The peripheral zone of the prostate is more prone to tumor development than the transitional zone: Is the ETS family the key?

Abstract

Abstract. Predisposition to develop prostate cancer (PCA) varies among the prostate zones, with the peripheral zone (PZ) more prone to tumor development than the transitional zone (TZ). In view of the fact that molecular differences between the zones may explain this difference, combined with the findings that translocations between TMPRSS2 and several ETS members are frequently observed in PCA, we hypothesized that the ETS family may be crucial to explaining this difference. Normal tissues from the PZ and the TZ of 20 PCA patients were laser microdissected to separate glands from stroma. Two oligo microarrays were performed in order to investigate the variation in ETS family gene expression between the glands and the stroma of the two zones. The ETS members, ELF-3, ELF-5, ERG, ETV-1, ETV-4, ETV-5, ETV-7 and FEV, were found to be differentially expressed. A striking observation was that ERG and ETV-1 were found to be up-regulated in the glands of the PZ compared to the TZ, particularly when considering that ERG and ETV-1 fusions account for 50-80% and 20% of PCA occurrences, respectively. These results indicate that the glands and stroma of the two zones display distinct molecular differences and zonal-specific expression of ETS members. Furthermore, ETS members up-regulated in PCA are already overexpressed in the normal PZ, suggesting that these members play a role in the development and progression of PCA. IntroductionProstate cancer (PCA) is a clinically heterogeneous and often multifocal disease with a clinical outcome that is difficult to predict (1,2). Therefore, advancements in the knowledge of the molecular basis of PCA should improve the prediction of prognosis, as genetic aberrations drive the formation and aggressiveness of prostate carcinoma (3).The prostate is supported by a stroma and can be divided into three anatomical zones: peripheral (the so-called prostate proper), transitional and central zones (4,5). The predisposition to develop PCA is different among these zones, as most manifest PCAs (75%) occur in the peripheral zone (PZ), at the dorsal and dorso-lateral side of the prostate, while only some (20%) occur in the transitional zone (TZ) (6,7).The latter cancers are mostly so-called incidental carcinomas with a nonaggressive clinical course, whereas cancers from the PZ are more aggressive, tend to invade the periprostatic tissues and have higher biochemical recurrence rates (6,8). The molecular basis underlying the differences in the susceptibility to PCA between the different zones of the prostate remains unknown. However, it has been suggested that some of the differences in susceptibility may have an embryological basis (9). As PCA rarely develops in the central zone compared with the PZ, it has been suggested that the central zone is derived from the Wolffian duct, the same duct from which the seminal vesicle is derived, and in contrast to the remainder of the prostate, which is derived from the urogenital sinus (5,9,10).In contrast to these varying predispositions of the TZ and the PZ t...

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“…In our study, we used tissues from prostates of patients undergoing radical prostatectomy for prostate cancer. Most prostate cancers are located in the peripheral zone (49,54). Our samples were exclusively taken from the periurethral zone, which is usually not affected by prostate cancer.…”

“…Samples were taken immediately after prostatectomy, following macroscopical examination by a uropathologist. All tissues were taken from the periurethral zone, considering that most prostate cancers arise in the peripheral zone (49,54). Upon pathologic evaluation, only tissue samples that did not exhibit histological signs of neoplasia, cancer, or inflammation were collected.…”

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P21-Activated Kinase Inhibitors FRAX486 and IPA3: Inhibition of Prostate Stromal Cell Growth and Effects on Smooth Muscle Contraction in the Human Prostate

“…Informed written consent was obtained from the participants; data were analysed anonymously. Tissues were taken from the periurethral zone, while most prostate tumors are located to the peripheral zone [ 31 , 32 ]. Tissue samples did not exhibit histological signs of neoplasia, cancer, or inflammation.…”