Mechanisms of Hormonal Prostate Carcinogenesis

As stipulated earlier, there are compelling reasons to assume that androgens play a critical role in prostate carcinogenesis, and there is experimental evidence to suggest that estrogens are involved as well [55]. Because of the hormonal nature of these steroids, receptor mediation has been proposed as the major mechanism by which androgens and estrogens act in the causation of prostate cancer [235]. For estrogens, however, non-receptor-mediated genotoxic effects are conceivable, in addition to receptor-mediated processes [55]. For an-drogens, mechanisms other than those mediated by androgen receptors seem unlikely, except for the generation of estrogens via aromatization. These potential mechanisms are discussed in the following sections.

Prostatic mesenchyme is known to be a mediator of androgen action in the developing and adult rodent prostate and possibly the human prostate [236, 237]. Therefore, interactions between epithelial and stromal cells in the normal prostate are undoubtedly critical and may be essential in prostate carcinogene-

sis. However, there are hardly any studies that have directly addressed the role of stromal-epithelial interaction in human or rodent prostate carcinogenesis [238]. Krieg et al. [184] measured steroid hormone concentrations in stromal and epithelial compartments of normal human prostates from subjects varying from 20 to 80 years of age. Epithelial DHT concentrations decreased considerably with aging, but they remained stable in stromal cells and testosterone concentrations appeared unaffected by age in either cell type. Thus, the activity of 5a-reductase in the epithelium may decrease with aging, but perhaps remains intact in the stroma. However, concentrations of 17^-estradiol and estrone in the stroma, but not the epithelium, increased markedly with aging. These findings suggest that the prostatic stroma is an important site for both androgen and estrogen action and metabolism such as aromatase activity, which seems to increase with aging because estrogens accumulate with aging and androgen levels remain stable, in contrast to concentrations of estrogens and androgens in the circulation or in epithelial cells which decrease with aging. Thus, it is conceivable that, with increasing age and increasing risk for prostate cancer, the prostatic stroma continues to be an important androgen signal mediator to the epithelium and is an increasingly important local producer of estrogens.

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