In situ androgen producing enzymes in human prostate cancer

in Endocrine-Related Cancer

Androgens have been proposed to be actively produced in situ in human prostate cancer. These locally produced androgens have also been considered to play important roles in the pathogenesis and development of prostate cancer. Therefore, it is important to examine the status of this in situ androgen metabolism and/or synthesis in detail in order to improve the clinical response to hormonal therapy in patients diagnosed with prostate cancer. Several studies have previously demonstrated the expression of androgen-producing enzymes such as 5α-reductase types 1 and 2, and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5), in human prostate carcinoma cells. However, their biological significance has remained largely unknown. In this study, we evaluated the immunoreactivities of these steroidogenic enzymes in human prostate cancer obtained from surgery (n=70), and correlated the findings with clinicopathological features of the patients. 17β-HSD5 immunoreactivity was detected in 54 cases (77%), 5α-reductase type 1 in 51 cases (73%) and 5α-reductase type 2 in 39 cases (56%). 5α-reductase type 2 immunoreactivity was significantly correlated with that of androgen receptor (AR), and 17β-HSD5 positive cases were significantly associated with clinical stage (TNM stage pT3 vs pT2). These data all suggest that androgen-producing enzymes, such as 5α-reductase type 1 and type 2, and 17β-HSD5 are expressed in a majority of prostate cancers, and are involved in the local production and actions of androgens in prostate cancers.

Abstract

Androgens have been proposed to be actively produced in situ in human prostate cancer. These locally produced androgens have also been considered to play important roles in the pathogenesis and development of prostate cancer. Therefore, it is important to examine the status of this in situ androgen metabolism and/or synthesis in detail in order to improve the clinical response to hormonal therapy in patients diagnosed with prostate cancer. Several studies have previously demonstrated the expression of androgen-producing enzymes such as 5α-reductase types 1 and 2, and 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5), in human prostate carcinoma cells. However, their biological significance has remained largely unknown. In this study, we evaluated the immunoreactivities of these steroidogenic enzymes in human prostate cancer obtained from surgery (n=70), and correlated the findings with clinicopathological features of the patients. 17β-HSD5 immunoreactivity was detected in 54 cases (77%), 5α-reductase type 1 in 51 cases (73%) and 5α-reductase type 2 in 39 cases (56%). 5α-reductase type 2 immunoreactivity was significantly correlated with that of androgen receptor (AR), and 17β-HSD5 positive cases were significantly associated with clinical stage (TNM stage pT3 vs pT2). These data all suggest that androgen-producing enzymes, such as 5α-reductase type 1 and type 2, and 17β-HSD5 are expressed in a majority of prostate cancers, and are involved in the local production and actions of androgens in prostate cancers.

Introduction

Androgens play important roles in the pathogenesis of prostate cancer (Lopez-Otin & Diamandis 1998). In addition, the in situ production of androgens has been proposed to play a critical role in the pathogenesis and/ or development of human prostate cancer (Lopez-Otin & Diamandis 1998). Moreover, suppression of androgen secretion and/or a blockade of their actions represent the basis for many forms of effective hormonal treatment of patients diagnosed with prostate cancer (Negri-Cesi et al. 1998). Therefore, it is very important to examine the status of expression of androgen metabolizing and/or producing enzymes in prostate cancer patients in order to obtain a better understanding of the possible roles of in situ androgen production and its action.

