This Article Full Text Full Text (PDF) Supplementary Data Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Montgomery, R. B. Articles by Nelson, P. S. Search for Related Content PubMed PubMed Citation Articles by Montgomery, R. B. Articles by Nelson, P. S.

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

Departments of ¹ Medicine, ² Urology, and ³ Pathology, University of Washington School of Medicine; ⁴ Divisions of Human Biology and Clinical Research, Fred Hutchinson Cancer Research Center, Seattle, Washington and ⁵ Oregon National Primate Research Center, Oregon Health and Sciences University, Beaverton, Oregon

Requests for reprints: Peter S. Nelson, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, MS D4-100, Seattle, WA 91809-1024. Phone: 206-667-3377; Fax: 206-667-2917; E-mail: pnelson{at}fhcrc.org.

Key Words: prostate cancer • castration-resistant • hormone refractory • intracrine • steroidogenesis

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]

This article has been cited by other articles:

				K. K. Waltering, M. A. Helenius, B. Sahu, V. Manni, M. J. Linja, O. A. Janne, and T. Visakorpi Increased Expression of Androgen Receptor Sensitizes Prostate Cancer Cells to Low Levels of Androgens Cancer Res., October 15, 2009; 69(20): 8141 - 8149. [Abstract] [Full Text] [PDF]

				R. R. Chhipa, K.-S. Lee, S. Onate, Y. Wu, and C. Ip Prx1 Enhances Androgen Receptor Function in Prostate Cancer Cells by Increasing Receptor Affinity to Dihydrotestosterone Mol. Cancer Res., September 1, 2009; 7(9): 1543 - 1552. [Abstract] [Full Text] [PDF]

				G. Attard, A. H.M. Reid, R. A'Hern, C. Parker, N. B. Oommen, E. Folkerd, C. Messiou, L. R. Molife, G. Maier, E. Thompson, et al. Selective Inhibition of CYP17 With Abiraterone Acetate Is Highly Active in the Treatment of Castration-Resistant Prostate Cancer J. Clin. Oncol., August 10, 2009; 27(23): 3742 - 3748. [Abstract] [Full Text] [PDF]

				C. Cai, H. Wang, Y. Xu, S. Chen, and S. P. Balk Reactivation of Androgen Receptor-Regulated TMPRSS2:ERG Gene Expression in Castration-Resistant Prostate Cancer Cancer Res., August 1, 2009; 69(15): 6027 - 6032. [Abstract] [Full Text] [PDF]

				K. E. Knudsen and H. I. Scher Starving the Addiction: New Opportunities for Durable Suppression of AR Signaling in Prostate Cancer Clin. Cancer Res., August 1, 2009; 15(15): 4792 - 4798. [Abstract] [Full Text] [PDF]

				J. Y. Chun, N. Nadiminty, S. Dutt, W. Lou, J. C. Yang, H.-J. Kung, C. P. Evans, and A. C. Gao Interleukin-6 Regulates Androgen Synthesis in Prostate Cancer Cells Clin. Cancer Res., August 1, 2009; 15(15): 4815 - 4822. [Abstract] [Full Text] [PDF]

				L. R. Molife, G. Attard, P. C. Fong, V. Karavasilis, A. H. M. Reid, S. Patterson, C. E. Riggs Jr, C. Higano, W. M. Stadler, W. McCulloch, et al. Phase II, two-stage, single-arm trial of the histone deacetylase inhibitor (HDACi) romidepsin in metastatic castration-resistant prostate cancer (CRPC) Ann. Onc., July 16, 2009; (2009) mdp270v1. [Abstract] [Full Text] [PDF]

				C. Cai, D. C. Portnoy, H. Wang, X. Jiang, S. Chen, and S. P. Balk Androgen Receptor Expression in Prostate Cancer Cells Is Suppressed by Activation of Epidermal Growth Factor Receptor and ErbB2 Cancer Res., June 15, 2009; 69(12): 5202 - 5209. [Abstract] [Full Text] [PDF]

				G. Attard, A. H.M. Reid, D. Olmos, and J. S. de Bono Antitumor Activity with CYP17 Blockade Indicates That Castration-Resistant Prostate Cancer Frequently Remains Hormone Driven Cancer Res., June 15, 2009; 69(12): 4937 - 4940. [Abstract] [Full Text] [PDF]

				R. M. Attar, C. H. Takimoto, and M. M. Gottardis Castration-Resistant Prostate Cancer: Locking Up the Molecular Escape Routes Clin. Cancer Res., May 15, 2009; 15(10): 3251 - 3255. [Abstract] [Full Text] [PDF]

				D. J. Vander Griend, L. Antony, S. L. Dalrymple, Y. Xu, S. B. Christensen, S. R. Denmeade, and J. T. Isaacs Amino acid containing thapsigargin analogues deplete androgen receptor protein via synthesis inhibition and induce the death of prostate cancer cells Mol. Cancer Ther., May 1, 2009; 8(5): 1340 - 1349. [Abstract] [Full Text] [PDF]

				J.-C. Pignon, B. Koopmansch, G. Nolens, L. Delacroix, D. Waltregny, and R. Winkler Androgen Receptor Controls EGFR and ERBB2 Gene Expression at Different Levels in Prostate Cancer Cell Lines Cancer Res., April 1, 2009; 69(7): 2941 - 2949. [Abstract] [Full Text] [PDF]

				Q. Wei, R. Galbenus, A. Raza, R. L. Cerny, and M. A. Simpson Androgen-Stimulated UDP-Glucose Dehydrogenase Expression Limits Prostate Androgen Availability without Impacting Hyaluronan Levels Cancer Res., March 15, 2009; 69(6): 2332 - 2339. [Abstract] [Full Text] [PDF]

				R. Hu, T. A. Dunn, S. Wei, S. Isharwal, R. W. Veltri, E. Humphreys, M. Han, A. W. Partin, R. L. Vessella, W. B. Isaacs, et al. Ligand-Independent Androgen Receptor Variants Derived from Splicing of Cryptic Exons Signify Hormone-Refractory Prostate Cancer Cancer Res., January 1, 2009; 69(1): 16 - 22. [Abstract] [Full Text] [PDF]

				H. Shen, N. Powers, N. Saini, C. E.S. Comstock, A. Sharma, K. Weaver, M. P. Revelo, W. Gerald, E. Williams, W. J. Jessen, et al. The SWI/SNF ATPase Brm Is a Gatekeeper of Proliferative Control in Prostate Cancer Cancer Res., December 15, 2008; 68(24): 10154 - 10162. [Abstract] [Full Text] [PDF]

				N. Sharifi, E. M. Hurt, S. B. Thomas, and W. L. Farrar Effects of Manganese Superoxide Dismutase Silencing on Androgen Receptor Function and Gene Regulation: Implications for Castration-Resistant Prostate Cancer Clin. Cancer Res., October 1, 2008; 14(19): 6073 - 6080. [Abstract] [Full Text] [PDF]