibodies targeting mesothelin have been isolated by phage display. Mitchell Ho and Ira Pastan at the NIH generated rabbit monoclonal antibodies targeting rare epitopes, including a poorly immunogenic region at the C terminus of human mesothelin. The rabbit antibodies have been humanized by antibody engineering using CDR grafting. The CAR T cells derived from the humanized YP218 antibody effectively inhibit the growth of large ovarian tumors in mice.
