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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | MSLN , MPF, SMRP, mesothelin | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 601051; MGI: 1888992; HomoloGene: 4249; GeneCards: MSLN; OMA:MSLN - orthologs | ||||||||||||||||||||||||||||||||||||||||||||||||||
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| Wikidata | |||||||||||||||||||||||||||||||||||||||||||||||||||
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Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene. [5] [6]
Mesothelin is a 40 kDa protein that is expressed in mesothelial cells. [7] The protein was first identified by its reactivity with monoclonal antibody K1. [8] 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. [9] [10] A knockout mouse line that lacks mesothelin reproduces and develops normally. [11]
Mesothelin is over expressed in several human tumors, including mesothelioma, ovarian cancer, pancreatic adenocarcinoma, [7] lung adenocarcinoma, [12] and cholangiocarcinoma. [13] 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. [14] 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. [15]
Mesothelin is a tumor differentiation antigen that is normally present on the mesothelial cells lining the pleura, [17] peritoneum and pericardium. [7] 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. [9] [18] A 2016 review indicates that some immunotherapeutic strategies have shown encouraging results in early-phase clinical trials. [19] Elevations of serum mesothelin specific to ovarian and other cancer patients may be measured using ELISA assays. [20] 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. [21]
Assays for blood-borne mesothelin and MPF for tumor diagnosis, especially applied to asbestos-related mesothelioma have been developed. [22] Elevated serum mesothelin was found in most patients with mesothelioma (71%) and ovarian cancer (67%). [23] 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). [24] Circulating mesothelin is reported in nearly all pancreatic cancers, [25] 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. [26] It was noted that the cutoff levels for normal could differ as much as 10-fold among publications, depending on the assay used [26] [24] [23] 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. [27]
Human monoclonal antibodies HN1 and SD1 targeting mesothelin have been isolated by phage display. [28] [29] 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. [16] The rabbit antibodies have been "humanized" by Ho and Zhang using human immunoglobulin germline framework sequences for CDR grafting based on computational structure modeling. [30] The CAR-T cells derived from the humanized YP218 antibody (hYP218) effectively inhibit the growth of human xenograft tumors in mice. [31] [32]
Mesothelioma is a type of cancer that develops from the thin layer of tissue that covers many of the internal organs. The area most commonly affected is the lining of the lungs and chest wall. Less commonly the lining of the abdomen and rarely the sac surrounding the heart, or the sac surrounding the testis may be affected. Signs and symptoms of mesothelioma may include shortness of breath due to fluid around the lung, a swollen abdomen, chest wall pain, cough, feeling tired, and weight loss. These symptoms typically come on slowly.
Mucin-16(MUC-16) also known as Ovarian cancer-related tumor marker CA125 is a protein that in humans is encoded by the MUC16 gene. MUC-16 is a member of the mucin family glycoproteins. MUC-16 has found application as a tumor marker or biomarker that may be elevated in the blood of some patients with specific types of cancers, most notably ovarian cancer, or other conditions that are benign.
Hybridoma technology is a method for producing large numbers of identical antibodies, also called monoclonal antibodies. This process starts by injecting a mouse with an antigen that provokes an immune response. A type of white blood cell, the B cell, produces antibodies that bind to the injected antigen. These antibody producing B-cells are then harvested from the mouse and, in turn, fused with immortal myeloma cancer cells, to produce a hybrid cell line called a hybridoma, which has both the antibody-producing ability of the B-cell and the longevity and reproductivity of the myeloma.
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Monoclonal antibodies (mAbs) have varied therapeutic uses. It is possible to create a mAb that binds specifically to almost any extracellular target, such as cell surface proteins and cytokines. They can be used to render their target ineffective, to induce a specific cell signal, to cause the immune system to attack specific cells, or to bring a drug to a specific cell type.
Glypicans constitute one of the two major families of heparan sulfate proteoglycans, with the other major family being syndecans. Six glypicans have been identified in mammals, and are referred to as GPC1 through GPC6. In Drosophila two glypicans have been identified, and these are referred to as dally and dally-like. One glypican has been identified in C. elegans. Glypicans seem to play a vital role in developmental morphogenesis, and have been suggested as regulators for the Wnt and Hedgehog cell signaling pathways. They have additionally been suggested as regulators for fibroblast growth factor and bone morphogenic protein signaling.
Ira Pastan is an American scientist at the National Cancer Institute. He is a member of the National Academy of Sciences, a Fellow of the AAAS and the American Society of Microbiology. In 2009, he was awarded the prestigious International Antonio Feltrinelli Prize for Medicine. His wife, Linda Pastan, was an American poet.
CD47 also known as integrin associated protein (IAP) is a transmembrane protein that in humans is encoded by the CD47 gene. CD47 belongs to the immunoglobulin superfamily and partners with membrane integrins and also binds the ligands thrombospondin-1 (TSP-1) and signal-regulatory protein alpha (SIRPα). CD-47 acts as a don't eat me signal to macrophages of the immune system which has made it a potential therapeutic target in some cancers, and more recently, for the treatment of pulmonary fibrosis.
Glypican-3 is a protein that, in humans, is encoded by the GPC3 gene. The GPC3 gene is located on human X chromosome (Xq26) where the most common gene encodes a 70-kDa core protein with 580 amino acids. Three variants have been detected that encode alternatively spliced forms termed Isoforms 1 (NP_001158089), Isoform 3 (NP_001158090) and Isoform 4 (NP_001158091).
Glypican-1 (GPC1) is a protein that in humans is encoded by the GPC1 gene. GPC1 is encoded by human GPC1 gene located at 2q37.3. GPC1 contains 558 amino acids with three predicted heparan sulfate chains.
Cluster of Differentiation 276 (CD276) or B7 Homolog 3 (B7-H3) is a human protein encoded by the CD276 gene.
A431 cells are a model human cell line used in biomedical research.
CA 242 is a tumor marker for sialylated Lewis carbohydrates associated with adenocarcinomas and e-selectin-mediated metastatic risk. It is commonly tested along with CEA, CA19-9, and CA242 for detecting pancreatic cancer. The specificity of CA 242 is higher than similar markers. Current research dictates that diagnostic efficiency is highest when various tumor markers are tested for at once.
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A rabbit hybridoma is a hybrid cell line formed by the fusion of an antibody producing rabbit B cell with a cancerous B-cell (myeloma).
Amatuximab is a chimeric monoclonal antibody designed for the treatment of cancer. It was developed by Morphotek, Inc.
Urelumab is a fully human, non‐ligand binding, CD137 agonist immunoglobulin‐γ 4 (IgG4) monoclonal antibody. It was developed utilizing Medarex's UltiMAb(R) technology by Bristol-Myers Squibb for the treatment of cancer and solid tumors. Urelumab promotes anti-tumor immunity, or an immune response against tumor cells, via CD137 activation. The application of Urelumab has been limited due to the fact that it can cause severe liver toxicity.
A cancer biomarker refers to a substance or process that is indicative of the presence of cancer in the body. A biomarker may be a molecule secreted by a tumor or a specific response of the body to the presence of cancer. Genetic, epigenetic, proteomic, glycomic, and imaging biomarkers can be used for cancer diagnosis, prognosis, and epidemiology. Ideally, such biomarkers can be assayed in non-invasively collected biofluids like blood or serum.
GL-ONC1 is an investigational therapeutic product consisting of the clinical grade formulation of the laboratory strain GLV-1h68, an oncolytic virus developed by Genelux Corporation. GL-ONC1 is currently under evaluation in Phase I/II human clinical trials in the United States and Europe.
Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21 that catalyzes the reaction:
