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Endocrinology |
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.
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Abstract |
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Introduction |
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The most parsimonious explanation for persistent AR signaling in the setting of anorchid serum testosterone concentrations is the continued presence of intracellular androgens at levels adequate to activate wild-type AR. Studies of primary prostate tissues after medical or surgical castration have measured intraprostatic testosterone or the active metabolite dihydrotestosterone (DHT) in quantities sufficient to stimulate AR-mediated gene expression and protein synthesis (6–8). Whereas the source of residual tissue androgens in the setting of anorchid serum testosterone levels has not been established, intracrine androgen production (the local synthesis or conversion of androgens within a tissue) may play a critical role in maintaining tumoral androgen levels (9). In this regard, the increased expression of genes mediating the conversion of adrenal androgens to testosterone has been reported in bone marrow metastases from men with castration-resistant prostate cancer (10).
In this study, we sought to determine if physiologically relevant androgen levels are present in metastatic soft tissue tumor deposits from patients with castration-resistant prostate cancer. To ascertain the potential for intracrine androgen synthesis, we comprehensively evaluated the expression of genes encoding each enzyme in the steroidogenic pathway leading from cholesterol to testosterone, DHT, and their metabolites. We show that metastatic human prostate cancers from anorchid men express transcripts encoding androgen-synthesizing enzymes and sustain intratumoral androgens at concentrations capable of activating AR target genes and maintaining tumor cell survival.
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Materials and Methods |
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LuCaP human prostate cancer xenografts. The establishment and maintenance of the LuCaP 23 and 35 xenografts from the lymph node metastases of two individuals with castration-resistant prostate cancer was performed as previously described (13, 14). The LuCaP 96 xenograft was generated from a specimen obtained by transurethral resection of the prostate from a patient 1 mo before documentation of castration-resistant prostate cancer. All lines were established as a component of the University of Washington Rapid Autopsy program, and all lines contain wild-type AR, produce serum PSA, and respond to castration with the subsequent development of castration-resistant or androgen-independent growth. All experiments involving animals were performed in accordance with protocols approved by the University of Washington Institutional Animal Care Use Committee. Castration-sensitive and castration-resistant strains of each xenograft were grown, respectively, in three to five intact (noncastrate) and three to five castrate male CB-17 SCID mice (Charles River Laboratories). Prior terminology describes these tumor phenotypes as androgen dependent and androgen independent, but our data indicate that these terms are misnomers and thus we use the castration-sensitive and castration-resistant nomenclature. When tumors reached 
500 mg in size, the animals were euthanized according to institutional protocol and the xenografts were harvested and flash frozen for determination of tissue androgens and extraction of total RNA. Samples of normal kidney and liver were simultaneously obtained from each intact and castrate animal for determination of tissue androgen levels in nontumor tissue. In addition, a set of LuCaP 35 xenografts were harvested from five mice in which castration-sensitive tumors had been subjected to castration-induced regression with subsequent androgen-independent or castration-resistant regrowth (CS
CR).
Steroid measurements. Androgen levels were determined by mass spectrometry (MS) using methods we have recently described (15). In brief, frozen tissue samples were individually thawed, weighed, and homogenized in PBS. The homogenates were extracted with 8 mL of diethyl ether, and the organic phase was decanted after freezing the aqueous phase in a dry ice/ethanol bath. The organic phase was dried and concentrated with 2 x 0.5 mL ether washes under a stream of purified air. Each individual concentrated extract was dissolved in 1.0 mL redistilled ethanol and stored at –20°C until MS analysis. Samples were added to internal standards: 50 pg of deuterated (D3)-DHT and D3-testosterone, vortexed briefly, and evaporated to dryness. The residue was then reconstituted in 0.5 mL of water before extraction with methylene chloride. The organic phase was removed under nitrogen, and the sample was dissolved in 0.1 mol/L hydroxylamine hydrochloride in 50% methanol/water, vortexed, and heated at 60° for 1 h. Standards for DHT and testosterone were prepared in parallel. The resulting oximes were analyzed by LC-MS-MS using a Waters Aquity HPLC and Premier XE mass spectrometer. Ions monitored were 350>309 and 347>306 for DHT-IS and DHT, respectively, and 307>124 and 304>124 for testosterone-IS and testosterone, respectively. This procedure resulted in a lower limit of quantitation of 100 and 500 attomol on column for testosterone and DHT, respectively. Intraassay coefficients of variation generated using human serum for high-range, mid-range, and low-range samples were 3.5%, 3.1%, and 3.8% for testosterone and 6.3%, 4.3%, and 15.8% for DHT, respectively.
