Localization of stem cells within the prostate epithelium

In the 1980s, John Isaacs and colleagues performed classic androgen cycling experiments and suggested that prostate epithelium must contain a SC population. Than, when rodents are deprived of androgen by surgical or medical castration, the gland atrophies due to apop-tosis of terminally differentiated cells which are dependent on androgen for their survival

[14]. However, when androgen is replaced the gland regenerates and resumes its normal functions. This involution and regeneration can be repeated for many sequential cycles. The regenerative capacity has been attributed to a population of long lived SCs within adult prostate epithelium that are thought not androgen-dependent for survival, but androgen-sensitive and androgen-responsive. Apoptosis occurs mostly in androgen-dependent lumi-nal cell epithelium, while the androgen-independent basal cells generally remain unaffected

[15]. In accordance with this, the regenerative capacity is referred to the action of basal SCs, while the harbor of these self-renewing cells is confined to the basal-cell layer [14, 16]. Later, also other observations and studies have supported this hypothesis in many ways; like, that basal cells exhibit a higher proliferation rate in normal and hyperplastic acini than luminal epithelial cells [9]. Or for example, as bromodeoxyuridine (BrdU) labeling studies have suggested that prostatic tumor-initiating cells reside in the basal cell compartment and express a p63+ signature [17]. And, that basal cells preferentially survive after androgen ablation;

whereas, 90% of luminal epithelial cells are lost through programmed cell death [18]. Androgen treatment restores the secretory glandular structure, hinting towards that the basal compartment contains SCs that undergo transit amplification to repopulate the luminal epithelium [19]. Cell types expressing an intermediate phenotype of basal and luminal cell characteristics have been identified in the developing and adult prostate [19].

On the other hand, there are also some studies that do not support the idea that SCs reside in the basal cell compartment. Experiments in mice where SCs were labeled with BrdU, suggested that stem cells are not restricted to the basal cell compartment; but, may also reside in luminal cell layer as a slow proliferating population in the proximal part of prostatic ducts [20]. Using tissue rescue experiments, Gerald R. Cunha and colleagues have demonstrated that the embryonic p63 null urogenital sinus developed into prostate when engrafted under the renal capsule of male mice [21]. Although, basal cells were absent the grafts contained luminal and NE cells, demonstrating that p63 was essential for basal but not for luminal and NE cell differentiation [21].

In human prostate, there is a consistent body of evidence that the SCs reside in the basal layer. Within the basal layer, CD133+/a2p1hi (high expression of a2pj integrin) cells represent a small subpopulation of quiescent cells with SC characteristics: they have a high pro-liferative potential in vitro and can reconstruct functional prostate acinar structures in vivo [22]. Molecular characterization of these cells revealed that they do not express AR at mRNA level [23], indicating that they are not dependent on androgen for their survival. Using CD49f and tumor-associated calcium signal transducer-2 (TROP2) as markers, Goldstein and collaborators identified basal cells with enhanced sphere-forming and tissue regenerating abilities [24].

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