Articles

Stress Proteins and Cytokines are Urinary Biomarkers for Diagnosis and Staging of Bladder Cancer

By: David Margela b 1, Meirav Pesvner-Fischera 1, Jack Baniela, Ofer Yossepowitcha and Irun R. Cohenb lowast

Published online: 01 January 2011

Keywords: Biomarkers, Heat shock proteins, Cytokines, Diagnosis, Bladder cancer

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Abstract

Background

Cancer often involves inflammatory processes. We hypothesized that immune mediators in urine may serve as biomarkers for bladder cancer (BCa).

Objective

To investigate whether BCa might be marked by urinary levels of heat shock proteins (HSPs; HSP60, HSP70, or HSP90) or cytokines (interferon [IFN]-γ, tumor necrosis factor [TNF]-α, tumor growth factor [TGF]-β, interleukin [IL]-1β, IL-2, IL-4, IL-5, IL-6, IL-8, IL-10, or IL-13).

Design, setting, and participants

This was a case–control study with a discovery and validation phase. We examined urine from 106 consecutive patients: healthy controls (n=18); hematuria with no evidence of BCa (n=20); non–muscle-invasive BCa (n=50); and muscle-invasive BCa (n=18). The concentrations of HSPs and cytokines were assessed by enzyme-linked immunosorbent assay. In the validation phase, independent urine samples from 40 patients were analyzed (controls [n=19] and BCa [n=21]).

Measurements

We used the area under the curve (AUC) of a receiver operating characteristic analysis to determine the ability of HSPs and cytokines to mark BCa and applied a multivariate logistic regression to create a formula able to diagnose BCa. The formula was applied to the validation set without recalculation, and positive and negative predictive values were calculated.

Results and limitations

Urinary concentrations of IL-8, IL-10, and IL-13 were significantly elevated in BCa; IL-13 was the most prominent marker (AUC: 0.93; 95% confidence interval [CI], 0.85–0.99). The multivariate regression analysis highlighted HSP60 (odds ratio [OR]: 1.206; 95% CI, 1.041–1.397, p=0.003) and IL-13 (OR: 1.020; 95% CI: 1.007–1.033, p=0.012).

The validation assay was performed using HSP60 and IL-13. The overall positive predictive value was 74% (95% CI, 64–84%); and the negative predictive value was 76% (95% CI, 66–86%). Since we examined a small number of patients, the results need to be confirmed in a larger cohort.

Conclusions

These results suggest that it might be possible to develop a urinary biomarker for BCa and raise the possibility that expression of anti-inflammatory cytokines and HSPs might allow BCa to evade immune surveillance.

Take Home Message

In this study we have demonstrated a significant association between bladder cancer (BCa) and urinary levels of heat shock proteins (HSPs) and anti-inflammatory cytokines. These findings are a good foundation for the development of a urinary biomarker for BCa. In addition, they raise the possibility that expression of anti-inflammatory cytokines and HSPs might allow BCa to evade immune surveillance.

Keywords: Biomarkers, Heat shock proteins, Cytokines, Diagnosis, Bladder cancer.

Footnotes

a Institute of Urology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel

b Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel

lowast Corresponding author. Department of Immunology, The Weizmann Institute of Science, Rehovot 76100, Israel. Tel. +972 8 9342911; Fax: +972 8 9344103.

1 D. Margel and M. Pesvner-Fischer contributed equally to the manuscript.