Prostate Epithelial Stem Cells

The existence of prostate epithelial stem cells and their putative role in prostate cancer development was proposed by Isaacs and Coffey (26-28). The stem cell model described in this paper is very similar to the one described above. Prostate cancers arise from prostate secretory acini. These acini are characterized by two cell layers that can be discriminated morphologically as undifferentiated basal cells and luminal cells primarily composed of terminally differentiated exocrine (prostate-specific antigen producing) cells. The neuroendocrine cells are found "supra" basally, with protrusions through the epithelium. The first evidence for a hierarchical relation between the basal cells and the luminal cells was provided by our group (29,30), using keratin antibodies as differentiation markers. We and others found further indications that the neuroendocrine and exocrine cells have a common progenitor, termed the transiently amplifying (TRANSIT) cell (31-34).

Clearly, most of these studies are descriptive and enable discrimination between the various cell types based on specific immunophenotypes. The location of the cells, as well as hormone manipulation studies (30), suggest a hierarchical relation between the basal cells and the luminal cells. The early and late progenitors are characterized by "intermediate" immunophenotypes (Fig. 1; Table 1). The first evidence for a hierarchical relation using primary epithelial cell cultures was described by our group (35). More recently, Collins and colleagues succeeded in isolating a purer candidate prostate epithelial stem cell, using CD133 selection (36). Thus, a very specific immunophenotype of the stem cell, the early and late progenitor cell populations, and the terminally differentiated exocrine and neuroendocrine cells emerges (see Table 1).

Fig. 1. Prostate epithelial cell hierarchy. The stem cells divide and give rise to a new stem cell by self-renewal and move committed progenitor cells )early and late) for the functional exocrine and neuroendocrine cell lineages. The exocrine lineage is critically dependent on DHT, and in fact this population represents > 90% of all epithelial cells in the adult prostate gland.

Fig. 1. Prostate epithelial cell hierarchy. The stem cells divide and give rise to a new stem cell by self-renewal and move committed progenitor cells )early and late) for the functional exocrine and neuroendocrine cell lineages. The exocrine lineage is critically dependent on DHT, and in fact this population represents > 90% of all epithelial cells in the adult prostate gland.

Table 1

Immunophenotype of the Cell Types in Nonmalignant Prostate Acini

Neuroendocrine Cells Markers
K14, keratin 14; K5, keratin 5; K18, keratin 18; AR, androgen receptor; NE, neuroendocrine markers (e.g., serotonin and chromogranin A).

The hierarchical relation between the cell types is schematically illustrated in Fig. 1. The exocrine lineage, resulting in the tall columnar prostate-specific antigen-producing cells, is critically dependent on the hormone, dihydrotestosterone. After castration, more than 90% of epithelial cells die through apoptosis (37,38). The remaining cells have renewal capacity, because the kinetics of regrowth after implanting testosterone-containing slow-release devices is independent of the time interval between castration and implantation of the silastic testosterone-containing devices (26,30). The population of cells remaining after castration are thought to represent the stem and early progenitor cells. In the developing prostate (embryogenesis and peripubertal), there is a relative enrichment in the progenitor cell populations (31). The early and late progenitors are thought to play a pivotal role in the development of benign and malignant prostate neoplasms (39-41). Implicit evidence that the remaining cell population after castration has renewal ability was provided by early experiments by Coffey and Isaacs (26) showing that the kinetics of prostate regrowth are independent of the time interval between castration and testosterone re-administration. Long-term culture experiments using CD133-selected cells proliferate and can be maintained for longer than 140 days. CSC reside in a "niche," and our understanding of the regulation of the expansion into the various epithelial lineages of differentiation is growing steadily through the pioneering work of Fuchs and colleagues (42-47). Unfortunately, relatively little is known on the location/niche of the prostate epithelial stem cell. Collins and colleagues show that there seems to be a niche in which the prostate epithelial stem cells are more firmly attached to the basement membrane (48). The branching morphology of the secretory ductal system is rather complex, and 3D reconstruction is difficult for the human prostate secretory system. The combined data indicate that the branching points and the tips of the acini are the candidate niche for the stem cell (31,39,49). The stroma plays an essential role in the induction of branching morphogenesis and essential mediators seem to be hepatocyte growth factor and fibroblast growth factor-10 (50-53). In general, despite the unique characteristics of the various specialized epithelial cells, common signaling mechanisms seem to play a role, such as wingless-, notch-hedgehog, and bone morphogenetic protein signaling (for a recent review, see ref. 17).

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