Testosterone, the main circulating androgen, is converted in prostate cancer tissues by 5α-reductases into the bioactive and potent androgen, 5α-dihydro-testosterone (DHT) (Russell & Wilson 1994). Therefore, 5α-reductases are considered to play important roles as local regulators of androgen and other sex steroid actions in prostate cancer tissues. The type 1 isozyme of 5α-reductase is located on the distal short arm of chromosome 5, and is mainly expressed in the liver and skin (Thigpen et al. 1993, Russell & Wilson 1994). The type 2 isozyme of 5α-reductase is located in band p23 of chromosome 2, and is, in addition to its strong expression in the liver, also markedly expressed in the prostate, seminal vesicle, and epididymis (Thigpen et al. 1992, Thigpen et al. 1993). In a recent study by Dufort and co-workers, 17β-HSD5, which specifically catalyzes the reduction of androstenedione to testosterone, was cloned (Dufort et al. 1999). Several studies have previously demonstrated the presence of 5α-reductase isozyme mRNAs and enzyme activities in human prostate carcinoma cells (Delos et al. 1998, Negri-Cesi et al. 1998, Soderstrom et al. 2002, Thomas et al. 2003). The mRNA for 17β-HSD5 was also reported to be expressed in prostate cancer tissues (Koh et al. 2002). These findings indicate that in situ production of 5α-dihydrotestosterone (DHT) from inactive androstenedione by 17β-HSD5 (reduction of androstenedione to testosterone), and via 5α-reductase (metabolism of testosterone to DHT) in human prostate tissue may be occurring. However, the status of expression for these enzymes and their relation to clinicopathological findings has not been examined in human prostate cancer. Therefore, in this study, we first examined the immunolocalization of 5α-reductase isozymes, and 17β-HSD5 in human prostate carcinoma tissue specimens obtained from surgery. We then correlated these findings with various clinicopathological parameters of patients including the status of the androgen receptor (AR) in 70 cases of human prostate carcinoma in order to evaluate the possible roles of these androgen metabolizing/synthesizing enzymes in human prostate cancer.

Materials and methods

Patients and tissues

Seventy surgical pathology specimens of prostate carcinoma were obtained from patients who underwent prostatectomy from 1998–2003 at the Department of Urology, Tohoku University Hospital (Sendai, Japan). The mean age of the patients was 65.7 years (range: 48–77). All patients examined in this study did not receive radiation, chemotherapy, nor hormone therapy before surgery. Clinical data, including patient age, serum prostate specific antigen (PSA) concentration, clinical stage according to the International Union Against Cancer TNM classification (1987), lymph node status, and Gleason’s score (Veltri et al. 1996) were retrieved from detailed patient charts describing individual patient histories. The histological grade of each tumor was evaluated by three of the authors (Y N, T S and H S). All specimens were fixed with 10% formalin and embedded in paraffin wax at the Department of Pathology, Tohoku University Hospital. The Ethic’s Committee at Tohoku University School of Medicine approved the research protocol for this study.

Antibodies

5α-reductase type 1 and type 2 antibodies used in this study were rabbit polyclonal antibodies against synthesized peptides corresponding to amino acids 232–256 for 5α-reductase type 1, and amino acids 227–251 for 5α-reductase type 2, respectively (Thigpen et al. 1993). These antibodies were kindly provided by Dr D W Russell (University of Texas Southwestern Medical Center, Dallas, TX). The polyclonal antibody for 17β-hydroxysteroid dehydrogenase type 5 (17β-HSD5) was raised in a rabbit against a synthetic peptide corresponding to amino acids 297–320 for 17β-HSD5 and was kindly provided by Dr V Luu (Laval University Hospital Center, Québec, Canada) (Pelletier et al. 1999). Characterization of these three antibodies was confirmed by immunoblotting, and the use of antibodies for 5α-reductase type 2 and 17β-HSD5 on immunohistochemistry has been previously reported (Thigpen et al. 1993, Silver et al. 1994, Pelletier et al. 1999). mAb against AR was purchased from DAKO Corporation (Carpinteria, CA).

