Hormone regulation of human prostate in organ culture.
We have established organ cultures of human prostate for in vitro analysis of the hormone responsiveness of prostatic carcinoma. Tissue samples were obtained from total prostatectomies for localized cancer. Normal prostate tissues with age-related hyperplastic changes were obtained from cystoprostatectomies of bladder cancer patients representing the same age group, and they wer cultivated as controls. The explants of prostates were cultured for 7 days in basal medium containing 5% dextran charcoal-treated fetal calf serum, insulin (0.08 IU/ml), and dexamethasone (10(-7) M) with or without dihydrotestosterone (DHT) (10(-7) M) or estradiol (10(-9) M). Control prostates showed involutive changes of morphology when cultured in basal medium. These changes were prevented by DHT, which also maintained a strong epithelial immunostaining for PSA (prostate specific antigen), which was used as a marker for tissue-specific functions. The concentration of PSA in the medium was high. The rate of [3H]thymidine incorporation into DNA was stimulated by DHT in some cultures of control prostates, but no increase was seen in the others. Androgen stimulation of [3H]thymidine incorporation was consistently inhibited by the antihormone cyproterone acetate. The main morphological response of cultured control prostates to estradiol was induction of squamous metaplasia. This was associated with increased incorporation of [3H]thymidine, which was radioautographically localized to the basal layer of epithelium. Estradiol effects were counteracted by the antihormone toremifene. The expression of androgen receptor mRNA and protein in cultured control prostate was demonstrated by Northern blotting and immunohistochemistry, respectively. Also, the expression of estrogen receptor was demonstrated by the polymerase chain reaction analysis of total mRNA from cultured control and cancer prostate. The cultured explants of prostate cancer maintained the overall morphology of the original carcinoma. However, the presence of DHT improved the morphology of cancerous acini in all better differentiated carcinomas (3 grade I and 5 grade II), and corresponding responses to DHT were observed in the rate of DNA labeling with [3H]thymidine. In 2 of 3 grade I carcinomas, DHT increased DNA synthesis, but in grade II cancers the patterns of hormone responses were more variable. The poorly differentiated grade III prostatic carcinomas did not respond to either hormone as measured by [3H]thymidine uptake, and no hormone effects could be seen in morphology. Immunostaining for PSA differed from that in control prostates: besides cancerous acini, the surrounding stroma was also intensively stained, which suggests unpolarized and impaired secretion of PSA by the cancer cells.(ABSTRACT TRUNCATED AT 400 WORDS)
Nevalainen
M T
MT
Department of Anatomy, University of Turku, Finland.
Härkönen
P L
PL
Valve
E M
EM
Ping
W
W
Nurmi
M
M
Martikainen
P M
PM
D000368:Aged; D002455:Cell Division / Q000187:drug effects; D004247:DNA / Q000378:metabolism; D004273:DNA, Neoplasm / Q000378:metabolism; D003907:Dexamethasone / Q000494:pharmacology*; D013196:Dihydrotestosterone / Q000494:pharmacology*; D004958:Estradiol / Q000494:pharmacology*; D006801:Humans; D007150:Immunohistochemistry; D007328:Insulin / Q000494:pharmacology*; D008297:Male; D008875:Middle Aged; D009924:Organ Culture Techniques; D011467:Prostate / Q000166:cytology / Q000187:drug effects / Q000473:pathology*; D011468:Prostatectomy; D011470:Prostatic Hyperplasia / Q000473:pathology* / Q000601:surgery; D011471:Prostatic Neoplasms / Q000473:pathology* / Q000601:surgery; D011944:Receptors, Androgen / Q000032:analysis / Q000378:metabolism
D004273:DNA, Neoplasm; D007328:Insulin; D011944:Receptors, Androgen; D013196:Dihydrotestosterone; D004958:Estradiol; D003907:Dexamethasone; D004247:DNA