Author(s): Vis AN, Schrder FH
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Abstract OBJECTIVE: Knowledge of the molecular and cellular changes that occur during the transition of hormone-naïve to castration-resistant prostate cancer (CRPC) is increasing rapidly. This might provide a window of opportunity for (future) drug development, and for treating patients with these potential devastating states of disease. The objective of this review is to provide an understanding of the mechanisms that prostate cancer cells use to bypass androgen-deprived conditions. METHODS: We searched PubMed for experimental and clinical studies that describe the molecular changes that lead to CRPC. RESULTS: CRPC remains dependent on a functional androgen receptor (AR), AR-mediated processes, and on the availability of intraprostatic intracellular androgens. CRPCs might acquire different (molecular) mechanisms that enable them to use intracellular androgens more efficiently (AR amplification, AR protein overexpression, AR hypersensitivity), use alternative splice variants of the AR protein to mediate androgen-independent AR functioning, and have altered co-activator and co-repressor gene and protein expression. Furthermore, CRPCs might have the ability to synthesise androgens de novo from available precursors through a renewed and up-regulated synthesis of steroid-hormone converting enzymes. Blocking of enzymes key to de novo androgen synthesis could be an alternative means to treat patients with advanced and/or metastatic disease. CONCLUSION: In CRPC, prostate cancer cells still rely on intracellular androgens and on an active AR for growth and survival. CRPCs have gained mechanisms that enable them to use steroids from the circulation more efficiently through altered gene expression, and through a renewed and up-regulated synthesis of steroid hormone-converting enzymes. Additionally, CRPCs might synthesise AR isoforms that enable AR mediated processes independent from available androgens.
This article was published in BJU Int
and referenced in Journal of Steroids & Hormonal Science