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

Abstract

PurposeNumerous 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 MethodsWe 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.ResultsThe 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.ConclusionsOur 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.

A comprehensive immunohistochemical and molecular approach to the PI3K/AKT/mTOR (phosphoinositide 3‐kinase/v‐akt murine thymoma viral oncogene/mammalian target of rapamycin) pathway in bladder urothelial carcinoma

“…Reported results on this issue have been quite inconsistent. Thus, p-mTOR [ 16 ] and p-4E-BP1 [ 23 ] expression levels were higher in UCs, concurring with the present fi ndings, but pS6 was underexpressed [ 23,24 ] . AKT, on the other hand, was reported to be down-regulated by Schultz et al [ 24 ] but up-regulated by Sun et al [ 22 ] in UC samples.…”

“…direct phosphorylation of mTOR by AKT itself, as well as via phosphorylation and inactivation of mTOR inhibitor TSC2 [ 33,34 ] . Schultz et al [ 24 ] also failed to elicit a correlation between p-AKT and pS6-the downstream target of p70S6K or total 4E-BP1, in harmony with the present fi ndings, whereas two other studies have reported a positive albeit weak correlation of p-mTOR with pS6 and p-4E-BP1 [ 22,23 ] . It thus seems that a one-to-one strong relationship between any two components in PI3K/AKT/mTOR pathway is rather unlikely to be obtained, as their activation depends on the equilibrium of a complex interaction of multifactorial oncogenic events [ 19,22 ] .…”

“…mTOR, p85aPI3K and AKT activation, on the contrary, which also appears to take place at an early stage of urothelial tumorigenesis is sustained throughout the neoplastic process, as no difference existed between low-and high-grade/stage cases. Published studies have yielded confl icting fi ndings as to the relationship of AKT/mTOR pathway with the pathological features of UCs, especially for pS6 and p-AKT, some investigators reporting an inverse relationship [ 24 ] and others a positive [ 22,23,39 ] or even no relationship [ 9,16 ] . The overall impression gained from these fi ndings is the diverse role of PI3K/ AKT/mTOR signalling components during the development of the neoplastic process in UCs.…”

“…The prognostic relevance of various PI3K/AKT/mTOR pathway members in UC has been dealt with in four reports [ 17,22 -24 ] and remains a matter of debate. One initial report assigned a favourable prognostic effect to pS6 over-expression [ 24 ] , which subsequently was proposed as an adverse prognosticator by Sun et al [ 22 ] and Park et al [ 23 ] along with p-mTOR and p-AKT [ 22 ] or p-4E-BP1 [ 23 ] . Our results conform to those of the latter group [ 26 ] , although we were not able to reproduce the prognostic signifi cance of p-p70S6K.…”

242 Phosphorylated P70S6K in noninvasive low grade urothelial carcinoma of the bladder: Correlation with tumor recurrence

“…Paraffin blocks were available in 95 cases and TMAs were constructed using a manual array device (TMA set, Labro, Seoul, Korea) for the 95 LG-URCa samples and 35 benign urothelium samples, as described previously. 8 All clinicopathological patient data were retrieved from electronic medical records and included demographics, pathological stage, tumor size, tumor multiplicity and concurrent carcinoma in situ. Follow-up data on postoperative intravesical bacillus Calmette-Guerin treatment, disease recurrence and progression were obtained via a review of patient medical records and letters of inquiry to patients.…”