Br J Cancer. 2016 Feb 18. doi: 10.1038/bjc.2015.470. [Epub ahead of print]

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

Kao SC1,2,3, Kirschner MB1, Cooper WA3,4,5, Tran T4, Burgers S6, Wright C1, Korse T6, van den Broek D6, Edelman J7, Vallely M3,7,8, McCaughan B3,9,Pavlakis N3,10, Clarke S3,10, Molloy MP11, van Zandwijk N1,3, Reid G1,3.

Author information

• 1Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.
• 2Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia.
• 3Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
• 4Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
• 5University of Western Sydney, Sydney, NSW 2150, Australia.
• 6Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
• 7Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
• 8Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
• 9Sydney Cardiothoracic Surgeons, RPAH Medical Centre, Sydney, NSW 2050, Australia.
• 10Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
• 11Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia.

Abstract

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.British Journal of Cancer advance online publication,