Immunohistochemistry

Immunohistochemical analysis was performed employing the streptavidin-biotin amplification method using a Histofine Kit (Nichirei, Tokyo, Japan) and has been previously described in detail (Suzuki et al. 1994). For immunostaining of AR, the slides were heated in an autoclave at 120 °C for 5 min in citric acid buffer (2 mmol/l citric acid and 9 mmol/l trisodium citrate dehydrate, pH 6.0) after deparaffinization for antigen retrieval. The dilutions of primary antibodies used in our study were as follows: 5α-reductase type 1, 1 : 1000; 5α-reductase type 2, 1 : 1000; AR, 1 : 100; and 17β-HSD5, 1 : 1000. The antigen–antibody complex was visualized with 3,3′-diaminobenzidine (DAB) solution [1 mmol/l 3,3′-DAB, 50 mmol/l Tris–HCl buffer (pH 7.6), and 0.006% H2O2] and counterstained with hematoxylin. Tissue sections of liver and prostate were used as positive controls for 5α-reductase types 1 and 2, respectively, and non-neoplastic breast tissue was used as a positive control for 17β-HSD5 (Thigpen et al. 1993, Pelletier et al. 1999). As a negative control, normal rabbit or mouse IgG was used instead of the primary antibodies, and no specific immunoreactivity was detected in these reported tissue sections.

Scoring of immunoreactivity

Scoring of immunoreactivity was performed based on previous reports with some modifications (Soslow et al. 2000, Suzuki et al. 2001). For statistical analyses of 5α-reductase type 1 and type 2, and 17β-HSD5 immunoreactivity, the carcinoma cases were classified into the following two groups: +, positive, more than 10% positive cells; and − , no immunoreactivity, less than 10% positive cells according to Soslow and colleagues (Soslow et al. 2000). The evaluation (+, positive carcinoma cells; and − no immunoreactivity) was performed by three of the authors (Y N, T S and H S), independently. Cases with discordant results among these investigators above were re-evaluated. Scoring of AR in carcinoma cells was performed on high power fields (×400) using standard light microscopy. In each case, more than 500 carcinoma cells were counted independently by the three authors above, and the percentage of immunoreactivity, i.e. labeling index (LI), was determined (Suzuki et al. 2001). In the present study, interobserver differences were less than 5%, and the mean of these three values was obtained. In addition, as a control, immunoreactivity for 5α-reductase type 1 and 2, 17β-HSD5, and AR was examined in the peripheral zone of non-neoplastic glands in each case.

Statistical analysis

Values for patient age, serum PSA levels, and LI for AR were presented as the mean±95% confidence interval (95% CI), and associations between 5α-reductase immunoreactivity and the parameters described above were evaluated using the Bonferroni test. Statistical differences between immunoreactivity for 5α-reductases and stage, lymph node status, histological grade, and immunoreactivity for 17β-HSD5, were evaluated in a cross-table using the χ2-test. P<0.05 was considered significant.

Results

Immunohistochemistry

Immunoreactivity for 5α-reductase type 1 and type 2, and 17β-HSD5 was detected in the cytoplasm of carcinoma cells, whereas AR immunoreactivity was detected in the nuclei of carcinoma cells (Fig. 1A–D). In the non-neoplastic peripheral zone, immunoreactivity for 5α-reductase type 2, 17β-HSD5, and AR was detected in the glandular epithelium, but 5α-reductase type 1 immunoreactivity was negative in this study (Fig. 1E–H). The number of positive cases and their corresponding percentages were as follows: 51/70 (73%) for 5α-reductase type 1, 39/70 cases (56%) for 5α-reductase type 2, and 54/70 cases (77%) for 17β-HSD5.

Correlation among 5α-reductases and 17β-HSD5 immunoreactivity

A statistically significant positive correlation was detected between 5α-reductase type 1 and type 2 immunoreactivity (P=0.0004), and between 5α-reductase type 2 and 17β-HSD5 immunoreactivity (P=0.0049) (Table 1) A similar trend was also detected between 5α-reductase type 1 and 17β-HSD5 immunoreactivity, but the correlation did not reach statistical significance (P=0.0993) (Table 1).

Correlation between immunoreactivities and clinicopathological parameters

Immunoreactivity for 5α-reductase type 1 was not significantly correlated with clinicopathological parameters including patient age, concentration of serum PSA levels, Gleason’s score, pT stage, lymph node states, and AR LI (Table 2) There was a statistically positive correlation between 5α-reductase type 2 immunoreactivity and AR LI (P=0.0281) (Table 3), however, it was not significantly correlated with other clinicopathological parameters (Table 3).

