Korean J Urol.  2011 Jul;52(7):466-473.

Role of the mTOR Pathway in the Progression and Recurrence of Bladder Cancer: An Immunohistochemical Tissue Microarray Study

• Park SJ
• Lee TJ
• Chang IH

Abstract

PURPOSE
Numerous trials have been conducted to develop new treatment regimens for superficial and invasive bladder cancer, because there is an urgent need to identify novel agents to prevent the recurrence and progression of these cancers. We evaluated the prognostic and biological significance of mTOR pathway-related markers in patients with bladder cancer who had undergone transurethral resection of their bladder tumors and radical cystectomy.
MATERIALS AND METHODS
We retrieved 208 bladder cancer specimens collected from patients between 1989 and 2007 and constructed a tissue microarray comprising 208 tumor samples and 25 benign urothelium samples. Immunohistochemical staining was performed for mTOR, phosphorylated (phos) S6, and phos4E-BP1. The pattern, percentage, and intensity of staining for all three markers were evaluated.
RESULTS
The median age at diagnosis of the patient cohort was 67 years (range: 29-87 years), and the median follow-up was 72 months (range: 1-257 months). The expression of phos4E-BP1 was higher in the bladder cancer cohort than in the benign cohort, whereas phosS6 expression was lower in the bladder cancer cohort than in the benign cohort. The expression of phosS6 was significantly higher in high-grade bladder cancer (p<0.01). There was a significant positive correlation between the H-scores of mTOR and phos4E-BP1 (coefficient of correlation, r=0.37, p<0.01) as well as between the H-scores of mTOR and phosS6 (r=0.17, p<0.05). In the multivariate analysis, strong phosS6 expression predicted shorter progression (p<0.01; hazard ratio [HR], 2.516) and disease-specific survival (p<0.01; HR, 2.396) but not overall survival (p=0.112), whereas strong phos4E-BP1 expression was a predictor of disease-specific survival (p<0.05; HR, 2.105). Moreover, strong phosS6 expression predicted shorter recurrence-free (p<0.05) and progression-free (p<0.05) survival in the superficial bladder cancer cohort.
CONCLUSIONS
Our results demonstrate that mTOR pathway activation, as assessed by phos4E-BP1 phosphorylation, is related to bladder cancer tumorigenesis and that S6 protein phosphorylation is associated with a high level of disease recurrence and progression and poor cancer-specific survival.

Keyword

Bladder; Cancer; mTOR protein

MeSH Terms

Cell Transformation, Neoplastic
Cohort Studies
Follow-Up Studies
Humans
Multivariate Analysis
Phosphorylation
Recurrence
TOR Serine-Threonine Kinases
Urinary Bladder
Urinary Bladder Neoplasms
Urothelium
TOR Serine-Threonine Kinases

Figure

• 

  FIG. 1 Expression of mTOR pathway-related markers in bladder tissues. (A) Immunohistochemical staining of mTOR, phosS6, and phos4E-BP1 in paraffin-embedded sections of benign urothelium, as well as low and high-grade bladder cancer tissues (×100). (B) Graph displaying comparisons of H-scores of mTOR, phosS6, and phos4E-BP1 with respect to benign and bladder cancer lesions. The mean H-scores for phos4E-BP1 were significantly higher and the mean H-scores for phosS6 were significantly lower in bladder cancer lesions, but the mean H-scores for mTOR were not significantly different between benign and cancerous lesions. (C) Graph displaying the H-scores for phosS6 and phos4EBP1 in relation to mTOR H-scores in bladder cancer cells. The mean H-scores of phos4EBP1 were significantly higher in tumor cells with strong mTOR immunostaining than in non-or weak immunostaining tumor cells, although the mean H- score of phosS6.

• 

  FIG. 2 Kaplan-Meier curves based on phospS6 and phos4E-BP1 staining results in superficial bladder cancer patients. (A) In the recurrence-free survival curves, bladder cancers with strong pS6 immunostaining exhibited decreased recurrence-free survival (p=0.046, log-rank test). (B) Tumors with strong pS6 immunostaining showed significantly decreased progression-free survival (p=0.035, log-rank test). (C, D) Phos4E-BP1 status, however, was not related to recurrence-free survival (C) or progression-free survival (D) in superficial bladder cancers.

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