Maintenance of Intratumoral Androgens in Metastatic Prostate Cancer: A Mechanism for Castration-Resistant Tumor Growth

TLDR

Advanced prostate cancer therapy relies on systemic androgen suppression and AR blockade, yet nearly all patients develop castration‑resistant disease even when serum androgens are undetectable. The authors hypothesize that intratumoral steroidogenesis sustains castration‑resistant growth and that effective treatment will require agents targeting intracrine androgen pathways. They quantified intratumoral androgen concentrations and steroidogenic enzyme transcripts in benign prostate, untreated primary tumors, castration‑resistant metastases, and xenografts using mass spectrometry and quantitative RT‑PCR. Metastatic tumors from anorchid men exhibited higher intratumoral testosterone and upregulated steroidogenic genes, and xenografts maintained these androgen levels in castrate hosts, indicating that intracrine steroidogenesis enables AR activation and tumor survival despite low circulating androgens. Cancer Research 2008;68(11):4447–54.

Abstract

Abstract Therapy for advanced prostate cancer centers on suppressing systemic androgens and blocking activation of the androgen receptor (AR). Despite anorchid serum androgen levels, nearly all patients develop castration-resistant disease. We hypothesized that ongoing steroidogenesis within prostate tumors and the maintenance of intratumoral androgens may contribute to castration-resistant growth. Using mass spectrometry and quantitative reverse transcription–PCR, we evaluated androgen levels and transcripts encoding steroidogenic enzymes in benign prostate tissue, untreated primary prostate cancer, metastases from patients with castration-resistant prostate cancer, and xenografts derived from castration-resistant metastases. Testosterone levels within metastases from anorchid men [0.74 ng/g; 95% confidence interval (95% CI), 0.59–0.89] were significantly higher than levels within primary prostate cancers from untreated eugonadal men (0.23 ng/g; 95% CI, 0.03–0.44; P < 0.0001). Compared with primary prostate tumors, castration-resistant metastases displayed alterations in genes encoding steroidogenic enzymes, including up-regulated expression of FASN, CYP17A1, HSD3B1, HSD17B3, CYP19A1, and UGT2B17 and down-regulated expression of SRD5A2 (P < 0.001 for all). Prostate cancer xenografts derived from castration-resistant tumors maintained similar intratumoral androgen levels when passaged in castrate compared with eugonadal animals. Metastatic prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and maintain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival. We conclude that intracrine steroidogenesis may permit tumors to circumvent low levels of circulating androgens. Maximal therapeutic efficacy in the treatment of castration-resistant prostate cancer will require novel agents capable of inhibiting intracrine steroidogenic pathways within the prostate tumor microenvironment. [Cancer Res 2008;68(11):4447–54]