17β-HSD5 immunoreactivity was significantly associated with clinical stage in this study (TNM stage pT3 vs pT2) (P=0.0115) (Table 4)

Discussion

It is well known that androgens play important roles in the pathogenesis of prostate cancer (Lopez-Otin & Diamandis 1998). Although plasma concentrations of testosterone have been shown to decrease more than 90% following castration, androgen levels in prostate cancer tissues decreased only 50–60%, suggesting the importance of in situ androgen production in prostate cancers (Labrie 1991, Mizokami et al. 2004). Results from our present study suggest that androgen-producing enzymes are co-expressed in human prostate cancers, and involved in the local production of DHT, which may play important roles in biological behavior of prostate carcinoma cells.

In the present study, the number of cases positive for steroidogenic enzymes and the corresponding percentages was 39/70 cases (56%) for 5α-reductase type 2. In addition, there was a statistically significant positive correlation between 5α-reductase type 2 immunoreactivity and AR LI. It has been reported that type 2 5α-reductase was expressed in prostate cancer, and was very important in the process of in situ production of DHT (Torres et al. 2003). In addition, type 2 5α-reductase has been also hypothesized to play a role in the pathogenesis and/or development of prostate cancer (Torres et al. 2003). Moreover, it has also been reported that men who have had some polymorphism of the type 2 5α-reductase gene have a significantly increased risk of prostate cancer development and/or progression (Nam et al. 2001). Our data are consistent with these reports, and suggest that 5α-reductase type 2 may play an important role in the in situ production and action of DHT in human prostate cancer tissues.

Results from the present study also demonstrated that 5α-reductase type 1 was frequently expressed in human prostate cancer (73%). In addition, we demonstrated that a significant positive correlation was demonstrated between 5α-reductase type 1 and type 2 immunoreactivity. It has been suggested that individuals with greater 5α-reductase are at an increased risk for developing prostate cancer. Furthermore, previous reports have demonstrated that type 1 5α-reductase mRNA and activity were much greater in prostate cancers than in benign prostate tissues (Steers 2001, Iehle et al. 1999). These data suggest that both type 1 and type 2 5α-reductases are likely to be important in the local production and action of DHT in human prostate cancer. It has also been reported that treatment of finasteride, a 5α-reductase type 2 inhibitor, to patients diagnosed with metastatic prostate cancer resulted in only minor effects in this cancer (Presti et al. 1992), and decreased serum PSA levels by only 7% in men with advanced adenocarcinoma of the prostate (Brufsky et al. 1997). In contrast, however, dutasteride, which inhibits both type 1 and type 2 5α-reductases, treatment has recently been reported to result in almost complete suppression of intraprostatic DHT, and increased regression of prostate cancer (Andriole et al. 2004). Results from these studies suggest that 5α-reductase type 1, as well as the type 2 isozyme, are associated with the growth of prostate cancer. Furthermore, knowing the expression pattern and profile of 5α-reductase isozymes may be important when considering the use of 5α-reductase inhibitors in reducing the progression of prostate carcinoma in patients diagnosed with this aggressive cancer via the inhibition of in situ DHT production. However, further investigations are required to clarify the role of 5α-reductase isozymes and related steroidogenic enzymes in the pathogenesis of prostrate carcinoma.

Iehle and colleagues demonstrated that 5α-reductase type 1 mRNA is abundantly expressed in the epithelial cells of normal prostate, whereas stromal cells of this glandular tissue demonstrated greatly reduced levels (Iehle et al. 1999). In our study, we could not identify significant immunoreactivity of 5α-reductase type 1 in the non-neoplastic peripheral zone of the prostate. A previous study also demonstrated that type 1 5α-reductase mRNA and activity were much lower in benign prostate tissues than in prostate cancers (Steers 2001). Therefore, protein expression levels of 5α-reductase type 1 in non-neoplastic areas of the human prostate were considered below the limits of detection by immunohistochemistry.