RNA isolation and quantitative reverse transcription–PCR. Samples were individually homogenized in Trizol (Invitrogen), and total RNA was isolated using the RNeasy kit (Qiagen, Inc.), followed by treatment with DNase using the Qiagen RNase-Free DNase Set (Qiagen, Inc.). RNA was quantitated in a Gene-Spec III spectrophotometer (Hitachi), and RNA integrity was evaluated using gel electrophoresis. cDNA was generated from each sample using 2 to 5 µg of total RNA in an oligo dT–primed reverse transcription reaction. Quantitative reverse transcription–PCR (qRT-PCR) reactions were performed in triplicate using an Applied Biosystems 7700 sequence detector with 5 ng of cDNA, 1 µmol/L of each primer pair, and SYBR Green PCR master mix (Applied Biosystems). Primers specific for genes of interest were designed using the Web-based primer design service Primer36 provided by the Whitehead Institute for Biomedical Research, except for AKR1C1, AKR1C2, AKR1C3 (16), and 17BHSD10 (17) for which previously published primer sequences were used. Sequences are provided in Supplementary Table S1.
Statistical analyses. To account for having multiple samples (i.e., two to four metastatic deposits) with replicate measurements from the same patient, statistical comparison of androgen levels in the human prostate and metastatic autopsy samples was performed using the following linear mixed effects model: [yij = β0 + bi + β1xij + 
ij], where yij is the androgen level (testosterone, DHT), bi is a random intercept with distribution N(0, 
2b), xij indicates tissue type, and ij is an individual-specific error term with distribution N(0, 2); here, i indexes patients and j indexes patient-specific observations. Furthermore, we assume that bi and ij are independent. This model accounts for within-individual correlations, which are assumed to be the same for each individual, and was used to derive P values for the comparison of mean tissue androgen levels among sample types. For each of the three xenograft lines, differences in androgen levels between the castration-sensitive and castration-resistant tumors were assessed by unpaired two sample t tests. P values of <0.05 were considered significant.
For analysis of the qRT-PCR data, the mean cycle threshold (Ct) obtained for each gene was normalized to the expression of the housekeeping gene RPL13A in the same sample (the 
Ct). Reactions with Cts of >35 were considered undetectable for that transcript, and the specificity of amplification in each reaction was assessed based on the melting point of the dissociation curve. Unpaired two-sample t tests were used to compare the mean Cts for each gene between the primary prostate cancers (n = 8) and metastatic autopsy samples (n = 16–22). Welch's modification of the t test was used if the F test to compare sample variances was significant (but was only applicable to one gene, UGT2B15). P values of <0.05 were considered significant. The fold change was calculated by unlogging the difference in mean Cts between the sample groups. Similarities among the human prostate and metastatic autopsy samples based on expression of steroidogenic gene transcripts were assessed by unsupervised, hierarchical, average linkage clustering using Cluster 3.0 software7 and plotted using TreeView version 1.6.8 This program organizes genes and samples into a tree structure based on their similarity, in which items are joined by short branches if they are similar to each other and by increasingly longer branches as their similarity decreases. In average linkage clustering, the distance between two items x and y is the mean of all pairwise distances between items contained in x and y and therefore provides a visual estimate of the similarity among different items in a sample.
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Results |
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50 ng/dL). Castration-resistant tumors generally showed intense nuclear staining for AR, as well as strong cytoplasmic PSA reactivity (Fig. 1A
), although heterogeneity in expression was found in a subset of tumors as we and others have previously described (11, 18). Quantification of AR, PSA, and FKBP5 gene expression by qRT-PCR showed increased expression of AR and equivalent levels of PSA and FKBP5 in the castration-resistant metastases compared with benign prostate tissue and primary prostate cancers (Fig. 1B). These data are consistent with prior reports (19–22) and show the continued activity of the AR signaling axis in most castration-resistant tumors despite anorchid serum androgen levels.
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Testosterone concentrations in metastatic prostate tumors from anorchid patients ranged from 0.2 to 1.78 ng/g (Fig. 2A
) up to 4-fold higher than levels in noncancerous control tissues acquired at autopsy or in primary prostate cancer samples from eugonadal patients (Table 1
; P < 0.0001). Higher levels of testosterone and DHT were observed in primary prostate cancers compared with paired benign prostate tissues (P = 0.01 for testosterone and P < 0.0001 for DHT; Fig. 2A and B; Table 1). Primary prostate tumors from eugonadal patients retained the 10:1 to 20:1 ratio of DHT to testosterone observed in benign prostate tissues. In contrast, this ratio was markedly reversed in metastatic tumors, which displayed a DHT/testosterone ratio of 0.25:1, consistent with a prior report evaluating locally recurrent, castration-resistant primary prostate tumors (7). Importantly, the testosterone concentrations measured in the prostate cancer metastases are higher than those in the nonprostatic control tissues, exceed mass equivalent concentrations in the serum of these anorchid men, and are well within a range known to stimulate the AR and support prostate cancer cell proliferation (22–24).
