The androgen receptor and stem cell pathways in prostate and bladder cancers (Review)

Abstract

Bladder cancer is three times more common in men than in women. However, the physiological basis of the male predominance of bladder cancer remains poorly understood. A higher than expected association of prostate and bladder cancers has also been reported which may indicate a common mechanism of carcinogenesis. Consistent with this, androgens and the androgen receptor (AR) play essential roles in prostate carcinogenesis and are believed to play a role in bladder carcinogenesis. There is also evidence implicating cancer stem cells in prostate and bladder cancers. Indeed putative prostate and bladder cancer stem cells share some common molecular features. We highlight key proteins (CD49f, CD133, PTEN, CD44) which are implicated in both prostate and bladder cancers and are enriched in putative prostate and bladder cancer stem cells. We examine published chromatin immuno-precipitation studies analyzing the genome-wide distribution of the AR to identify AR association with, and by inference potential AR-regulation of, these loci. We discuss recent evidence indicating a role for the AR in the splicing of the key urological stem cell protein CD44. We propose a model whereby aberrant AR regulation of these putative stem cell proteins contributes to malignant transformation of prostate and bladder cells. For these reasons we propose that the relationship between androgens and cancer stem cell associated proteins warrants further investigation.

MiR137is an androgen regulated repressor of an extended network of transcriptional coregulators

“…The AR plays essential roles in carcinogenesis and metastases, most notably in prostate and bladder cancers [ 59 ]. For this reason, androgen deprivation therapies (ADTs) are commonly used to treat PCa.…”

“…Although significant pharmacologic barriers remain to the deployment of miRs as systemic cancer therapies, we tested the effect of restoration of miR137 in the PC3 model of advanced castrate resistant PCa. We found that restoration of miR137 expression decreases expression of the pro-angiogenic factor VEGFA (Figure 5G ), a key mediator of PCa metastases and therapy resistance [ 59 ].…”

<p>Expression of CD133 and CD24 and their different phenotypes in urinary bladder carcinoma</p>

“…Some tumors contain cells that have maintained the self-renewal capacity of non-malignant adult stem cells but have bypassed their growth regulatory pathways 1. These stem cell-like tumor cells are also known as cancer stem cells (CSCs) or tumor initiating cells 2. The ability of these rare undifferentiated tumorigenic cells to self-renew and differentiate into heterogeneous lineages of neoplastic cells is the explicit biological criterion responsible for tumor initiation, maintenance, dissemination, and initiation of relapse 3…”

“…The heterogeneous molecular pathogenesis of bladder cancer1 and the frequent recurrence of superficial urothelial carcinoma (UC)2 suggest the contribution of CSCs to their tumorgenicity 4. The escape of CSCs, which retain full capacity to restore the tumor cell bulk, from antitumor treatments may account for the contemporary failure of therapies in this type of cancer 4.…”

Modelling bladder cancer in mice: opportunities and challenges

“…Notably, the epithelium of the bladder and prostate, although highly specialized and distinct, share a common embryological origin, namely the urogenital sinus 55 . Thus, it has been proposed that the increased prevalence of bladder cancer in males versus females reflects, at least in part, androgen receptor function in bladder cancer 56 , as supported by recent analyses of genetically-engineered mouse models 57, 58 .…”