Fibulin-3 levels in malignant pleural mesothelioma are associated with prognosis but not diagnosis

Abstract

Background:Fibulin-3 (FBLN3) was recently presented as a promising novel biomarker for malignant pleural mesothelioma (MPM), warranting independent validation studies.Methods:ELISA was used to measure cellular and secreted FBLN3 in cell lines, in plasma of xenograft tumour-bearing mice, in plasma from two independent series of MPM and non-MPM patients and in pleural fluid from a third series. Diagnostic and prognostic potential of FBLN3 was assessed by receiver operating characteristics curve analysis and Kaplan–Meier method, respectively.Results:FBLN3 was expressed in all MPM and benign mesothelial cell lines tested, and a correlation was observed between cellular protein expression and secreted levels. Human FBLN3 was detectable in plasma of tumour-bearing mice, suggesting that MPM cells contribute to levels of circulating FBLN3. Plasma FBLN3 was significantly elevated in MPM patients from the Sydney cohort, but not the Vienna cohort, but the diagnostic accuracy was low (63%, (95% CI: 50.1–76.4) and 56% (95% CI: 41.5–71.0), respectively). Although FBLN3 levels in pleural effusions were not significantly different between cases and controls, FBLN3 levels in pleural effusion fluid were found to be independently associated with prognosis (hazard ratio of 9.92 (95% CI: 2.14–45.93)).Conclusions:These data confirm the potential prognostic value of pleural effusion FBLN3, but question the diagnostic value of this protein in MPM patients.

Diagnostic and prognostic biomarkers for malignant mesothelioma: an update

“…Novel, and potentially more sensitive and specific MM biomarkers were evaluated, including MPF(31), OPN (60,64,66), fibulin-3 (70,72,73), HMGB1 (82), with promising results. In addition, a variety of deregulated miRNAs [reviewed in (109)], including the miR-score signature with prognostic significance (98), as well as different approaches based on proteomics technology, have been proposed as suitable MM markers (100,109).…”

“…The results showed that fibulin-3 preferentially stained tumor cells and that the ROC for fibulin-3 displayed a sensitivity of 96.7% and a specificity of 95.5%, findings suggesting that fibulin-3 was a valuable biomarker for MM. However, other research teams reported a much lower sensitivity of fibulin-3 for MM diagnosis (32,72).…”

Comparison of SKIP expression in malignant pleural mesotheliomas with Ki-67 proliferation index and prognostic parameters

“…The present study also indicates SKIP expression to be useful for predicting poor outcome in patients with MPM. Biomarkers such as survivin, fibulin-3 and mesothelin have also been suggested as prognostic factors to predict poor outcome in MPM, but they are not sufficient for use as prognostic biomarkers [8,9,10]. It is known that the Ki-67 proliferation index increases in MPM patients and that it is related to poor prognosis [9,14].…”

“…Various studies have been performed to determine the correlation of MPM progression with markers such as survivin, fibulin-3 and mesothelin [8,9,10]. Although a relationship with prognosis and diagnosis was found for some of these markers, it was not found in some others.…”

Overexpressed genes in malignant pleural mesothelioma: implications in clinical management

“…Surprisingly in the external validation cohort, the diagnostic accuracy decreased (AUC, 0.87) (119) but later, in the study performed by Creaney et al (25) pleural effusion fibulin-3 was proven a more potent prognostic marker than mesothelin. Afterwards the potential prognostic value of pleural effusion FBLN3 has been confirmed in two independent mesothelioma cohorts (120). The first evidence of the diagnostic value of fibulin-3 appeared in 2012 (83), but in 2014 these data were not confirmed and soluble mesothelin related peptide was declared a more potent diagnostic marker in serum than fibulin-3 (25).…”