PROSTATE EPITHELIAL STEM CELL
SCIENTIFIC REVIEW

Introduction:
The most recent model of cancer pathology and metastases is based on the discovery of the existence of various stem cells in different organs [1,5]. In this model, cancer is thought to be due to uncontrolled stem cell division following genetic mutation or transformation of either an adult stem cell or de-differentiation of a differentiated progenitor cell [1, 5]. Thus, elucidation of the factors influencing prostate stem cell proliferation and differentiation may lead to novel treatments for prostate diseases such as prostate cancer and benign prostatic hyperplasia.

Prostate Development & Biology:
The human prostate is a partly glandular and partly muscular that approximates the shape and size of a chestnut [3]. Several follicular pouches make up the gland, which open into canals that join to form excretory ducts [3]. Each duct can then be divided into three regions: proximal (adjacent to the urethra), intermediate and distal [4] (Fig. 1). Although the actual distribution of prostate epithelial stem cells in the prostate is currently unknown, it is possible that they reside predominantly in the urethra and proximal region of the ducts, whereas transit-amplifying cells and partially differentiated stem cells may exist in the intermediate and distal regions along with differentiated luminal cells [4].

The prostate develops from the urogenital sinus upon stimulation with testosterone [1]. It begins in the embryo as a multilayered epithelium surrounded by mesenchyma [1]. Ductal budding begins approximately ten weeks after gestation, in which epithelial outgrowths invade the mesenchyma, forming excretory ducts that branch out from the urethra and end in acini [1]. The prostate continues to grow up to one year post-natal, after which there is a period of dormancy, followed by further growth during puberty corresponding to a surge in testosterone [1]. Prostate growth during puberty changes the multilayered epithelium of the prostate to a bi-layered epithelium of peripheral flattened/cuboidal basal cells and inner secretory cylindrical epithelium [1] (Fig. 2). The mature prostate consists of five inter-related cell types: stem cells, basal epithelial cells, transit-amplifying cells, secretory luminal epithelial cells and neuroendocrine cells [5].

The exocrine compartment of the prostate is composed of luminal cells which are terminally differentiated and secrete prostate specific antigen (PSA) and prostate acid phosphatase (PAP) into the glandular lumina [1]. Androgen is necessary for the survival of luminal cells and as can be surmised, luminal cells express high levels of androgen receptor (AR) [1]. They have a relatively low proliferative capacity and a high apoptotic index [5]. Upon androgen withdrawal, secretory cells of the prostate epithelium undergo massive apoptosis [8].       

Basal cells, on the contrary, are relatively undifferentiated and have no secretory activity. Basal cells have a high proliferative capacity [8] and low apoptotic index [5]. Basal cells express low levels of androgen receptor, and while androgen withdrawal will result in atrophy of secretory luminal cells, androgen withdrawal does not affect the basal layer [1, 5]. However, androgen treatment induces the proliferation and differentiation of basal cells to the secretory luminal phenotype [5]. Basal cells express oestrogen receptor and proliferate under oestrogen treatment [1].

Transit-amplifying cells are thought to serve as intermediaries between undifferentiated stem cells of the basal layer and highly differentiated exocrine and neuroendocrine cells of the lumen [5]. Transit-amplifying luminal cells replicate more rapidly than basal cells [9] and are believed to be the hierarchically related progeny of the prostatic epithelial stem cell [5, 8].

Neuro-endocrine cells are terminally differentiated and can be found in the epithelium of acini and throughout all parts of the prostate gland ducts [1].

Prostate Epithelial Stem Cells:
The first evidence suggesting the existence of prostate epithelial stem cells in the adult gland was reported for male rats [1]. Castration of adult male rats became androgen-deprived [1]. When re-administered with androgen, the prostate gland became fully restored [1]. Moreover, this involution and regeneration cycle can be repeated over thirty times [9]. The ability to restore the prostate is believed to be from basal cells that are a2b1hi, CD133+ [1]. Castration enriches for these cells which have been shown to fully reconstitute a prostate gland in immunocompromised mice [1, 4].

A contrasting model based primarily on kinetic studies proposes that secretory cells are capable of sustaining their own renewal without the aid of basal cells [8]. However, it has been postulated that the more rapid response of luminal cells to androgens could result from transit-amplifying cells being more responsive to androgen than basal cells [9].

Transforming growth factor-beta (TGFb) has been shown to be differentially regulated by androgen and inhibitory effects of TGFb are critical for proximal prostate stem cell renewal and quiescence [8]. The proximal region of prostatic ducts is wrapped in a band of smooth muscle cells, part of the urogenital mesenchyme [6], which are known to produce high levels of TGFb [9]. TGFb is expressed in a gradient-like fashion, highest in the stroma surrounding the proximal epithelium and lowest in the distal region, the site of cell proliferation [9].

