Androgen action in prostate function and disease

Abstract

Benign prostatic hyperplasia (BPH) is an enlargement of the prostate gland that is frequently found in aging men. Androgens are essential for the development and differentiated function of the prostate, as well as for proliferation and survival of prostatic cells. In man, dog and rodent, there are age-related decreases in serum testosterone. Despite the lower serum testosterone levels, benign prostatic hyperplasia increases with age in men and dogs, while age-dependent prostatic hyperplasia develops in the dorsal and lateral lobes of the rat prostate. The possible mechanisms that lead to prostate hyperplasia have been extensively studied over many years. It is clear that androgens, estrogens and growth factors contribute to the condition, but the exact etiology remains unknown. Prostate cancer (CaP) represents a significant cause of death among males worldwide. As is the case of BPH, it is clear that androgens (testosterone and dihydrotestosterone) and their metabolites play important roles in the disease, but cause-effect relationships have not been established. Androgen deprivation therapy has been used for decades, primarily in the metastatic stage, to inhibit androgen-dependent prostate cancer cell growth. Androgen deprivation, which can be achieved by targeting hormone biosynthesis or androgen receptor activation, results in symptom amelioration. However, most patients will develop hormone refractory cancer or castration-resistant prostate cancer (CRPC). Prostatic epithelial cells demonstrate enormous plasticity in response to androgen ablation. This characteristic of prostatic epithelial cells may give rise to different populations of cells, some of which may not be dependent on androgen. Consequently, androgen receptor positive and negative cells might co-exist within CRPC. A clear understanding of this possible cellular heterogeneity and plasticity of prostate epithelial cells is necessary to develop an optimal strategy to treat or prevent CRPC.

Keywords: BPH; CRPC; Leydig cell; Prostate; aging; androgens.

Figure 1

Age-dependent changes in androgen sensitivity in the dorsolateral lobe of Brown Norway rat prostatic acini. Prostatic epithelial cells of young adults (age 4 months) are androgen-dependent, and therefore castration reduces the size of the dorsolateral lobe. However, epithelial cells of the aging dorsolateral prostate become relatively insensitive to changes in androgens, and therefore are relatively unaffected by castration or by normally occurring androgen reductions.

Figure 2

Model by which the treatment naïve prostate cancer (CaP) changes from complete androgen dependence to castration-resistant prostate cancer (CRPC). Treatment with 1^st generation of anti-androgens kills a majority of wild-type, androgen receptor (AR)-expressing androgen sensitive cells. However, some of these cells acquire AR mutations, some express AR splice variants, and some trans-differentiate to cancer stem-like cells by expressing stemness genes. Second generation anti-androgens attacks only some of the mutated AR expressing cells; because of the plasticity of the CaP cells, some survive, repopulate heterogeneous cancer cells throughout the prostate, and there is cancer relapse. To target all mutated and splice variant AR positive-cells and cancer stem-like cells, total AR degradation together with inhibitors of stem-like cells will be necessary. Only this way will a lethal environment be created that will eradicate all CaP cells irrespective of their heterogeneity.