Endocrine effects on PCSCs

In PC, the stromal niche or microenvironment plays a critical role in regulating differentiation of CSCs, probably by altered endocrine and/or paracrine signaling. Direct androgen binding to epithelial ARs is not required for epithelial differentiation, but is essential for the induction and maintenance of a secretory activity [11].

AR is a member of the steroid hormone receptor family and its over-expression is involved prostate tumorigenesis. Consequently, androgen deprivation therapy (ADT) has been used to treat locally advanced and metastatic PC [86]. Despite initial regression of the tumor the majority of patients inevitably develop castrate-resistant prostate cancer (CRPC), which establishes metastases relatively rapidly and is subsequently incurable by current treatment strategies. Mouse model studies revealed that androgen ablation can select for more aggressive and metastatic disease, which means that current hormonal therapies do not affect the AR'-CSCs [87]. ADT may promote disease progression by causing an increase in the castrate-resistant SC pool and/or activating quiescent SCs to repopulate the tumor with andro-gen-independent SCs. Vander et al. reported that unlike normal adult human prostate SCs, CD133+ PCSCs are AR+ and suggested that AR+ prostate TICs are derived from a malignantly transformed intermediate cell that acquired "stem-like activity". The AR signaling pathway might therefore comprise another therapeutic target, especially for prostate TICs [88].

In addition to androgens, estrogens play key roles in prostate carcinogenesis and progression. However, the mechanisms are not fully understood. Although there is still no direct evidence that estrogens initiate PC in humans, there is accumulating evidence pointing towards a central role for estrogens in PC [89]. To give just some examples are the rising E2:T ratio in aging men, association of estrogen metabolizing gene polymorphisms and elevated urine hydroxy-estrone ratios with higher PC risk, progressive increase in aromatase expression in PCs upon advancement to metastatic disease, and marked alterations in estrogen receptor expression with cancer progression. Normal human prostate progenitor cells are responsive to estrogens with increased rates of self-renewal, implicating them as direct estrogen targets.

The importance of estrogen receptor (ER) expression, e.g. ERa and ERp, is unknown; but, is of interest based on the integral role of estrogens in prostate carcinogenesis. The expression of ERa is low and hard to detect in prostatic epithelial cells, where ERp is predominantly expressed. An ERp agonist compound could selectively induce apoptosis in castrate-resistant CD133+ basal cells, providing a rationale for further exploring the role of ERp in PC and PCSCs [90].

Prolactin (PRL) is a peptide hormone that is secreted by the pituitary gland. It regulates several physiological functions, many of which relate to male and female reproduction. In humans PRL is also produced by prostate epithelial cells under normal physiological conditions. Local PRL profoundly affects the prostate epithelial compartment, with dramatic expansion of basal and stem-like epithelial cells, markedly enhanced epithelial cell proliferation, and strong activation of the STAT5 pathway as three hallmarks of tumorigenesis [91].

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