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


METHODS
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]).


METHODS
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.


CONCLUSIONS
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.
Institute of Urology, Rabin Medical Center, Beilinson Campus, Petach Tikva, Israel.
David
D
Margel
Meirav
M
Pevsner-Fischer
Meirav
M
Pesvner-Fischer
Jack
J
Baniel
Ofer
O
Yossepowitch
Irun R
IR
Cohen
D000368:Aged; D000369:Aged, 80 and over; D000704:Analysis of Variance; D014408:Biomarkers, Tumor / Q000652:urine*; D016022:Case-Control Studies; D018834:Chaperonin 60 / Q000652:urine; D016207:Cytokines / Q000652:urine*; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006360:Heat-Shock Proteins / Q000652:urine*; D006801:Humans; D018793:Interleukin-13 / Q000652:urine; D007557:Israel; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009361:Neoplasm Invasiveness; D009367:Neoplasm Staging; D016017:Odds Ratio; D011237:Predictive Value of Tests; D012372:ROC Curve; D015203:Reproducibility of Results; D001749:Urinary Bladder Neoplasms / Q000175:diagnosis* / Q000473:pathology / Q000652:urine
D014408:Biomarkers, Tumor; D018834:Chaperonin 60; D016207:Cytokines; D006360:Heat-Shock Proteins; D018793:Interleukin-13