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Androgen and Glucocorticoid Receptors in the Stroma and Epithelium of Prostatic Hyperplasia and Carcinoma1

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Androgen and Glucocorticoid Receptors in the Stroma and Epithelium of Prostatic Hyperplasia and Carcinoma1 Vol. 2. 889-895, Ma’ 1996 Clinical Cancer Research 889 Androgen and Glucocorticoid Receptors in the Stroma and Epithelium of Prostatic Hyperplasia and Carcinoma1 James L. Mohler,2 Yeqing Chen, tatic carcinoma warrants further study of GR, particularly in the area of stromal-epithelial interaction. Katherine Hamil, Susan H. Hall, John A. Cidlowski, Elizabeth M. Wilson, INTRODUCTION Frank S. French, and Madhabananda Sar American men suffered 42,400 deaths and 244,000 new Departments of Surgery (Division of Urology) lJ. L. M., Y. C.]. Cell diagnoses of CaP3 in 1995 (1). In spite of the impact of CaP, Biology and Anatomy lM. S.], Physiology [J. A. C.]. Pediatrics (Laboratories for Reproductive Biology) [K. H., S. H. H.. E. M. W., little is known about its pathogenesis or predictors of response F. S. Fl, Biochemistry and Biophysics [E. M. WI. and University of to various therapies. Studies on prostate morphogenesis, growth, North Carolina-Lineberger Comprehensive Cancer Center U. L. M.. and function have focused upon androgenic regulation of epi- J. A. C., E. M. W., F. S. F.], University of North Carolina at Chapel thelial cells. However, recent studies indicate that at least some Hill. Chapel Hill, North Carolina 27599 responses of prostatic epithelial cells to hormonal stimuli may be the consequence of growth factors, morphogens, or inductors ABSTRACT produced in neighboring stromal cells (2-5). In view of the Differences in stromal and epithelial cell staining for potential importance of stromal-epithelial interactions during androgen and glucocorticoid receptors (ARs and GRs) were prostatic development, investigation of hormonal regulation by investigated in 20 patients with clinically localized prostatic the stromal compartment may lead to a better understanding of carcinoma treated by radical prostatectomy. Sections of prostatic disease and may provide insight into how abnormal benign prostatic hyperplasia and prostatic carcinoma from growth processes are modified by hormonal therapy. each patient were stained with antibodies to AR and GR Various programs of hormonal therapy have been used for using an avidin-biotin peroxidase technique. The specificity the treatment of patients with CaP since the pioneering work of of the GR immunoreactivity was established in benign pros- Huggins and Hodges (6). Approximately 80% of patients with tatic hyperplasia and prostatic carcinoma by immunohisto- metastatic CaP respond to androgen deprivation with an exten- chemistry using the GR antibody absorbed with synthetic sion of life expectancy from approximately 9 to 43 months. A peptide and Western blotting. Nuclear staining intensity and quantitative and/or functional difference of the AR may con- percentage of nuclei stained were summed to obtain AR and tribute to clinical response to androgen deprivation therapy (7, GR immunostaining scores. AR staining of prostatic carci- 8). However, Sadi et a!. (9) found no correlation between the noma epithelial [103 ± 58 (SD)] and stromal (126 ± 48) proportion of epithelial cells staining positive for AR and inter- nuclei was less than in benign prostatic hyperplasia (142 ± val to progression in 10 patients. Quantitative analysis in a 47 and 169 ± 56; paired Student’s t tests, P 0.02 and P = larger group of patients disclosed that heterogeneity of AR 0.01); however, no difference in staining intensity occurred staining among nuclei from individual tumors correlated with between stroma and epithelium in either tissue type. GR response (10). Similar to prostatic development, androgen-me- stained intensely in stromal cells from benign prostatic hy- diated growth of CaP may occur via paracrine factors produced perplasia (189 ± 50) and prostatic carcinoma (163 ± 60). by the stroma. The AR status of the epithelial compartment in However, prostatic carcinoma epithelial cells (34 ± 57) had early CaP may provide an incomplete description of disordered low levels of glucocorticoid receptor staining (P < 10), growth control. and benign prostatic hyperplasia epithelium (74 ± 51) was Approximately 20% of patients with androgen-independent intermediate. In most patients, GR could not be detected in CaP respond to aminoglutethimide or ketoconazole and corti- nuclei of prostatic carcinoma epithelial cells but was undi- costeroids (1 1-13). Responses have been attributed to the dim- minished in stromal cell nuclei. There was no relationship by ination of adrenal androgens (14). Antibodies