Abstract
BackgroundIntra-tumoral steroidogenesis and constitutive androgen receptor (AR) activity have been associated with castration-resistant prostate cancer (CRPC). This study aimed to examine if CRPC bone metastases expressed higher levels of steroid-converting enzymes than untreated bone metastases. Steroidogenic enzyme levels were also analyzed in relation to expression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables.Methodology/Principal FindingsUntreated, hormone-naïve (HN, n = 9) and CRPC bone metastases samples (n = 45) were obtained from 54 patients at metastasis surgery. Non-malignant and malignant prostate samples were acquired from 13 prostatectomy specimens. Transcript and protein levels were analyzed by real-time RT-PCR, immunohistochemistry and immunoblotting. No differences in steroidogenic enzyme levels were detected between CRPC and HN bone metastases. Significantly higher levels of SRD5A1, AKR1C2, AKR1C3, and HSD17B10 mRNA were however found in bone metastases than in non-malignant and/or malignant prostate tissue, while the CYP11A1, CYP17A1, HSD3B2, SRD5A2, and HSD17B6 mRNA levels in metastases were significantly lower. A sub-group of metastases expressed very high levels of AKR1C3, which was not due to gene amplification as examined by copy number variation assay. No association was found between AKR1C3 expression and nuclear AR staining, tumor cell proliferation or patient outcome after metastases surgery. With only one exception, high AR-V protein levels were found in bone metastases with low AKR1C3 levels, while metastases with high AKR1C3 levels primarily contained low AR-V levels, indicating distinct mechanisms behind castration-resistance in individual bone metastases.Conclusions/SignificanceInduced capacity of converting adrenal-gland derived steroids into more potent androgens was indicated in a sub-group of PC bone metastases. This was not associated with CRPC but merely with the advanced stage of metastasis. Sub-groups of bone metastases could be identified according to their expression levels of AKR1C3 and AR-Vs, which might be of relevance for patient response to 2nd line androgen-deprivation therapy.
Highlights
The first-line treatment for patients with advanced prostate cancer (PC) is androgen deprivation therapy (ADT)
Not known when these steroidogenic enzymes are up-regulated. Are they increased already in previously untreated HN metastases, or as the androgen receptor (AR)-Vs [8] increased as result of castration treatment? One aim of this study was to analyze expression of steroidconverting enzymes potentially involved in synthesis of testosterone and DHT in a set of HN and castration-resistant prostate cancer (CRPC) bone metastases obtained from patients at metastasis surgery
Transcript levels of enzymes in the early steps of steroidogenesis were reduced in HN and CRPC bone metastases as compared to non-malignant prostate tissue (Figure 2); median CYP11A1, CYP17A1, and HSD3B2 mRNA levels were 0.15, 0.29, and 0.32 times in HN and 0.14, 0.32, and 0.31 times in CRPC bone metastases compared to the levels in non-malignant prostate tissue (P = 0.004, 0.025 and 0.071, and P = 0.00004, 0.019 and 0.01, respectively)
Summary
The first-line treatment for patients with advanced prostate cancer (PC) is androgen deprivation therapy (ADT). Some CRPC patients respond to 2nd line ADT and this might be due to intra-tumoral steroidogenesis and production of testosterone, dihydrotestosterone (DHT), or other androgens at levels high enough for AR activation, as reported by others [13,14,15,16]. It is, not known when these steroidogenic enzymes are up-regulated. Steroidogenic enzyme levels were analyzed in relation to expression of constitutively active AR variants (AR-Vs) and to clinical and pathological variables
Sign-in/Register to view highlights & summary Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a callDisclaimer: All third-party content on this website/platform is and will remain the property of their respective owners and is provided on "as is" basis without any warranties, express or implied. Use of third-party content does not indicate any affiliation, sponsorship with or endorsement by them. Any references to third-party content is to identify the corresponding services and shall be considered fair use under The CopyrightLaw.
