Canonical androstenedione reduction is the predominant source of signaling androgens in hormone-refractory prostate cancer.

PURPOSE: It has been recognized for almost a decade that concentrations of signaling androgens sufficient to activate the androgen receptor are present in castration-resistant prostate cancer tissue. The source of these androgens is highly controversial, with three competing models proposed. We, therefore, wished to determine the androgenic potential of human benign and malignant (hormone-naïve and treated) prostate tissue when incubated with various precursors and examine concomitant changes in enzyme expression. EXPERIMENTAL DESIGN: Freshly harvested prostate tissue [benign, hormone-naïve, and hormone-refractory prostate cancer (HRPC)] was incubated in excess concentrations of cholesterol, progesterone, DHEA, androstenedione, or testosterone for 96 hours, and steroid concentrations in the conditioned media measured by gas chromatography-mass spectroscopy. Changes in the expression of androgen synthetic and/or degradative enzymes were determined by expression microarray and qPCR. Significant changes were confirmed in an independent dataset. RESULTS: Of the precursor molecules tested, only incubation with androstenedione gave rise to significant concentrations of signaling androgens. Although this was observed in all tissue types, it occurred to a significantly greater degree in hormone-refractory compared with hormone-naïve cancer. Consistent with this, gene set enrichment analysis of the expression microarray data revealed significant upregulation of 17HSD17B activity, with overexpression of the canonical enzyme AKR1C3 confirmed by qPCR in the same samples and in a publicly available expression dataset. Importantly, we found no evidence to support a significant contribution from either the "backdoor" or "5-α dione" pathway. CONCLUSIONS: Reduction of androstenedione to testosterone by the canonical HSD17B AKR1C3 is the predominant source of signaling androgens in HRPC.

Circulating endothelial cells and progenitors: potential biomarkers of renal cell carcinoma.

OBJECTIVE: To compare the levels of circulating endothelial cells (CECs) and progenitors (CEPs) between tumour-bearing mice and healthy controls, in human renal cell carcinoma (RCC) xenograft models. The secondary objective was to correlate CEC and CEP levels with tumour variables such as tumour volume, weight and vascularity, indicators of disease severity. MATERIALS AND METHODS: Two human RCC xenograft models were used. Tumour cells were inoculated either subcutaneously or beneath the renal subcapsule (orthotopic). Tumour dimensions were recorded and blood samples were taken throughout the experiment, as well as at the end of the experiment, upon which tumours were excised and prepared for histological examination. All blood samples were analysed by flow cytometry. RESULTS: CEC and CEP levels were significantly elevated in tumour-bearing mice compared with healthy controls. In particular, there was a divergence in CEC levels between RCC-bearing mice and controls during early phases in disease, whereas CEP levels were only elevated towards the end. Additionally, CEC levels correlated with tumour variables such as tumour volume, when tumour volume was <200 mm³ and with tumour vascularity in certain models. CEP levels did not correlate significantly with most tumour variables examined. CONCLUSION: In human RCC xenograft models, CEC levels showed promise as an adjuvant biomarker in evaluating disease burden. RESULTS from correlating CEC levels with tumour variables such as tumour volume, weight and vascularity suggested that CEC levels were a better prognostic indicator during early phases of tumour growth. CEP levels were elevated in tumour-bearing mice compared with controls; however, enumerated numbers were small and require further validation in future studies.