title: A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma.
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.
authors.affiliation: Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.|Department of Medical Oncology, Chris O'Brien Lifehouse, Sydney, NSW 2050, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Steven C
authors.initials: SC
authors.lastname: Kao
authors.affiliation: Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.
authors.forename: Michaela B
authors.initials: MB
authors.lastname: Kirschner
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.|Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.|University of Western Sydney, Sydney, NSW 2150, Australia.
authors.forename: Wendy A
authors.initials: WA
authors.lastname: Cooper
authors.affiliation: Department of Tissue Pathology and Diagnostic Oncology, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
authors.forename: Thang
authors.initials: T
authors.lastname: Tran
authors.affiliation: Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Sjaak
authors.initials: S
authors.lastname: Burgers
authors.affiliation: Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.
authors.forename: Casey
authors.initials: C
authors.lastname: Wright
authors.affiliation: Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Tiny
authors.initials: T
authors.lastname: Korse
authors.affiliation: Division of Thoracic Oncology, The Netherlands Cancer Institute, Amsterdam 1066 CX, The Netherlands.
authors.forename: Daan
authors.initials: D
authors.lastname: van den Broek
authors.affiliation: Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.
authors.forename: James
authors.initials: J
authors.lastname: Edelman
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.|Department of Cardiothoracic Surgery, Royal Prince Alfred Hospital, Sydney, NSW 2050, Australia.|Australian School of Advanced Medicine, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Michael
authors.initials: M
authors.lastname: Vallely
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.|Sydney Cardiothoracic Surgeons, RPAH Medical Centre, Sydney, NSW 2050, Australia.
authors.forename: Brian
authors.initials: B
authors.lastname: McCaughan
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.|Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Nick
authors.initials: N
authors.lastname: Pavlakis
authors.affiliation: Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.|Department of Medical Oncology, Royal North Shore Hospital, Sydney, NSW 2065, Australia.
authors.forename: Stephen
authors.initials: S
authors.lastname: Clarke
authors.affiliation: Australian Proteome Analysis Facility, Macquarie University, Sydney, NSW 2109, Australia.
authors.forename: Mark P
authors.initials: MP
authors.lastname: Molloy
authors.affiliation: Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Nico
authors.initials: N
authors.lastname: van Zandwijk
authors.affiliation: Asbestos Diseases Research Institute, PO Box 3628, Rhodes, Sydney, NSW2139, Australia.|Sydney Medical School, The University of Sydney, Sydney, NSW 2006, Australia.
authors.forename: Glen
authors.initials: G
authors.lastname: Reid
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000378:metabolism*; D045744:Cell Line, Tumor; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D008175:Lung Neoplasms / Q000378:metabolism* / Q000473:pathology; D008297:Male; D013058:Mass Spectrometry; D008654:Mesothelioma / Q000378:metabolism* / Q000473:pathology; D000086002:Mesothelioma, Malignant; D051379:Mice; D008875:Middle Aged; D015999:Multivariate Analysis; D009368:Neoplasm Transplantation; D015676:Osteonectin / Q000378:metabolism*; D010997:Pleural Neoplasms / Q000378:metabolism* / Q000473:pathology; D011379:Prognosis; D016016:Proportional Hazards Models; D040901:Proteomics; D012189:Retrospective Studies; D015996:Survival Rate; D046888:Tissue Array Analysis
chemical_list: D014408:Biomarkers, Tumor; D015676:Osteonectin; C577241:SPARC protein, human