Principles of stem cell biology and cancer: future applications and therapeutics. Edited by T. Regad, T. J. Sayers and R. C. Rees. John Wiley & Sons (2015)
Prostate stem cells (PSCs) are a small population of undifferentiated cells possessing unique self-renewal and differentiation capacities (Schalken and van Leenders, 2003). They are thought to generate all the cell types found within the prostate. The evidence for their existence in adult prostate tissue came from studies on mice models displaying a regressive prostate phenotype, resulting from androgen deprivation. Androgen restoration favoured the regenerative ability of the prostate in those mice, reverting it to normal size; this process of serial ablation/restoration could be repeated multiple times on the same tissue (Tsujimura et al., 2002).
Adult PSCs are thought to be of basal origin, as they are able to regenerate and initiate prostate following multiple cycles of androgen regression (DeKlerk and Coffey, 1978; Kyprianou and Isaacs, 1988; Montpetit et al., 1988). They are believed to give rise to highly proliferative TACs, which, in turn, differentiate into NE and terminally differentiated luminal cells (Bonkhoff and Remberger, 1996). This is supported by the fact that 70% of proliferating human epithelial cells reside in the basal compartment, as well as by identification of subsets of basal/luminal and basal/NE intermediate profiles, which further suggests a basal origin (Verhagen et al., 1992; Bonkhoff et al., 1994). Human PSC population represent approximately 1% of the total cancer cell population, presenting high colony-forming efficiency in vitro, accompanied by the ability to form prostatic-gland structures in vivo. This subset population has been associated with a collection of cell-surface markers, namely CD133 (prominin-1, Prom1), α2β1 integrin and CK6a (Collins et al., 2001; Richardson et al., 2004; Schmelz et al., 2005). Further studies have identified several other PSC markers, including aldehyde dehydrogenase (ALDH), ATP binding cassette transporter family membrane efflux pump (ABCG2), tumour-associated calcium signal transducer 2 (Trop-2), p63 and CD44 (Liu et al., 1997; Bhatt et al., 2003; Lawson et al., 2007; Goldstein et al., 2008; Burger et al., 2009; Yao et al., 2009; Pignon et al., 2013). Basal-specific p63 have been shown to be essential in the development of limbs and epithelial organs, such as mammary and prostatic glands in mice (Mills et al., 1999; Yang et al., 1999; Signoretti et al., 2000). PSCs’ balance of quiescence, self-renewal potential and ability to differentiate into a heterogenous, highly specialized population is maintained by specific interactions provided by surrounding cells, along with elements of extracellular matrix (ECM), together comprising a complex tumour microenvironment or niche (Fuchs et al., 2004).
The signalling crosstalk between PSCs and neighbouring cells in the stem cell niche is theorized to be mediated by three main pathways: Wnt, Sonic hedgehog (Shh) and Notch. This is supported by experiments in which inhibition of the Wnt receptor resulted in the disruption and loss of intestinal epithelial cell niches (Kuhnert et al., 2004). Notch-1 shows a high level of expression in mouse prostate epithelium from its birth and remains highly expressed throughout morphogenesis, leading to its decline in adulthood (Shou et al., 2001). Notch-1 knockout in transgenic mice causes a marked impairment in the ability of stem cells to regenerate tissue and, later, a significant inhibition of cell growth, differentiation and branching processes in both in vitro and in vivo androgen ablation-restoration experiments (Wang et al., 2004). Shh expression has been shown to be involved in the promotion of early ductal morphogenesis via activation of transcription factor Gli-1 during epithelial evagination of the UGS (Lamm et al., 2002; Freestone et al., 2003) (Figure 10.1). Several transcription factors involved in prostate development appear to play roles in the maintenance of PSC stemness. Members of the Hox homeobox gene family are expressed in prostate growth, regulating branching and stages of differentiation – in particular HOXB13, which has also been found expressed in adult prostate (Edwards et al., 2005). Similarly, the expression of Nkx3.1 is maintained throughout life and is thought to be important for tissue homeostasis. Nkx3.1 plays a role in the protection of prostate epithelium from oxidative DNA damage, and its loss both disturbs prostate differentiation and fosters the mutational inactivation of related genes, such as PTEN (Bowen et al., 2000; Kim et al., 2002; Ouyang et al., 2005). FoxA1, a member of the Forkhead box gene (Fox) family, also plays an important role in ductal morphogenesis and epithelial cell maturation in prostate embryogenesis (Prins and Putz, 2008). Its marked expression is also sustained in adult life and has been found to be required for both probasin expression via direct interactions with FoxA cis-regulatory elements and PSA expression via interactions with ARs on gene promoters (Gao et al., 2010). Sustained expression of a number of these nuclear transcription factors and core signalling pathways mediates early morphogenesis events in the adult prostate (embryonic prostate) (Figure 10.1).
Figure 10.1. Gene expression and branching morphogenesis during rat prostate development within 5 weeks prepartum and 30 weeks postpartum. The key developmental genes identi?ed in prostate development are recorded based on relative expression of each other. The display of the branching pattern is represented in correlation with the temporal gene expression measured by RT-rPCR.
The existence of this distinct PSC population is advantageous for adult prostate maintenance due to its unique self-renewal and differentiation potential, which provide a great regenerative capacity. Conversely, when targeted by potential mutations, PSCs risk spreading abnormally functioning offspring cells and thus increasing the risk of developing life-threatening prostatic disorders such as benign prostate hyperplasia (BPH) and prostate cancer.