Elsevier

The Lancet

Volume 362, Issue 9396, 15 November 2003, Pages 1612-1616
The Lancet

Articles
Mesothelin-family proteins and diagnosis of mesothelioma

https://doi.org/10.1016/S0140-6736(03)14794-0Get rights and content

Summary

Background

Mesothelioma is a highly aggressive tumour for which there are no reliable serum tumour markers. Identification of such a marker would be useful in diagnosis of mesothelioma and for monitoring responses to treatment and screening at-risk individuals.

Methods

We assayed serum concentrations of soluble mesothelin-related proteins (SMR) using a double determinant (sandwich) ELISA in a blinded study of serum samples from 44 patients with histologically proven mesothelioma; 68 matched healthy controls, 40 of whom had been exposed to asbestos; and 160 patients with other inflammatory or malignant lung and pleural diseases.

Findings

37 (84%) of 44 patients with mesothelioma had raised concentrations of SMR at a serum dilution of 1/80, compared with three (2%) of 160 patients with other cancers or other inflammatory lung or pleural diseases, and with none of 28 controls who had not been exposed to asbestos. SMR concentrations correlated with tumour size and increased during tumour progression. Seven of the 40 asbestos-exposed individuals had increased serum concentrations of SMR; three of those seven developed mesothelioma and one developed lung carcinoma within 1–5 years. None of the 33 asbestos-exposed participants whose serum samples had normal concentrations of SMR and who were followed up over 8 years developed mesothelioma.

Interpretation

Determination of SMR in serum could be a useful marker for diagnosis of mesothelioma and to monitor disease progression. It might also prove helpful for screening asbestos-exposed individuals for early evidence of mesothelioma.

Introduction

Malignant mesothelioma is a highly aggressive tumour of serosal cavities, most commonly of the pleura.1 Its worldwide incidence is increasing because of the widespread exposure of many individuals in developed countries to asbestos, the major causal agent. In general, mesothelioma is resistant to chemotherapy and radiotherapy, and is rarely cured by radical resection.2, 3

Mesothelioma can be difficult to diagnose.4 Serum markers are frequently used to confirm the diagnosis of several types of cancer and can be used to follow response to treatment.5, 6, 7, 8, 9 Furthermore, sensitive markers can facilitate early diagnosis of cancer, and early therapeutic intervention in patients with mesothelioma is more likely to be beneficial than late intervention.4, 10, 11, 12, 13, 14 Thus, a simple, sensitive marker of early mesothelioma could lead to more effective treatment.

Mesothelin is a 40 kDa glycoprotein that is attached to the cell surface by phosphatidylinositol and is thought to have a role in cell-adhesion and possibly in cell-to-cell recognition and signalling. 15, 16, 17, 18, 19 It is synthesised as a precursor 69 kDa protein16 and forms two proteins, the membrane-bound mesothelin and a soluble protein megakaryocyte potentiating factor (MPF). We have identified the mesothelin gene promoter region previously.20 A monoclonal antibody, OV569, which recognises mesothelin, binds to the surface of cells from mesotheliomas, ovarian cancers, and some other tumours but not to healthy tissues except for mesothelium.19 A third member of the mesothelin/ MPF family was identified by its ability to bind to OV569.19 Here, we refer to any soluble molecule related to mesothelin/MPF that is recognised by OV569 as soluble mesothelin related.

Increased concentrations of soluble mesothelin related proteins (SMR) have been detected in serum samples of patients with ovarian carcinoma and in a few patients with other carcinomas.19 Since most mesotheliomas retain some mesothelial differentiation characteristics, we postulated that raised concentrations of SMR might occur in the serum of patients with mesothelioma.

Section snippets

Patients and controls

From 1997 to 2002, we obtained serum samples from consecutive patients presenting at the respiratory clinics of either the Sir Charles Gairdner Hospital or the Hollywood Specialist Centre in Perth, Western Australia. Participants had been exposed to asbestos either in association with the Wittenoom crocidolite operation or through downstream use of crocidolite in industry. We investigated 39 men and five women with mesothelioma whose diagnosis was confirmed with published criteria and by

Procedures

We stored serum samples in aliquots at −80°C until use. Platelet counts were determined with a Beckman Coulter STKS Hematology Flow Cytometer (Beckman Coulter, Fullerton, CA, USA).

Serum SMR concentrations were determined by a sandwich ELISA with two monoclonal antibodies (OV569 and 4H3), which bind to different SMR epitopes.19 The assays were done by investigators who were unaware of the patient's diagnosis on coded serum samples. A positive value was taken to be greater than 0·218, that is 3

Results

Of 29 patients who were assessed histologically, 25 had mainly epithelial tumours and four had mainly sarcomatoid tumours. The remaining 15 patients were not classified histologically because their diagnosis was based on a combination of clinical findings and typical pleural fluid cytological and ultrastructural findings without any histopathological examination.4

Serum samples from 37 of 44 patients with established malignant mesothelioma had significantly higher concentrations of SMR at all

Discussion

Molecules that are secreted or shed from tumour cells into the circulation could be clinically useful markers of disease.5 Our results showed that most patients with mesothelioma have raised serum concentrations of SMR, even when the tumour was very small, supporting the notion that SMR is a sensitive marker of disease when tumour bulk is small.

Only three of 160 patients with non-mesothelioma inflammatory or malignant lung or pleural disease had raised concentrations of SMR, and those

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