In the present study, 17β-HSD5 immunoreactivity was detected in carcinoma cells of 77% of prostate cancer tissues, and was positively associated with clinical stage (P<0.05; TNM stage III vs TNM stage II). It is well-known that cell proliferation in the normal prostate and in prostate cancer is mainly controlled by testosterone following intracellular conversion to DHT (Ross & Henderson 1994, Imperato-McGinley et al. 1992). However, it has also been demonstrated that the remodeling of prostate stromal tissue via testosterone may play a role in the early stage of prostate carcinogenesis, which is generally considered to be favorable for tumor development (Li et al. 2001). Therefore, 17β-HSD5 may be involved in increasing the local concentration of testosterone in prostate cancer tissues, resulting in the progression, invasion, and further development of prostate cancer.

In summary, we have demonstrated that 5α-reductase types 1 and 2, and 17β-HSD5 were all detected in the great majority of prostate cancer tissues, and significant positive association was detected between 5α-reductase types 2 and AR and/or 17β-HSD5 and clinical stage. These data also indicate the importance of these androgen metabolizing/synthesizing enzymes in the local production and action of androgens in human prostate cancer.

Table 1

Correlation among 5α-reductases immunoreactivity and 17β-HSD type 5 immunoreactivity in human prostate cancer

Pvalue
*P<0.05.
5α-reductase type 1 and 5α-reductase type 20.0004*
5α-reductase type 1 and 17β-HSD type 50.0993
5α-reductase type 2 and 17β-HSD type 50.0049*
Table 2

Correlation between 5α-reductase type 1 immunoreactivity and clinicopathological parameters in human prostate cancer

+(n=51)(n=19)Pvalue
Age (years)65.2±0.966.6±1.30.3851
PSA (ng/ml)14.0±1.817.2±4.00.6540
Gleason score
    2–68 (11.4%)5 (7.1%)
    722 (31.4%)10 (14.3%)0.2612
    8–1021 (30.0%)4 (5.7%)
Stage
    pT220 (28.6%)9 (12.9%)
    pT331 (44.3%)10 (14.3%)0.5380
Lymph node status
    +6 (8.6%)2 (2.9%)
    −45 (64.3%)17 (24.3%)0.0849
AR LI (%)68.1±3.269.1±4.00.8703
Table 3

Correlation between 5α-reductase type 2 immunoreactivity and clinicopathological parameters in human prostate cancer

+(n=39)(n=31)Pvalue
*Data was considered significant.
Age (years)65.3±1.166.0±0.90.6203
PSA (ng/ml)13.5±1.917.0±3.30.4390
Gleason score
    2–66 (8.6%)7 (10.0%)
    719 (27.1%)13 (18.6%)0.7203
    8–1014 (20.0%)11 (15.7%)
Stage
    pT214 (20.0%)15 (21.4%)
    pT325 (35.7%)16 (22.9%)0.2920
Lymph node status
    +3 (4.3%)5 (7.1%)
    −36 (51.4%)26 (37.1%)0.2704
AR LI (%)73.4±3.162.1±4.00.0281*
Table 4

Correlation between 17β-HSD type 5 immunoreactivity and clinicopathological parameters in human prostate cancer

+(n=54)(n=16)Pvalue
*Data was considered significant.
Age (years)65.5±0.965.8±1.10.8716
PSA (ng/ml)14.7±1.713.8±6.20.6204
Gleason score
    2–68 (11.4%)5 (7.1%)
    725 (35.7%)7 (10.0%)0.2895
    8–1021 (30.0%)4 (5.7%)
Stage
    pT218 (25.7%)11 (15.7%)
    pT336 (51.4%)5 (7.1%)0.0115*
Lymph node status
    +7 (10.0%)1 (1.4%)
    −47 (67.1%)15 (21.5%)0.4585
AR LI(%)69.4±2.864.8±6.10.4572
Figure 1
Figure 1

