Mesothelin Variant 1 Is Released from Tumor Cells as a Diagnostic Marker

Hellström, Ingegerd; Raycraft, John; Kanan, Sandra; Sardesai, Niranjan Y.; Verch, Thorsten; Yang, Yi; Hellstrom, Karl Erick

doi:10.1158/1055-9965.epi-05-0334

Cited by 102 publications

(84 citation statements)

References 27 publications

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“…Supporting the first hypothesis, two variants of mesothelin with different N-terminal structures have been described but they represent less than 5% of mesothelin transcripts, and some authors hypothesised that they could be the result of a sequencing error or the cloning of an incompletely processed mRNA [40]. On the other side, it has been demonstrated that mesothelin is cleaved from the membrane but the mechanism (and the precise enzymes involved) is unknown [41][42][43]. There is no common agreement on how this molecule should be named: currently SMRP, soluble mesothelin or N-ERC/mesothelin are used in the literature and referred to the same molecule.…”

Section: Mesothelinmentioning

confidence: 99%

Clinical utility of diagnostic markers for malignant pleural mesothelioma

Grigoriu

Grigoriu²,

Chahine

et al. 2016

Monaldi Arch Chest Dis

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Malignant mesothelioma has a very dismal prognosis with very few patients surviving one year after diagnosis. Early multimodal treatment, however, is expected to improve the outcome. Today, there is a strong need to have disease markers which could be used for screening, diagnosing, and/or monitoring tumour response to treatment. Old markers such as hyaluronic acid, various cytokeratin fragments (CYFRA 21.1, TPA) and other cancer antigens (CA 15.3, CA 125 or CA 19.9 or CEA) are not sensitive or specific enough and cannot be used in practice. More recently new molecules, such as soluble mesothelin and osteopontin, have been proposed for diagnostic purposes. Soluble mesothelin has a good specificity but has a suboptimal sensitivity being negative in all sarcomatoid and in up to one half of epithelioid mesothelioma. On the contrary osteopontin has an inadequate specificity. Combining different markers together does not lead to an improvement in diagnostic accuracy. Neither marker can be used for screening purposes, the main limitation being the very low incidence of the disease in the at-risk, asbestos exposed population. Mesothelin is also a promising marker for monitoring response to treatment but published data is still insufficient to make recommendations. There is still a strong need for research is this area both in order to discover new markers as well as to correct the positioning of each existing molecule (alone or in combination) is the evaluation of the patients with a mesothelioma.

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Section: Mesothelinmentioning

confidence: 99%

Clinical utility of diagnostic markers for malignant pleural mesothelioma

Grigoriu

Grigoriu²,

Chahine

et al. 2016

Monaldi Arch Chest Dis

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“…To the Editors: We read with great interest the article by Hellstrom et al (1) about characterization of soluble mesothelin proteins (SMP) in cancer patients. The authors found that the SMP in ascites from a patient with ovarian carcinoma contained the sequence of extracellular domain of a membrane-bound mesothelin (2, 3) rather than a soluble form speculated previously by Scholler et al (4).…”

