Activation of the PI3K/Akt/mTOR pathway correlates with tumour progression and reduced survival in patients with urothelial carcinoma of the urinary bladder.

AIMS: Phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway dysregulation has been implicated in the development of urothelial carcinoma. However, its clinical relevance has not been substantially validated in human samples. The aim of this study was to assess the expression of the pathway in a large cohort of bladder cancers using the tissue microarray technique. METHODS AND
RESULTS: Immunohistochemical stains for phosphatase and tensin homologue (PTEN), phosphorylated Akt, mTOR, S6 and 4E-BP1 were performed for 887 cases, and the results were correlated with clinicopathological characteristics. The high expression of p-S6 and p-Akt corresponded significantly with high-grade and advanced-stage, while losses of PTEN and p-4E-BP1 were observed more often in high-grade and high-stage tumours. High expression of p-Akt and p-S6 predicted progression and cancer-specific mortality for non-muscle-invasive cancers treated by transurethral resection, and p-Akt was an independent factor in multivariate analysis. High expression of p-mTOR and p-Akt correlated with higher cumulative incidence of cancer-specific mortality for muscle-invasive cancer, and p-mTOR was an independent prognostic factor.
CONCLUSIONS: We have demonstrated the impact of PI3K/Akt/mTOR alteration on the biological behaviour of bladder tumours. Proper immunohistochemical examination of the PI3K/Akt/mTOR pathway can provide useful prognostic information, and the findings may represent an additional therapeutic avenue in the treatment of bladder cancers.