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Intratumoral androgen levels in prostate cancer xenografts grown in intact and castrate mice. We next evaluated androgen levels in a series of prostate cancer xenografts grown in noncastrate (intact) and castrate male SCID mice. Xenografts were derived from castration-resistant lymph node metastases (LuCap23.1 and LuCap35) or primary prostate tumor (LuCap96). Castration-sensitive xenografts were passaged in intact mice, whereas isogenic castration-resistant variants were maintained in castrate hosts. Remarkably, testosterone levels in the LuCap23.1 and LuCap35 xenografts derived from lymph node metastases were equivalent whether tumors were grown in castrate or intact mice (Fig. 4 ; Supplementary Table S2). Testosterone levels in the prostate-derived LuCap96 were higher in tumors from intact eugonadal mice, but remained easily detectable in the castration-resistant tumors from the castrate hosts. Similarly, while more heterogeneous among replicates, DHT levels in the majority of castration-resistant xenograft samples from castrate mice were equivalent or higher than those measured in the isogenic castration-sensitive xenografts grown in intact mice. Testosterone and DHT levels in normal tissue samples (kidney and muscle) from either the intact or castrate host animals did not approach those in tumor tissue.
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Discussion |
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Our data show that transcripts encoding the full complement of enzymes involved in the sequential biosynthesis of testosterone, and DHT from cholesterol precursors were expressed in the majority of castration-resistant metastatic tumors examined. Furthermore, the specific steroidogenic genes altered in our data confirm and extend previous studies of gene expression in castration-resistant bone marrow metastases (10) to include up-regulated expression of CYP17A1, a critical enzyme mediating sequential steps in the production of adrenal androgens from progestins, as well as increased expression of HSD17B3, which mediates the same metabolic step as AKR1C3, the conversion of androstenedione to testosterone (29). A clear limitation of our study is the degree to which transcript alterations correlate with changes in biosynthetic enzyme activity. Whereas demonstration of enzymatic function is beyond the scope of the present work, the presence of transcripts encoding each gene in the androgen biosynthetic pathway is a necessary prerequisite to steroidogenesis, and a comprehensive assessment of genes in this pathway has not been previously reported in prostate cancer metastases.
The increased expression of AR transcripts in the castration-resistant metastases may be of particular importance in promoting tumor cell growth at the androgen levels detected in these samples. Gregory et al. have shown that prostate cancer cell lines derived from recurrent tumors show increased expression and stability of the AR, in association with an increased sensitivity to proliferation at low levels of DHT. Furthermore, Chen et al. have shown that increased AR expression is instrumental in the progression from androgen-dependent to castration-resistant growth in a xenograft model, with the degree of AR up-regulation observed sufficient to allow tumor cell proliferation in 80% lower androgen concentrations (3). Importantly, ligand binding was required for hormone refractory growth, and modest increases in AR expression were sufficient to support signaling in a low androgen environment. Conversely, AR protein expression was equivalent in a series of locally recurrent prostate tumors compared with benign prostate epithelium (7). As such, increased AR message may not necessarily result in uniformly higher AR protein expression, but may contribute to maintaining AR protein expression at levels required for sustaining tumor cell growth.
Our study found a marked reversal in the ratio of testosterone to DHT in the castration-resistant tumor metastases compared with the primary prostate tissues. This observation is consistent with the study of Mohler et al., in which testosterone levels in locally recurrent, castration-resistant primary prostate tumors were maintained at levels found in untreated benign prostatic hyperplasia tissues whereas DHT levels were significantly decreased (7). Although DHT is 10-fold more potent than testosterone in binding and activating AR (30), kinetic experiments have shown that testosterone at high concentrations interacts with AR similarly to DHT (31). In studies evaluating androgen-induced prostate regrowth in castrated rats, Wright et al. found that 1.6-fold to 1.9-fold increases in testosterone compared with DHT were sufficient to achieve comparable measures of prostate regrowth (32). Conversely, Xu et al. have shown that dutasteride treatment inhibited the growth of Dunning R-3327H rat prostate tumors and LNCaP human prostate xenografts, despite a concomitant 2-fold increase in tissue testosterone levels. However, whereas dutasteride reduced tumor DHT levels to essentially the same nadir as castration, it did not produce the same magnitude of tumor growth inhibition as castration. Moreover, the combination of dutasteride plus castration produced greater growth inhibition of LNCaP xenografts than either castration or dutasteride alone, suggesting that whereas testosterone may not be as potent as DHT, it is capable of stimulating prostate tumor growth. In earlier studies evaluating the growth response of androgen-dependent xenografts, Van Weerden et al. found that androgen-induced increases in tumor cell growth only occurred when tissue androgen levels exceeded a critical threshold value, corresponding to 0.9 ng/g of DHT (33). Although higher than the DHT levels observed in the tumor metastases in our study, this value may reflect the androgen dependence of the xenografts evaluated by van Weerden and does not preclude the possibility of tumor cell stimulation at the lower androgen levels detected in the castration-resistant metastases.