Section: Mesothelin Is Shed From Tumor Cellsmentioning

confidence: 99%

Mesothelin Is Shed from Tumor Cells

Onda

Wang

et al. 2006

Cancer Epidemiology, Biomarkers &Amp; Prevention

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To the Editors: We read with great interest the article by Hellstrom et al. (1) about characterization of soluble mesothelin proteins (SMP) in cancer patients. The authors found that the SMP in ascites from a patient with ovarian carcinoma contained the sequence of extracellular domain of a membrane-bound mesothelin (2, 3) rather than a soluble form speculated previously by Scholler et al. (4). Their results indicate that membrane-bound mesothelin could be shed from the tumor cells to generate SMP detected in patient sera by ELISA. We agree with their conclusion that membrane-bound mesothelin is the predominant protein present in the serum and here provides direct evidence showing that such shedding does in fact take place.Our experiments are summarized in Fig. 1. Using an SS1P affinity column, we purified SMP from culture supernatants of a well-documented A431/K5 cell line (3) expressing only membrane-bound mesothelin. SS1P is an immunotoxin with an Fv specific for mesothelin. About 100 ng/mL SMP was found in the culture supernatant. The molecular weight of purified SMP was f40 kDa (Fig. 1A), consistent with the SMP described in Hellstrom et al.(1). The full-length mesothelin precursor proteins were not detected in culture supernatant. After deglycosylation with PNGase, the molecular weight of SMP was f34 kDa. The SMP bands were cut out from a Coomassie-stained gel, protein in the gel was digested with trypsin, and the tryptic peptides were analyzed using liquid chromatography ion trap mass spectrometry (Fig. 1B). The sequence of NH 2 terminal (EVEK) was determined by automated Edman degradation, and peptides corresponding to multiple internal regions of mesothelin were determined using the mass spectrometry/mass spectrometry mode on the ion trap mass spectrometer. Our results confirmed that the SMP was the extracellular domain of membrane-bound mesothelin shed from cells.Mesothelin is a glycosyl-phosphatidylinositol-anchored protein. Release of such proteins from the cell surface into the serum and other body fluids can be mediated by phospholipase or proteases (5). To determine whether the shedding of mesothelin is dependent on phosphatidylinositol-specific phospholipase C, we did anti-cross-reacting determinant assay (Prozyme, San Leandro, CA) by Western blot. The SMP was not recognized by anti-cross-reacting determinant (Anti-CRD) antibodies (Fig. 1C).In conclusion, our data show that the extracellular domain of membrane-bound mesothelin can be shed from tumor cells. The shedding may not require phosphatidylinositol-specific phospholipase C phospholipolysis. The precise mechanisms need further investigation.

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“…42,43 ). There are three variants of these proteins, with variant 1 being most common [44][45][46] . These result from proteolytic cleavage of a part of a mesothelin molecule, probably by the action of a phospholipase or protease or by gene mutation 47,48 .…”

Section: Introductionmentioning

confidence: 99%

Significance of serum mesothelin in an asbestos-exposed population in the Czech Republic

Jakubec¹,

Pelclová²,

Smolková³

et al. 2015

Biomed Pap Med Fac Univ Palacky Olomouc Czech Repub

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Aims. Pleural mesothelioma is a highly aggressive and difficult-to-treat form of cancer induced by asbestos in 80-90% of cases. The population group most at risk of the condition are asbestos-exposed workers. Mesothelin or soluble mesothelin-related protein (SMRP) is studied as a potential marker of mesothelioma in the at-risk population. Methods. The study comprised 239 subjects with a mean duration of occupational exposure to asbestos of 19.9 years. In all of them, a complete medical history was taken, focused on exposure duration and a physical examination, a chest X-ray or other imaging investigations and a lung function test were performed. Their serum SMRP levels were measured and biopsy samples were taken to diagnose pleural disease. Based on the above examinations, the subjects were classified into subgroups and serum SMRP concentrations were statistically analyzed with respect to individual parameters. Results. In asbestos-exposed individuals, mesothelin levels were significantly higher in those with pathological X-ray findings than in those with normal X-ray results (0.78 ± 0.63 vs. 0.50 ± 0.35, P<0.0001). The group of patients with benign disease had statistically significantly higher mesothelin levels than those with normal X-ray findings (0.755 ± 0.543 vs. 0.50 ± 0.35, P<0.001). In the group with present malignant processes, mesothelin levels were higher than in individuals with benign disease (1.19 ± 0.89 vs. 0.76 ± 0.54, P=0.015). Only a weak correlation was found between mesothelin levels and asbestos exposure duration. There were relatively high sensitivity and high specificity (75% and 90.6%, respectively) of serum mesothelin for pleural mesothelioma. However, given the small number of mesothelioma cases in the group, the results cannot be considered as statistically significant. Conclusions. In persons followed up for asbestos exposure, increased mesothelin levels signalize pathological processes in the chest and correlate with severity of the disease. The study suggests that mesothelin cannot be considered a reliable marker for the early stage of malignant degeneration of pleural disease but only an additional criterion for examination of the followed-up individuals.

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Mesothelin Variant 1 Is Released from Tumor Cells as a Diagnostic Marker

Cited by 102 publications

References 27 publications

Clinical utility of diagnostic markers for malignant pleural mesothelioma

Clinical utility of diagnostic markers for malignant pleural mesothelioma

Mesothelin Is Shed from Tumor Cells

Significance of serum mesothelin in an asbestos-exposed population in the Czech Republic

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