A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma

• Published in: British journal of cancer 2016-03, Vol.114 (5), p.524-531
• Main Authors: Kao, Steven C, Kirschner, Michaela B, Cooper, Wendy A, Tran, Thang, Burgers, Sjaak, Wright, Casey, Korse, Tiny, van den Broek, Daan, Edelman, James, Vallely, Michael, McCaughan, Brian, Pavlakis, Nick, Clarke, Stephen, Molloy, Mark P, van Zandwijk, Nico, Reid, Glen
• Format: Article
• Language: English
• Subjects: 631/61/475; 692/4028/67/1641; 692/53/2422; Animals; Biomarkers; Biomarkers, Tumor - metabolism; Biomedical and Life Sciences; Biomedicine; Cancer Research; Cancer therapies; Cell Line, Tumor; Disease; Drug Resistance; Enzyme-Linked Immunosorbent Assay; Epidemiology; Female; Fibroblasts; Hospitals; Humans; Immunohistochemistry; Lung Neoplasms - metabolism; Lung Neoplasms - pathology; Male; Mass Spectrometry; Medical prognosis; Medical research; Mesothelioma; Mesothelioma - metabolism; Mesothelioma - pathology; Mesothelioma, Malignant; Mice; Middle Aged; Molecular Diagnostics; Molecular Medicine; Multivariate Analysis; Neoplasm Transplantation; Oncology; Osteonectin - metabolism; Plasma; Pleural Neoplasms - metabolism; Pleural Neoplasms - pathology; Prognosis; Proportional Hazards Models; Proteins; Proteomics; Retrospective Studies; Scientific imaging; Survival Rate; Thoracic surgery; Tissue Array Analysis; Tumors
• ISSN: 0007-0920; 1532-1827
• DOI: 10.1038/bjc.2015.470

Background: We aimed to identify prognostic blood biomarkers using proteomics-based approaches in malignant pleural mesothelioma (MPM). Methods: Plasma samples from 12 MPM patients were used for exploratory mass spectrometry and ELISA analyses. The significance of secreted protein acidic and rich in cysteine (SPARC) was examined in sera from a Dutch series ( n =97). To determine the source of the circulating SPARC, we investigated SPARC expression in MPM tumours and healthy controls, as well as the expression and secretion from cell lines and xenografts. Results: Secreted protein acidic and rich in cysteine was identified as a putative prognostic marker in plasma. Validation in the Dutch series showed that the median survival was higher in patients with low SPARC compared with those with high SPARC (19.0 vs 8.8 months; P =0.01). In multivariate analyses, serum SPARC remained as an independent predictor (HR 1.55; P =0.05). In MPM tumour samples, SPARC was present in the tumour cells and stromal fibroblasts. Cellular SPARC expression was higher in 5 out of 7 cell lines compared with two immortalized mesothelial lines. Neither cell lines nor xenograft tumours secreted detectable SPARC. Conclusions: Low circulating SPARC was associated with favourable prognosis. Secreted protein acidic and rich in cysteine was present in both tumour cells and stromal fibroblasts; and our in vitro and in vivo experiments suggest that stromal fibroblasts are a potential source of circulating SPARC.