The mechanisms regulating the renewal of adult prostate epithelium remain unclear [8] and the identity and location of human prostate epithelial stem cells is mostly speculative due to poor understanding of the organization of the prostate gland but are believed to reside in the basal epithelial layer [5]. In mice, researchers have found that distal tips of dorsolateral lobes of rats undergo massive epithelial growth when recombined with urogenital sinus mesenchyme, thus suggesting the presence of stem cells in the distal tips [5]. Transit-amplifying cells have also been found in the distal regions of prostate ducts, however, telomerase activity has been found to be significantly higher in proximal ducts than in distal tips, thereby suggesting the existence of stem cells here [5]. These candidate cells have also been shown to be slow cycling, possess high in vitro proliferative potential and can reconstitute highly branched glandular ductal structures in vitro [9]. Tsujimura, et al. proposed a model in which prostatic epithelial stem cells, maintained in a dormant state in the proximal ducts, differentiate into transit-amplifying cells which migrate distally to maintain a normal prostate gland or to repopulate the prostate gland under androgen-induced regeneration [9]. Tsujimura, et al. argued that although low numbers of stem cells can be found in both the intermediate and distal regions of the prostate, they are concentrated in the proximal region in a regenerated prostate [9].

When a2b1hi expression is used as a marker for sorting stem cells from other cells of the prostate (digested tissue from dissection of isolated distal and/or proximal duct regions), three different types of colonies were found to be formed: i) those that did not grow for a week then formed large colonies, ii) those that grew rapidly from the onset, and iii) those that formed small terminal colonies [5]. Sorted cells that quickly attached to Type I collagen were combined with stromal cells and then injected into mice and were found to occasionally form epithelial structures containing both basal and secretory cells [5]. These findings are considered further evidence of the existence of prostate epithelial stem cells [5].

Prostate Stem Cell Diseases & the Future of Prostate Stem Cell Research:
According to the National Cancer Institute, prostate cancer is the second leading cancer-related cause of death in men in the United States [2]. The NCI estimates that 235,000 American men will be diagnosed with prostate cancer in 2006 with an estimated 10% mortality rate [2]. The incidence of prostate cancer appears to be related to age (>65 years old), diet (high fat diet increases risk), genetics, and nationality (African American more at risk) [2]. Another common prostate condition in men, benign prostatic hyperplasia (BPH), has been sometimes confused with prostate cancer because of symptoms similar to both diseases [2]. However, BPH is a result of a non-cancerous overgrowth of prostate tissue which then blocks the flow of urine by pushing against the urethra and bladder [2].

BPH and prostate cancer are both disorders of cell differentiation and cell proliferation [7]. The most recent model of cancer pathology indicates that stem cells are responsible for the development of cancer. Research has shown that most primary tumors of prostatic cancer consist of terminally differentiated luminal cells but that metastatic tumors contain basal cells in which Bcl-2 (anti-apoptotic) and telomerase, typically restricted to basal cells, are over-expressed in prostate cancer [1, 5]. Research to determine if these a2b1hi, CD133+ basal stem cells can be tumor-initiating in Severe Combined Immuno-Deficient hosts needs to be done [1].

The human prostate can be anatomically divided into three regions: central, transitional, and peripheral zones [9]. Interestingly, benign prostatic hyperplasia is found to develop primarily in the transition zone, whereas carcinoma arises mainly in the peripheral zone [9]. It remains to be determined whether these differences are due to the existence and location of stem cells [9].

Prostate stem cell antigen (PSCA) is also thought to be a lineage-specific marker of prostate progenitor cells within the basal epithelium [5]. mRNA for PSCA has been shown to be expressed in high-grade prostatic intraepithelial neoplasia and in prostate cancer, supporting the current model of the role of stem cells in cancer pathology [5]. Moreover, when SCA-1+ and SCA-1- cells are isolated, researchers found that only SCA-1+ cells are able to contribute to carcinoma in situ (Lam, et al. 2006).

References:

• Collins AT, Maitland NJ (2006) Prostate cancer stem cells. Eur J Cancer 42:1213-18.
• Early Prostate Cancer: Questions and Answers. National Cancer Institute. 31 Oct 2006. <http://www.cancer.gov/cancertopics/factsheet/Detection/early-prostate>.
• Gray, Henry. Gray’s Anatomy, 15th Edition. Barnes & Noble Books, 1995: 993-995.
• Goto K, Salm SN, Coetzee S, Xiong X, Burger P, Shapiro E, Lepor H, Moscatelli D, Wilson EL (2006) Proximal prostatic stem cells are programmed to regenerate a proximal-distal ductal axis. Stem Cells 24:1859-68.
• Lam JS, Reither RE (2006) Stem cells in prostate and prostate cancer development. Urologic Oncol: Sem and Original Invest 24:131-40.
• Richardson GD, Robson CN, Lang SH, Neal DE, Maitland NJ, Collins AT (2004) CD133, a novel marker for human prostatic epithelial stem cells. J Cell Sci 117:3539-45.
• Schmelz M, Moll R, Hesse U, Prasad AR, Gandolfi JA, Hasan SR, Bartholdi M, Cress AE (2005) Identification of a stem cell candidate in the normal prostate gland. Eur J Cell Biol 84:341-54.
• Signoretti S, Loda M (2007) Prostate stem cells: From development to cancer. Sem Cancer Biol 17:219-24.
• Tsujimura A, Koikawa Y, Salm S, Takao T, Coetzee S, Moscatelli D, Shapiro E, Lepor H, Sun T, Wilson EL (2002) Proximal location of mouse prostate epithelial stem cells: a model of prostatic homeostasis. J Cell Biol 157:1257-65.