One mechanism active in castration-resistant prostate cancer (CRPC) is the ability for CRPC cells to upregulate their steroidogenic biosynthetic enzymes and generate intracrine androgens to activate the androgen receptor. This study determined the steroidogenic and metabolic potential of freshly cultured CRPC tissue compared with BPH patient tissue.Freshly resected BPH and CaP tissue was obtained from 15 patients undergoing a TURP. Of these, 7 patients had BPH only while 8 patients had pathologically confirmed CaP with clinical CRPC. Tissue was separately cultured in an excess of cholesterol, progesterone, androstenedione, DHEA or testosterone for 4 days. Samples were isolated for steroid metabolite identification by gas chromatography/mass spec. Steroidogenic enzyme gene expression was also determined from total RNA from tissues using the HumanHT-12 v4 BeadChip.
Analysis of 15 different steroid metabolites indicated that BPH tissue possessed the capacity to initiate de novo steroidogenesis and synthesize testosterone from cholesterol. However, this was noted to occur at very low levels. This ability was not apparent in the CRPC tissue, as there was no detectable testosterone or DHT production from cholesterol or progesterone. They also found very low levels of testosterone produced with DHEA as the precursor, but this was upregulated in the CRPC samples. In BPH cultures, androstenedione was efficiently converted to testosterone at levels 200-fold higher than with any other precursor. This occurred at a level 500-fold higher in CRPC tissue. Testosterone was converted to DHT in BPH tissue and this conversion was upregulated 2.5-fold in the cultures from CRPC patients. Steroidogenic enzyme expression levels correlated with the observed metabolic profiles of the tissue samples.
They concluded that the most efficient precursor of prostate intracrine testosterone production is the adrenal androgen, androstendione and that de novo steroidogenesis plays a very limited role.
Presented by Christopher M. Hovens, MD, et al. at the 26th Annual European Association of Urology (EAU) Congress - March 18 - 21, 2011 - Austria Centre Vienna, Vienna, Austria