specific for the multivariate regression analysis between AR or GR staining GR have been developed recently (15) but, to our knowledge, and age, serum prostate-specific antigen, Gleason grade, or they have not been applied to studies of prostatic tissue. pathological stage. In comparison with AR, the greater var- We reported previously ( I 6) methodology for sensitive and iability of GR staining in epithelium versus stroma of pros- specific detection of AR in frozen sections of fresh human prostate tissue using the polyclonal antibody AR-52 (17) and the avidin-biotin peroxidase method. Epithelial cell nuclei stained less intensively and more heterogeneously for AR in CaP than BPH. In the present study, we used antibodies specific for both Received 8/22/95: revised I 2/27/95: accepted 1/24/96. I Supported by Grant 5 UOl AG1 1343-02 from the NIH, National Institute on Aging. 2 To whom requests for reprints should be addressed, at Division of Urology, Campus Box 7235, University of North Carolina at Chapel 3 The abbreviations used are: CaP, prostatic carcinoma; AR, androgen Hill, Chapel Hill, NC 27599-7235. Phone: (919) 966-2574; Fax: (919) receptor: GR, glucocorticoid receptor; BPH, benign prostatic hyperpla- 966-5722. sia. Downloaded from clincancerres.aacrjournals.org on September 23, 2021. © 1996 American Association for Cancer Research. 890 Prostatic Steroid Receptor Immunohistochemistry Table 1 Raw data : Patient characteristics an d immunohistochemistry scores Pathological AR intensity score GR inten sity score BPH CaP BPH CaP PSA Patient AgeIRace’ (ng/ml) Clinical stageb Grade’9 Stage Epi Str Epi Str Epi Str Epi Str 1 47B 24.2 T3 7 OC 160 220 105 40 55 180 7 110 2 68W 0.7 T2a 5 OC 150 140 150 120 170 255 120 230 3 61W 10.6 T2b 7 CP, M 80 190 130 120 120 200 0 120 4 63W 6.4 T2a 6 CP 170 190 90 100 170 180 5 170 5 62W 8.8 T2a 6 OC 180 190 0 180 80 200 0 170 6 64W 25.4 T2b 7 SV 190 240 200 200 30 240 10 205 7 63W 5.9 T2a 8 OC 50 80 140 200 140 210 0 70 8 71W 10.5 T2a 7 OC 120 110 80 90 65 80 5 120 9 55W 12.1 T2b 9 CP, SV, M 190 130 100 100 95 190 20 190 10 66W 7.7 T2a 7 OC 140 160 150 80 60 255 0 190 1 1 53W 23.5 T2b 7 N 45 60 5 170 40 185 15 290 12 54W 18.0 T25 7 N 180 260 170 190 70 260 160 210 13 53W 12.3 T2a 7 CP, SV 190 220 90 90 0 130 0 120 14 69W 4.7 T2c 6 OC 140 190 55 150 0 140 0 150 15 75W 11.9 T2b 7 OC 75 110 160 120 75 115 60 180 16 75W 9.0 T2a 5 OC 150 170 150 140 60 140 0 70 17 58W 12.9 T2a 7 CP, M 170 200 140 80 140 255 180 235 18 64 B 27.6 T2 7 CP, M 120 160 0 155 40 200 5 170 19 75W 8.2 T2a 5 OC 150 110 80 50 20 160 0 60 20 59W 5.9 T, 7 OC 190 240 70 150 50 200 9 190 a B, black; W, white; PSA, prostate-specific antigen (Hybritech); OC, organ-confined; CP, capsular penetration; SV, seminal vesicle invasion; M, margin positive; N, nodes positive; AR, androgen receptor; GR, glucocorticoid receptor; Epi, epithelium; Str, stroma. b Schroder et al. (18). C Gleason et al. (19). AR and OR to compare intensity of staining of epithelium and frozen sections were air dried and fixed with PBS containing 4% stroma in BPH and CaP. paraformaldehyde, 10% sucrose, and 0. 1 M sodium phosphate (pH 7.2). Sections were transferred into 2% hydrogen peroxide MATERIALS AND METHODS in PBS for 5 mm, washed, and permeablized in 0.2% Triton Patients. Tissue was obtained in the operating room from x-l00 for 10 mm. Nonspecific staining was blocked with 2% 20 patients [63 ± 8 (SD) years old] treated by radical prosta- normal goat serum. Sections were incubated with AR-52 (17) at tectomy for clinically localized CaP (Table 1). Serum prostate- an IgG protein concentration of 5 p.g/ml or GR-57 (15) at a specific antigen (Hybritech) was 12.3 ± 7.5 ng/ml. Pathological purified IgG protein concentration of 2 pg/ml in a moisture sum Gleason grade (19) was 6.7 ± 1.0 and CaP proved organ- chamber for 16-18 h at 4#{176}C.Sections were exposed at room confined in 1 1 patients (55%), specimen-confined in 3 patients temperature to biotinylated goat antirabbit IgG secondary anti- (15%), extended beyond surgical margins in 4 patients (20%), body (3.75 p.g/ml; I :400 dilution; Vector Labs Inc., Burl- and metastasized to obturator lymph nodes in 2 patients (10%). ingame, CA) for 60 mm, reacted with avidin-biotin peroxidase Tissue was obtained from the center of grossly recognizable (ABC; Vector Labs, Inc.), diluted 1:400 for 60 mm, and exposed nodules of CaP and from the transition zone opposite the car- for 10 mm with a solution containing 75 mg diaminobenzadine cinoma. Gross diagnoses were confirmed later histologically, (Aldrich Chemical Co., Milwaukee, WI) and 8.5 pA fresh 30% and no patient had undergone prior treatment for prostatic hydrogen peroxide in 100 ml 0.05 M Tris (pH 7.6).
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