Abstract

Muscle invasive bladder cancer (MIBC, stage ≥T2) is generally associated with poor prognosis, constituting the second most common cause of death among genitourinary tumours. Due to high molecular heterogeneity significant variations in the natural history and disease outcome have been observed. This has also delayed the introduction of personalized therapeutics, making advanced stage bladder cancer almost an orphan disease in terms of treatment. Altered protein glycosylation translated by the expression of the sialyl-Tn antigen (STn) and its precursor Tn as well as the activation of the PI3K/Akt/mTOR pathway are cancer-associated events that may hold potential for patient stratification and guided therapy. Therefore, a retrospective design, 96 bladder tumours of different stages (Ta, T1-T4) was screened for STn and phosphorylated forms of Akt (pAkt), mTOR (pmTOR), S6 (pS6) and PTEN, related with the activation of the PI3K/Akt/mTOR pathway. In our series the expression of Tn was residual and was not linked to stage or outcome, while STn was statically higher in MIBC when compared to non-muscle invasive tumours (p = 0.001) and associated decreased cancer-specific survival (log rank p = 0.024). Conversely, PI3K/Akt/mTOR pathway intermediates showed an equal distribution between non-muscle invasive bladder cancer (NMIBC) and MIBC and did not associate with cancer-specif survival (CSS) in any of these groups. However, the overexpression of pAKT, pmTOR and/or pS6 allowed discriminating STn-positive advanced stage bladder tumours facing worst CSS (p = 0.027). Furthermore, multivariate Cox regression analysis revealed that overexpression of PI3K/Akt/mTOR pathway proteins in STn+ MIBC was independently associated with approximately 6-fold risk of death by cancer (p = 0.039). Mice bearing advanced stage chemically-induced bladder tumours mimicking the histological and molecular nature of human tumours were then administrated with mTOR-pathway inhibitor sirolimus (rapamycin). This decreased the number of invasive lesions and, concomitantly, the expression of STn and also pS6, the downstream effector of the PI3K/Akt/mTOR pathway. In conclusion, STn was found to be marker of poor prognosis in bladder cancer and, in combination with PI3K/Akt/mTOR pathway evaluation, holds potential to improve the stratification of stage disease. Animal experiments suggest that mTOR pathway inhibition could be a potential therapeutic approach for this specific subtype of MIBC.

Highlights

  • Bladder cancer is the second most deadly genitourinary tumour and presents significantly worse prognosis upon muscularis propria invasion [1]

  • Particular interest was set in the identification of biomarkers for late stage disease based on the comparison between non-muscle invasive bladder cancer (NMIBC) and muscle invasive bladder cancers (MIBC)

  • We have started by investigating the expression of sialyl-Tn antigen (STn) precursor, the Tn antigen, in bladder tumours

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Summary

Introduction

Bladder cancer is the second most deadly genitourinary tumour and presents significantly worse prognosis upon muscularis propria invasion [1]. Alterations in cell-surface protein glycosylation have be implicated in the activation of intracellular oncogenic signalling pathways [7], including the phosphoinositide-3 kinase (PI3K)/Akt signalling pathway [8] which is thought to play a critical role in bladder cancer development. These preliminary observations support the hypothesis that STn expression may play a key role in disease outcome, which warrants a deeper investigation. Several studies suggest that Tn antigen, which is a precursor of STn, may be implicated in oncogenic events [7]; nothing is known about the expression of this glycan in bladder tumours

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