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| Identifiers | |||||||||||||||||||||||||||||||||||||||||||||||||||
| Aliases | MSLN , MPF, SMRP, mesothelin | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 601051 MGI: 1888992 HomoloGene: 4249 GeneCards: MSLN | ||||||||||||||||||||||||||||||||||||||||||||||||||
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Mesothelin, also known as MSLN, is a protein that in humans is encoded by the MSLN gene. [5] [6]
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| Aliases | MSLN , MPF, SMRP, mesothelin | ||||||||||||||||||||||||||||||||||||||||||||||||||
| External IDs | OMIM: 601051 MGI: 1888992 HomoloGene: 4249 GeneCards: MSLN | ||||||||||||||||||||||||||||||||||||||||||||||||||
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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.
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Thymidine kinase is an enzyme, a phosphotransferase : 2'-deoxythymidine kinase, ATP-thymidine 5'-phosphotransferase, EC 2.7.1.21. It can be found in most living cells. It is present in two forms in mammalian cells, TK1 and TK2. Certain viruses also have genetic information for expression of viral thymidine kinases. Thymidine kinase catalyzes the reaction:
A single-domain antibody (sdAb), also known as a Nanobody, is an antibody fragment consisting of a single monomeric variable antibody domain. Like a whole antibody, it is able to bind selectively to a specific antigen. With a molecular weight of only 12–15 kDa, single-domain antibodies are much smaller than common antibodies which are composed of two heavy protein chains and two light chains, and even smaller than Fab fragments and single-chain variable fragments.
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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.
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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).
Cluster of Differentiation 276 (CD276) or B7 Homolog 3 (B7-H3) is a human protein encoded by the CD276 gene.
Tumor-associated glycoprotein 72 (TAG-72) is a glycoprotein found on the surface of many cancer cells, including ovary, breast, colon, lung, and pancreatic cancers. It is a mucin-like molecule with a molar mass of over 1000 kDa.
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