The detection of testosterone as the primary androgen in the castration-resistant metastases may reflect the subtotal decrease in tumoral SRD5A activity that has been consistently observed in prostate tumors since its original demonstration in lymph node metastases and primary prostate cancers by Klein et al. (34) More recently, studies have shown a decrease in SRD5A2 expression in neoplastic compared with benign prostate tissues, accompanied by a relative shift in expression and enzymatic activity to SRD5A1 in primary and recurrent prostate tumors (10, 35–39). These findings are consistent with our measurements of 9-fold decrease and 2.5-fold increase in SRD5A2 and SRD5A1 expression, respectively, in the tumor metastases. Alternatively, the concentrations of DHT detected in the tumor metastases we analyzed may actually be an underestimate of the in vivo tumor androgen levels, as several studies have shown that DHT levels in autopsy samples may be factitiously low due to ongoing postmortem androgen metabolism or degradation (40, 41). We cannot exclude this possibility, which may also underlie the relatively higher levels of DHT observed in the prostate cancer xenografts, as these tissues can be immediately frozen upon harvesting. Interestingly, the androgen levels detected in the castration-resistant xenografts suggests these tissues may be capable of de novo androgen biosynthesis, as some (albeit not all) studies have suggested that castrate rodents do not make adrenal androgens due to a lack of CYP17 expression in the rodent adrenal gland (42, 43).
In conclusion, we propose that metastatic prostate cancers may adapt to low systemic testosterone levels by maintaining intratumoral androgens through the modulation of enzymes involved in intracrine steroidogenesis and androgen catabolism. Our data suggest that secondary hormonal manipulations and pharmacologic inhibitors of androgen biosynthesis derive a component of their activity by directly targeting intratumoral androgen production. This mechanism may explain the relatively high response rates observed in recent clinical studies evaluating specific CYP17A1 inhibitors for castration-resistant prostate cancer when compared with historical rates observed with adrenalectomy (28, 44–46). Moreover, elevated tumoral androgen levels may underlie the lack of substantial survival benefit associated with the use of AR antagonists, as agents such as bicalutamide have an affinity for the AR which is 30-fold lower than the endogenous ligand (47, 48). These observations strongly suggest that improving clinical outcomes in castration-resistant prostate cancer will require combinatorial treatment strategies designed to abrogate intracrine and systemic contributions to the tumoral androgen axis. Furthermore, the application of agents targeting intratumoral androgen production during the treatment of androgen-sensitive prostate cancer may delay or prevent the progression to castration-resistant disease.
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Disclosure of Potential Conflicts of Interest |
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Acknowledgments |
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The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact.
We thank the patients and their families who made this work possible through their altruistic donation of tissues, Roger Coleman for technical assistance, Ilsa Coleman and Roman Gulati for providing assistance with statistical analyses, and members of University of Washington Urology Department and Tissue Acquisition Necropsy team for assisting with sample collections.
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Footnotes |
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R.B. Montgomery and E.A. Mostaghel contributed equally to this work.
6 www.cgihttp://jura.wi.mit.edu/rozen/papers/rozen-and-skaletsky-2000-primer3.pdf 
7 http://bonsai.ims.u-tokyo.ac.jp/-mdehoon/software/cluster/software.htm
8 http://rana.lbl.gov/EisenSoftware.htm
Received 1/21/08. Revised 2/28/08. Accepted 3/10/08.
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-dihydrotestosterone interact differently with the androgen receptor to enhance transcription of the MMTV-CAT reporter gene. Mol Cell Endocrinol 1992;88:15–22.[CrossRef][Medline]-reductase. Endocrinology 1999;140:4509–15.-reductase 2 in human prostate cancer: implications for finasteride therapy of prostate carcinoma. Prostate 2003;57:134–9.[CrossRef][Medline]-reductase type 1 and type 2 levels during development and progression of prostate cancer. Prostate 2005;63:231–9.[CrossRef][Medline]}-Reductase Isozymes I and II in Recurrent Prostate Cancer. Clin Cancer Res 2005;11:4365–71. hydroxylase C17,20-lyase inhibitor in androgen-independent prostate cancer (AiPC). 2007 ASCO Annual Meeting Proceedings Part I. J Clin Oncol 2007;25:5064.This article has been cited by other articles:
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  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]
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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]
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 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]
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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]
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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]
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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]
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 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]
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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]
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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]
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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]
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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]
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