Prostate stem cells and benign prostatic hyperplasia

Abstract

Pharmacological approaches are available to medically-managed patients with symptomatic BPH before surgical intervention is required. These include daily treatment with alpha-blockers and 5-alpha-reductase inhibitors alone or in combination. These medical approaches have two major problems. First, treatments are chronic and must be taken daily. Second, there are significant financial costs and quality of life issues for such chronic treatments. Is it possible to develop effective acute therapy for symptomatic BPH without the long-term androgen deprivation-induced side effects? Two seminal but rarely cited studies of Walsh [Peters, Walsh: N Engl J Med 317:599-604, 1987] and Coffey et al. [Sufrin et al.: Invest Urol 13:418-423, 1976], combined with the growing understanding of the stem cell organization of the prostate stromal (S) and epithelial (E) compartments and their reciprocal paracrine and autocrine interactions provides the rationale for an acute approach.The Walsh study documents that: (1) androgen deprivation disrupts the reciprocal interaction between the prostate S and E thereby decreasing the weight of both compartments and (2) once BPH develops, androgen deprivation does not decrease the number of stem cell units in either the S or E compartments since subsequent androgen restoration fully restores the enlarged gland. The Coffey study documents that acute androgen deprivation sensitizes S-E interactions to radiation induced disruptions so that following radiation, androgen restoration does not induce full gland regrowth. Therefore, effective therapy for symptomatic BPH should be achievable by acute treatment with reversible androgen deprivation for a limited period followed by a single dose of conformal external beam radiation before allowing the man to recovery his normal serum testosterone.

Targeting the Unique Methylation Pattern of Androgen Receptor (AR) Promoter in Prostate Stem/Progenitor Cells with 5-Aza-2′-deoxycytidine (5-AZA) Leads to Suppressed Prostate Tumorigenesis

“…The AR 4 is expressed in most stem cells (13)(14)(15)(16)(17)(18). The AR in prostate stem/progenitor cells plays key roles in prostate development and differentiation processes (19,20) as well as in prostate cancer (PCa) initiation and progression (21,22).…”

Sonic hedgehog signals to multiple prostate stromal stem cells that replenish distinct stromal subtypes during regeneration

“…Furthermore, in human prostate cancer, the extent of reactive stroma correlates with disease severity and can be used as a prognostic indicator for disease-free survival (44). As well, prostate stromal stem cells have been proposed to contribute to the pathogenesis of BPH in some instances (45). In light of our finding that SHH signals to unipotent stromal stem/progenitor cells, it is important to explore whether increasing HH signaling in prostate stromal stem cells leads to overgrowth of the stroma and whether paracrine signaling then alters the epithelium.…”

Exploring the Origins of the Normal Prostate and Prostate Cancer Stem Cell

“…These cells proliferate and undergo transit amplification, expressing phenotypes intermediate between basal and luminal cells [22]. It is generally thought that PCPs do not express AR or p63 [23]. Regression/regeneration studies have shown that even after more than 30 rounds, androgen treatment could still restore secretory glandular structure [24].…”