Stress proteins and cytokines are urinary biomarkers for diagnosis and staging of bladder cancer

Eur Urol. 2011 Jan;59(1):113-9. doi: 10.1016/j.eururo.2010.10.008. Epub 2010 Oct 15.


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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Validation Study

MeSH terms

  • Aged
  • Aged, 80 and over
  • Analysis of Variance
  • Biomarkers, Tumor / urine*
  • Case-Control Studies
  • Chaperonin 60 / urine
  • Cytokines / urine*
  • Enzyme-Linked Immunosorbent Assay
  • Female
  • Heat-Shock Proteins / urine*
  • Humans
  • Interleukin-13 / urine
  • Israel
  • Logistic Models
  • Male
  • Middle Aged
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Odds Ratio
  • Predictive Value of Tests
  • ROC Curve
  • Reproducibility of Results
  • Urinary Bladder Neoplasms / diagnosis*
  • Urinary Bladder Neoplasms / pathology
  • Urinary Bladder Neoplasms / urine


  • Biomarkers, Tumor
  • Chaperonin 60
  • Cytokines
  • Heat-Shock Proteins
  • Interleukin-13