Molecular mechanisms of castration-resistant prostate cancer progression

Abstract

Hormone-refractory prostate cancer is the result of regrowth of prostate cancer cells that have adapted to the hormone-deprived environment of the prostate. The process by which castration-resistant prostate cancer (CRPC) cells are generated appears to be varied. The complex mechanism of hormone resistance has been the topic of research in most laboratories that have analyzed the process from different angles. This review compiles research findings that explain the methods of development of hormone resistance in prostate cancer. Research data show many different processes to be involved in the acquisition of hormone resistance. Interestingly, one observes interdependence between these processes, indicating a complex network at play in the development of hormone resistance. Cytokines such as IL-6 have been shown to initiate an alternative signaling pathway, compared with the androgen receptor signaling pathway, in CRPC. IL-6 has been proposed to be the effector of the intracrine signaling pathway by influencing the levels of metabolic enzymes. Neuroendocrine cells are present at low levels in normal prostate, and signify the transitory phase of normal hormone-sensitive cells to hormone-refractory cells. IL-6 induces growth of neuroendocrine cells or neuroendocrine-like features in cells in CRPC. The increased presence of neuroendocrine cells in CRPC signifies a change in the prostate cell microenvironment. The stromal microenvironment also influences the development of CRPC in the hormone-refractory stage. In addition, intracrine androgen metabolic enzymes play a significant role in the development of the hormone refractory process. Despite hormone ablation, there is a residual level of hormones in cells due to active intracrine metabolic pathways. It is acknowledged that the androgen receptor plays the most influential role in development of prostate cancer. In addition to mutation and amplification, the androgen receptor has been characterized and shown to differ in sequence in CRPC compared with the androgen-sensitive prostate cancer cells. These variants of the androgen receptor through sequence changes may preserve the basic function of the molecule, but have far-reaching consequences on the cell as a whole. A multicombinatorial drug treatment approach has been suggested to target these multiple pathways in an effort to reduce the possibility of recurrence of CRPC.

Figure 1. Pathways of androgen biosynthesis from cholesterol to DHT

Broken lines show enzymes targeted by inhibitors. DHEA: Dihydroepiandrosterone; DHT: Dihydrotestosterone.

Figure 2. Androgen receptor activation by growth factors and cytokines, intraprostatic androgens and coactivators

Growth factors such as IL-6, ErbB3 and EGFR activate AR through tyrosine kinases such as JAK, Src and FAK, which in turn mediate their activity through Stat3 or β-catenin. In the absence of androgen ligand, intracrine metabolism with the help of enzymes such as AKR1C3 or HSD3B2 occurs where precursors such as DHEA and androstenedione are converted to testosterone and, finally, DHT. Coactivators such as TIF2 provide an alternate mechanism of AR activation in the absence of androgen ligand in a castration-resistant environment. AR: Androgen receptor; DHEA: Dihydroepiandrosterone; DHT: Dihydrotestosterone; EGFR: Epidermal growth factor receptor.