α-blockade, apoptosis, and prostate shrinkage: how are they related?

Central European Journal of Urology 189  FUNCTIONAL UROLOGY r e v ie w P a pe r   α–blockade, apoptosis, and prostate shrinkage: how are they related? Piotr Chłosta1, Tomasz Drewa2, Steven Kaplan3 Department of Urology, Collegium Medicum Jagiellonian University, Kraków, Poland Department of Tissue Engineering, N. Copernicus University, Bydgoszcz, Poland; N. Copernicus Hospital, Toruń, Poland 3 Weill Cornell Medical College, Cornell University, New York, USA 1 2 Article history Submitted: Jan. 25, 2013 Accepted: Feb. 18, 2013 Correspondence Tomasz Drewa Department of Tissue Engineering Nicolaus Copernicus University 24, Karłowicza Street 85–090 Bydgoszcz, Poland phone: +48 52 58 53 736 tomaszdrewa@wp. Purpose. The α1–adrenoreceptor antagonists, such as terazosin and doxazosin, induce prostate programmed cell death (apoptosis) within prostate epithelial and stromal cells in vitro. This treatment should cause prostate volume decrease, However, this has never been observed in clinical conditions. The aim of this paper is to review the disconnect between these two processes. Methods. PubMed and DOAJ were searched for papers related to prostate, apoptosis, and stem cell death. The following key words were used: prostate, benign prostate hyperplasia, programmed cell death, apoptosis, cell death, α1–adrenoreceptor antagonist, α–blockade, prostate epithelium, prostate stroma, stem cells, progenitors, and in vitro models. Results. We have shown how discoveries related to stem cells can influence our understanding of α–blockade treatment for BPH patients. Prostate epithelial and mesenchymal compartments have stem (progenitors) and differentiating cells. These compartments are described in relation to experimental in vitro and in vivo settings. Conclusions. Apoptosis is observed within prostate tissue, but this effect has no clinical significance and cannot lead to prostate shrinkage. In part, this is due to stem cells that are responsible for prostate tissue regeneration and are resistant to apoptosis triggered by α1–receptor antagonists. Key Words: α1–receptor antagonists ‹› benign prostate hyperplasia ‹› apoptosis ‹› stem/progenitors cells INTRODUCTION METHODS α1–adrenoreceptor antagonists, such as terazosin and doxazosin are able to induce programmed cell death (apoptosis) within prostate epithelial and mesenchymal cells [1, 2]. In theory, α1–adrenoreceptor antagonist treatment with ensuing apoptosis of prostate epithelial and mesenchymal cells should lead to prostate shrinkage. However, clinically, α1–adrenoreceptor antagonists treatment does not result in prostate volume reduction. This review is designed to 1) analyze the possible pitfalls related to this discrepancy and 2) to demonstrate how stem cell differentiation could influence in vitro and in vivo results presented in this field. PubMed and DOAJ were searched for papers related to prostate, apoptosis, and stem cells. The following key words were used; prostate, benign prostate hyperplasia, programmed cell death, apoptosis, cell death, α1–adrenoreceptor antagonist, α–blockade, prostate epithelium, prostate stroma, stem cells, progenitors, and in vitro models. Cent Eur J Urol 2013; 66: 189-194  Stem cell classification Stem cells are classified according to their mitotic and differentiating potential. This potential can be described as the possibility to regenerate tissue, orDOI: 10.5173/ceju.2013.02.art19 190 Central European Journal of Urology gans, or even a whole new organism. These properties can be described as unipotential, multipotential, pluripotential, or totipotential. Totipotential stem cells possess the ability to build a whole new organism. Pluripotential stem cells isolated from an embryo inner cell mass can differentiate into all cells, but cannot form a new organism. Epithelial, endothelial, and mesenchymal stem cells are referred as multipotential. Progenitors or unipotential stem cells can regenerate only one defined cell population. Multipotential and unipotential cells are isolated from tissues of adult organisms, so they are usually called „Adult Stem Cells” (ASC). On the other hand many authors suggested that cells with pluripotential characteristics can be isolated from adults, so this classification will probably be changed in the near future [3, 4]. The behavior of CD133+ cells in vitro culture resembled progenitors properties. The viability of these cells after detachment reached 100% in some cases, but the proliferation rate was lower when comparing to CD133(+)/CD133(–) co–cultures. CD133(–) cultures are probably composed of differentiated cells without clonogenic potential. CD133(–) cells had no potential for in vitro proliferation, even in the serum conditioned medium. It can be speculated that CD133(–) cells probably have no ability to regenerate the prostate ducts. These cells were not able to anchor and form monolayer [11]. Some of them can be alive in culture, but the most of them enter an apoptotic pathway. The apoptotic inductions among these cells were probably due to the lack of anchor growth [2, 12]. Receptor status and cell differentiation Stem cells and progenitors regenerate prostate epithelium Receptor status is supposed to be the most important Adult stem cells (ASC) are able to self renew and maintain the structural and functional integrity of their original tissue. Transit amplifying cells (TAC) are committed progenitors within ASC and their terminally differentiated daughter cells. ASC and TAC are protected and controlled in their self–renewing capacity and differentiation. ASC and TAC occurrence have been considered in many human tissues including prostate epithelium [5, 6]. The prostatic epithelium is composed of five cell type compartments: stem cells, basal epithelial cells, TAC, neuroendocrine cells, and secretory epithelial cells [7]. Basal cells form a single layer on the basement membrane. The stem cells are localized within the basal layer. Prostate epithelial stem cells provide progenitors that differentiate down either a neuroendocrine or exocrine pathway. The maturation along the exocrine pathway initially involves TAC, which differentiate into intermediate cells. These intermediate cells migrate into the luminal layer where they terminally differentiate into non–proliferative secretory luminal cells [8]. Generally two populations of cells capable of regenerating prostatic ducts can be distinguished. The first population (with considerable huge growth potential) resides in the proximal region of ducts and in the urethra, and the survival of these cells does not require the presence of androgens. The second population (with more limited growth potential) is found in the remaining ductal regions and requires androgens for survival [9]. The prostate epithelial basal cells express high levels of integrin α2β1 and this population can be subdivided into basal stem (α2β1(hi) CD133+) and TAC (α2β1(hi) CD133–) [10]. part of the molecular targe (...truncated)