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

Our plain-English summary of A proteomics-based approach identifies secreted protein acidic and rich in cysteine as a prognostic biomarker in malignant pleural mesothelioma, by S.C. Kao, M.B. Kirschner, W.A. Cooper, et al (British Journal of Cancer, 2016).

The study

• Authors: S.C. Kao, M.B. Kirschner, W.A. Cooper, T. Tran, S. Burgers, C. Wright, T. Korse, D. van den Broek, J. Edelman, M. Vallely, B. McCaughan, N. Pavlakis, S. Clarke, M.P. Molloy, N. van Zandwijk, G. Reid
• Journal: British Journal of Cancer
• Published: 2016;114(5):524-31
• Cited by: 19 articles, as counted by NIH iCite
• Read it: PubMed · Publisher · Free full text

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.

In plain English

This study looked for a blood marker of survival in people with malignant pleural mesothelioma (MPM). It did not measure asbestos exposure. The authors first compared plasma proteins in 12 Australian patients: the six shortest and six longest survivors. The protein SPARC stood out. Median survival was 32.1 months with low SPARC versus 1.2 months with high SPARC. In 97 patients treated at the Netherlands Cancer Institute between 1995 and 2011, median survival was 19.0 months (95% CI 12.1 to 25.9) with low serum SPARC versus 8.8 months (95% CI 7.8 to 9.9) with high SPARC. After accounting for age, gender, stage and tumour subtype, high SPARC had a hazard ratio of 1.55 (95% CI 1.00 to 2.42). Tumour samples from Sydney surgical patients showed SPARC in tumour cells and surrounding fibroblasts, at higher levels than normal mesothelium. Mesothelioma cell lines and tumours grown in mice released no detectable SPARC. The authors said this suggests the tumour's supporting tissue as the likely source. They noted the study was retrospective and said the finding needs prospective confirmation before clinical use.

We wrote this plain-English summary from the full article with the help of AI, and a second AI model checked each sentence against the article. It is not the authors' wording; the abstract and the article are their own account.

What the study did and found

• Design: Retrospective biomarker study using three patient series (discovery, validation and archival tumour tissue), plus laboratory experiments on cell lines and mice carrying human mesothelioma tumours (xenografts)
• Who was studied: Discovery series: 12 MPM patients from Australian phase II thalidomide trials (recruited April 2001 to August 2003), the six shortest and six longest survivors. Validation series: 97 pathologically confirmed MPM patients treated at the Netherlands Cancer Institute, 1995 to 2011. Tissue series: archival tumour samples from 74 MPM patients treated with palliative pleurectomy with or without decortication at Royal Prince Alfred Hospital, Sydney, 1991 to 2009, compared with normal mesothelium from 13 cardiac or aortic surgery patients.
• Exposure: Asbestos exposure was not measured. The factor studied was the level of the protein SPARC (secreted protein acidic and rich in cysteine) in blood and tumour tissue. Patients were split into SPARC-high and SPARC-low groups at the median level.
• Main results:
  • Discovery series (12 patients): median overall survival was 32.1 months with low plasma SPARC versus 1.2 months with high SPARC.
  • Dutch validation series (97 patients): median overall survival was significantly higher with low serum SPARC (19.0 months; 95% CI 12.1 to 25.9) than with high SPARC (8.8 months; 95% CI 7.8 to 9.9).
  • Dutch series, multivariate analysis adjusting for age, gender, stage and histological subtype: SPARC remained an independent prognostic factor, with low SPARC associated with longer survival (hazard ratio 1.55 for high vs low SPARC).
  • Table 2, Dutch series: the 95% confidence interval for the hazard ratio of 1.55 (high vs low SPARC) was 1.00 to 2.42.
  • Tumour tissue series: 72 patients were assessed for SPARC in tumour cells and 69 for SPARC in stromal fibroblasts. SPARC expression was higher in MPM than in the 13 normal mesothelium controls.
  • Tumour tissue series: high stromal SPARC (more than 50% of cells) was independently associated with non-epithelial subtype (odds ratio 7.7; 95% CI 2.3 to 26.2).
  • Tumour tissue series: low stromal SPARC (50% or less) was associated with longer survival (10.9 vs 7.6 months).
  • Tumour tissue series, multivariate analysis (69 patients): stromal SPARC was not an independent predictor (hazard ratio 1.42; 95% CI 0.76 to 2.63).
  • Laboratory: SPARC inside the cells was higher in 5 of 7 cell lines than in the two immortalised mesothelial lines.
  • Laboratory: no cell line secreted detectable SPARC into its culture medium.
  • Mouse experiments: human SPARC was not detectable in the blood of mice carrying human MPM tumours.
• The authors' conclusion: The authors concluded that circulating SPARC is a promising prognostic biomarker in MPM and that the stroma is the likely source of circulating SPARC. They said the finding should be confirmed prospectively before it could potentially be used clinically.
• Limitations the authors state:
  • The study was retrospective, and treatment groups were not randomly allocated.
  • Further independent validation, preferably in a prospective study, is needed.
  • Cell types other than stromal fibroblasts, such as tumour-associated macrophages, could be the source of circulating SPARC.
  • The study did not examine why SPARC is increased in MPM.

Topics

The National Library of Medicine indexes this study under subjects our site covers: Lung cancer, Mesothelioma.

Medical terms in this study, explained in our Lexicon: Biomarker, Pleural Mesothelioma, Median Survival, Fibroblast, Prognosis.

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