Zonal and cellular organization of the prostate

Fig. 12.5 Cellular heterogeneity within the normal prostate

Histological architecture of the prostate is comprised of blood vessels that provide nutrients, including androgen, to the fibrous stromal layer which consists primarily of fibroblasts and smooth muscle cells, and to the epithelial layer. Epithelium can be subdivided into a basal epithelium, which contains AR negative proliferating cells, and secretory luminal epithelium, which consists of fully differentiated AR and p27Kip1 positive, nonproliferating cells.

Fig. 12.5 Cellular heterogeneity within the normal prostate

Histological architecture of the prostate is comprised of blood vessels that provide nutrients, including androgen, to the fibrous stromal layer which consists primarily of fibroblasts and smooth muscle cells, and to the epithelial layer. Epithelium can be subdivided into a basal epithelium, which contains AR negative proliferating cells, and secretory luminal epithelium, which consists of fully differentiated AR and p27Kip1 positive, nonproliferating cells.

of the transit amplifying cells are believed to be located in the basal epithelial layer (Figs. 12.5 and 12.6).

Basal cells express the p53 related p63 protein, the plasma membrane receptor for hepatocyte growth factor (known as c-MET), and pro-survival protein, bcl-2 (Gmyrek etal. 2001; McDonnell etal. 1992; Signoretti etal. 2000; Watabe etal. 2002). A minority of stem cell progeny differentiate into NE cells which secrete neuroendocrine peptides such as bombesin, calcitonin, and parathyroid hormone-related peptide (Rumpold etal. 2002). A subset of these basal cells shows high proliferative activity as evidenced by positive staining for Ki-67 and are termed transit amplifying cells, which initially do not express the androgen receptor (Bonkhoff etal. 1994; 1998). During this hierarchical expansion, these transit amplifying cells undergo a maturation process in which they progress to "intermediate-like" cells expressing prostate specific stem cell antigen (PSCA), and begin expressing the androgen receptor (AR). As these intermediate cells mature, they stop proliferating and terminally differentiate into mature secretory luminal cells which are non-proliferative and positive for AR and p27Kip1cyclin-dependent kinase inhibitor (Bonkhoff etal. 1994; 1998; De Marzo et al. 1998) (Fig. 12.5). Because of hierarchical expansion, these non-proliferating AR /p27Kip1 positive secretory luminal cells are quantitatively the major subtype of epithelial cells present in the normal prostate. They also express

Fig. 12.6 Stem cell model of prostatic epithelial cell compartmentalization

The prostate gland consists of a number of stem cell units which arise from one stem cell. Such a stem cell is located in the basal epithelial layer of the prostate and, upon division, gives rise to a population of transit amplifying cells. The latter divide in the basal layer and mature into an intermediate cell type. These intermediate cells migrate into the luminal layer where they differentiate into the secretory luminal cells. Expression of a number of genetic markers characteristic of each cell subtype is as indicated. NE denotes neuroendocrine cells; + denotes expression of marker; — denotes lack of detectable expression of marker.

Fig. 12.6 Stem cell model of prostatic epithelial cell compartmentalization

The prostate gland consists of a number of stem cell units which arise from one stem cell. Such a stem cell is located in the basal epithelial layer of the prostate and, upon division, gives rise to a population of transit amplifying cells. The latter divide in the basal layer and mature into an intermediate cell type. These intermediate cells migrate into the luminal layer where they differentiate into the secretory luminal cells. Expression of a number of genetic markers characteristic of each cell subtype is as indicated. NE denotes neuroendocrine cells; + denotes expression of marker; — denotes lack of detectable expression of marker.

the prostate-specific differentiation markers, prostatic specific acid phosphatase (PSAP), prostate specific antigen (PSA), NKX 3.1, human glandular kallikrein-2 (hK2), prostate specific membrane antigen (PSMA), and prostate stem cell antigen (PSCA), as well as vascular endothelial growth factor (VEGF) (Jain et al. 2002; Joseph et al. 1997; Liu et al. 1997; Ornstein et al. 2001; Schuur et al. 1996). The transcriptional expression of these prostate-specific differentiation marker genes is enhanced by occupancy of the AR by physiologic androgen and the subsequent binding of the occupied AR at androgen response elements in the promoter and enhancer sequence of these genes within the nuclei of these secretory luminal cells (Jain etal. 2002; Schuur etal. 1996; Watt etal. 2001; Zelivianski etal. 2002; Mitchell etal. 2000).

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