Immunohistochemistry of 5α-reductase type 1 (A) and type 2 (B), 17β-HSD5 (C), and AR (D) in human prostate carcinoma, and immunohistochemistry of 5α-reductase type 1 (E) and type 2 (F), 17β-HSD5 (G), and AR (H) in non-neoplastic glands of the peripheral zone of human prostate. Immunoreactivity of 5α-reductase type 1 (A) and type 2 (B), 17β-HSD5 (C) was detected in the cytoplasm of carcinoma cells, whereas that of AR (D) was detected in the nucleus of carcinoma cells. In addition, immunoreactivity of 5α-reductase type 2 (F), and 17β-HSD5 (G) was detected in the cytoplasm of non-neoplastic glands of the peripheral zone, whereas that of AR (H) was detected in the nucleus of non-neoplastic glands of the peripheral zone. However, immunoreactivity of 5α-reductase type 1 (E) was not detected. Original magnification, ×400.

Citation: Endocrine-Related Cancer Endocr Relat Cancer 12, 1; 10.1677/erc.1.00914

References

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    Immunohistochemistry of 5α-reductase type 1 (A) and type 2 (B), 17β-HSD5 (C), and AR (D) in human prostate carcinoma, and immunohistochemistry of 5α-reductase type 1 (E) and type 2 (F), 17β-HSD5 (G), and AR (H) in non-neoplastic glands of the peripheral zone of human prostate. Immunoreactivity of 5α-reductase type 1 (A) and type 2 (B), 17β-HSD5 (C) was detected in the cytoplasm of carcinoma cells, whereas that of AR (D) was detected in the nucleus of carcinoma cells. In addition, immunoreactivity of 5α-reductase type 2 (F), and 17β-HSD5 (G) was detected in the cytoplasm of non-neoplastic glands of the peripheral zone, whereas that of AR (H) was detected in the nucleus of non-neoplastic glands of the peripheral zone. However, immunoreactivity of 5α-reductase type 1 (E) was not detected. Original magnification, ×400.

References

  • AndrioleGL Humphrey P Ray P Gleave ME Trachtenberg J Thomas LN Lazier CB & Rittmaster RS 2004 Effect of the dual 5alpha-reductase inhibitor dutasteride on markers of tumor regression in prostate cancer. Journal of Urology172915–919.

    • Search Google Scholar
    • Export Citation
  • BrownCT & Nuttall MC 2003 Dutasteride: a new 5-alpha reductase inhibitor for men with lower urinary tract symptoms secondary to benign prostatic hyperplasia. International Journal of Clinical Practice57705–709.

    • Search Google Scholar
    • Export Citation
  • BrufskyA Fontaine-Rothe P Berlane K Rieker P Jiroutek M Kaplan I Kaufman D & Kantoff P 1997 Finasteride and flutamide as potency-sparing androgen-ablative therapy for advanced adenocarcinoma of the prostate. Urology49913–920.

    • Search Google Scholar
    • Export Citation
  • DelosS Carsol JL Fina F Raynaud JP & Martin PM 1998 5alpha-reductase and 17β-hydroxysteroid dehydrogenase expression in epithelial cells from hyperplastic and malignant human prostate. International Journal of Cancer75840–846.

    • Search Google Scholar
    • Export Citation
  • DufortI Rheault P Huang XF Soucy P & Luu-The V 1999 Characteristics of a highly labile human type 5 17β-hydroxysteroid dehydrogenase. Endocrinology140568–574.

    • Search Google Scholar
    • Export Citation
  • IehleC Radvanyi F Gil Diez de Medina S Ouafik LH Gerard H Chopin D Raynaud JP & Martin PM 1999 Differences in steroid 5alpha-reductase iso-enzymes expression between normal and pathological human prostate tissue. Journal of Steroid Biochemistry and Molecular Biology68189–195.

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