Maintenance of intratumoral androgens in metastatic prostate cancer

A mechanism for castration-resistant tumor growth

R. Bruce Montgomery, Elahe A. Mostaghel, Robert Vessella, David Hess, Thomas F. Kalhorn, Celestia S. Higano, Lawrence D. True, Peter S. Nelson

    Research output: Contribution to journalArticle

    912 Citations (Scopus)

    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 steroidogenesismay 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.

    Original languageEnglish (US)
    Pages (from-to)4447-4454
    Number of pages8
    JournalCancer Research
    Volume68
    Issue number11
    DOIs
    StatePublished - Jun 1 2008

    Fingerprint

    Castration
    Androgens
    Prostatic Neoplasms
    Maintenance
    Growth
    Prostate
    Neoplasms
    Neoplasm Metastasis
    Androgen Receptors
    Heterografts
    Enzymes
    Confidence Intervals
    Tumor Microenvironment
    Genes
    Reverse Transcription
    Testosterone
    Mass Spectrometry
    Cell Survival
    Polymerase Chain Reaction
    Therapeutics

    ASJC Scopus subject areas

    • Cancer Research
    • Oncology

    Cite this

    Montgomery, R. B., Mostaghel, E. A., Vessella, R., Hess, D., Kalhorn, T. F., Higano, C. S., ... Nelson, P. S. (2008). Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth. Cancer Research, 68(11), 4447-4454. https://doi.org/10.1158/0008-5472.CAN-08-0249

    Maintenance of intratumoral androgens in metastatic prostate cancer : A mechanism for castration-resistant tumor growth. / Montgomery, R. Bruce; Mostaghel, Elahe A.; Vessella, Robert; Hess, David; Kalhorn, Thomas F.; Higano, Celestia S.; True, Lawrence D.; Nelson, Peter S.

    In: Cancer Research, Vol. 68, No. 11, 01.06.2008, p. 4447-4454.

    Research output: Contribution to journalArticle

    Montgomery, RB, Mostaghel, EA, Vessella, R, Hess, D, Kalhorn, TF, Higano, CS, True, LD & Nelson, PS 2008, 'Maintenance of intratumoral androgens in metastatic prostate cancer: A mechanism for castration-resistant tumor growth', Cancer Research, vol. 68, no. 11, pp. 4447-4454. https://doi.org/10.1158/0008-5472.CAN-08-0249
    Montgomery, R. Bruce ; Mostaghel, Elahe A. ; Vessella, Robert ; Hess, David ; Kalhorn, Thomas F. ; Higano, Celestia S. ; True, Lawrence D. ; Nelson, Peter S. / Maintenance of intratumoral androgens in metastatic prostate cancer : A mechanism for castration-resistant tumor growth. In: Cancer Research. 2008 ; Vol. 68, No. 11. pp. 4447-4454.
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    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 steroidogenesismay 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.",
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