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Endocrinology Vol. 140, No. 11 5412-5421
Copyright © 1999 by The Endocrine Society

ARTICLES

Prolactin Is a Survival Factor for Androgen-Deprived Rat Dorsal and Lateral Prostate Epithelium in Organ Culture1

Tommi J. Ahonen, Pirkko L. Härkönen, Jukka Laine, Hallgeir Rui, Paula M. Martikainen and Marja T. Nevalainen

Institute of Biomedicine (T.J.A., P.L.H., M.T.N.), Department of Anatomy and the Medicity Research Laboratory, University of Turku, FIN-20520 Turku, Finland; Departments of Pathology (J.L., P.M.M.), University of Turku, FIN-20520 Turku, Finland and Tampere University Hospital, FIN-33521, Tampere, Finland; and Department of Pathology (T.J.A., H.R., M.T.N.), Uniformed Services University of the Health Sciences, Bethesda, Maryland 20814

Address all correspondence and requests for reprints to: Marja T. Nevalainen, Uniformed Services University of Health Sciences, Department of Pathology, 4301 Jones Bridge Road, Bethesda, Maryland 20814.


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
PRL is one of several polypeptide factors that regulate growth and differentiation of prostate epithelium besides steroid hormones. This hormone may also participate in the development of pathologic changes of the prostate, as evidenced by marked prostate hyperplasia in hyperprolactinemic mice. We have previously demonstrated expression of PRL receptors and androgen-dependent local production of PRL in rat and human prostate epithelium, suggesting the existence of an autocrine loop. We now show that PRL acts as a survival factor for epithelial cells of rat dorsal and lateral prostate but not ventral prostate, using long-term organ cultures as an in vitro model. Culture of prostate explants in androgen-free medium was associated with a transient surge of apoptosis during the first 2–4 days of culture in rat ventral, dorsal, and lateral prostate tissues, as quantified by either nuclear morphology or in situ DNA fragmentation analysis. PRL significantly inhibited apoptosis in androgen-deprived dorsal and lateral prostate cultures, by 40–60%, as determined by the two methods. The present study has established conditions and methodology for analysis of apoptosis in organ cultures of rat prostate and suggests a physiological role for PRL as a survival factor for prostate epithelium.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
PRL, A MEMBER of the helix bundle peptide hormone/cytokine superfamily (1, 2), participates in the regulation of growth and differentiation of prostate (3, 4, 5, 6, 7, 8, 9, 10). PRL is possibly also involved in prostate pathology, because induction of hyperplastic enlargement of prostate by hyperprolactinemia was recently demonstrated in transgenic mice (11). We have previously described, using organ culture as an in vitro model, a characteristic and direct effect of PRL on rat and human prostate morphology with a hyperplastic and disorganized epithelium (12, 13). Consistent with the actions of PRL on prostate morphology, this hormone also stimulated proliferation of prostate tissue in culture and induced the expression of genes encoding prostate-specific secretory proteins (12, 13). Furthermore, PRL is locally produced in rat and human prostate tissue in an androgen-dependent fashion (13, 14). Coupled with expression of receptors for PRL (15) in prostate epithelium (13, 16), local PRL production implies an autocrine loop of PRL in prostate tissue.

In this study, we specifically investigated whether PRL contributes to prostate growth by antagonizing apoptotic cell death. Programmed cell death is initiated through the activation of endogenous proteases of the caspase family (17, 18), leading to increased nuclease activity and internucleosomal fragmentation of DNA and to the associated morphological features of apoptotic cells (19, 20). These include condensation of chromatin, cytoskeletal disruption (with cell shrinkage), and intracellular membrane-enclosed fragments termed apoptotic bodies (21, 22). The activation of this energy-dependent active death process is initiated either by external signals delivered through death receptors (23, 24, 25) or by intracellular changes triggered by various exogenous damaging agents or by withdrawal of survival factors like hormones, cytokines, and growth factors (26, 27). Androgens are principal suppressors of apoptosis in prostate (28). However, removal of androgen results only in a transient postcastrational apoptotic program. As cell numbers decrease, a new equilibrium between cell proliferation and cell death is established (27). This suggests the existence of prostate cell survival factors other than androgens. Likewise, the typical progression of prostate carcinomas to an androgen-independent state after antiandrogen therapy may be facilitated by similar survival factors.

To study the role of PRL as a survival factor for normal prostate epithelium, we used prostate organ culture as an experimental model. The effect of PRL on the preservation of prostate epithelium was investigated by analyzing the extent of apoptosis occurring in rat dorsal, lateral, and ventral prostate explants cultured with or without PRL. In prostate organ culture, the hormone responsiveness and specific tissue functions of rat (12, 14, 16, 29, 30, 31) and human prostate (13, 32) are well maintained. The presence of all tissue components in this prostate in vitro model preserves the interactions between epithelium and stroma that have been demonstrated to be important for maintenance of the differentiated state of prostate epithelium (33, 34, 35). The hormone responsiveness of distinct rat prostate lobes has been shown to be different (36, 37, 38), the dorsal and lateral parts of rat prostate being considered most sensitive to PRL (3, 9, 39, 40). Furthermore, the dorsolateral lobes are most homologous to human prostate (41) and give rise to spontaneous and experimental tumors (42, 43, 44, 45, 46, 47). Using organ cultures of rat prostate, we now show that the polypeptide hormone PRL functions as a survival factor for rat dorsal and lateral prostate epithelium in an androgen-independent manner.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Prostate samples
Adult Sprague Dawley rats, outbred strain, (10–12 weeks old; BW, 250–280 g) were used in the studies. Male rats were euthanized by cervical dislocation under light carbon dioxide anesthesia; and ventral, dorsal, and lateral prostate lobes were separated from one another and excised, and the tissues were taken for organ cultures. For use as positive controls and to validate the methods for quantifying of apoptosis in prostate tissue, six male rats were orchiectomized, via scrotal route, under ether anesthesia. Three of the rats were injected daily sc with 2 mg testosterone (Te) (17ß-hydroxy-4-androsten-3-one, from Sigma, St. Louis, MO) for the following 6 days. On day 7, all rats were killed as described above, and ventral prostates were taken for histology and histochemistry.

Organ culture
Rat ventral, dorsal, and lateral prostate lobes were cut with a razor blade into small pieces of approximately 1 mm3 in culture medium without hormones. The organ culture method of Trowell (48) was used, with some modifications (30), as described earlier (12, 13, 14, 16, 32). The tissue pieces were transferred to lens papers lying on stainless steel grids in Petri dishes. The medium was phenol-free medium 199 with Earle’s salts (Flow Laboratories, Newcastle, UK) supplemented with G-penicillin (100 IU/ml), streptomycin sulfate (100 µl/ml), and glutamine (100 µg/ml). In addition, the basal culture medium contained the combination of insulin (I) (Insulin Lente, Novo Industries, Copenhagen, Denmark) and corticosterone (C) (11ß,21-dihydroxypregnene-3,20-dione from Sigma) at the concentrations of 0.08 IU/ml and 10-7 M, respectively. No serum was added in any culture media. A humidified atmosphere with a mixture of O2, CO2, and N2 (40:5:55) at 37 C was used. The explants were cultured from 2–10 days with or without 100 nM ovine PRL (Sigma), and the medium was changed every second day. In addition, controls were cultured with or without Te (17ß-hydroxy-4-androsten-3-one, Sigma; 10-7 M) dissolved in propylene glycol (Fluka AG, Buchs, Switzerland) at a final concentration of 0.03%. Three or four parallel dishes were always cultured for each hormone combination in separate cultures. The concentration of Te used corresponds to physiological levels of Te in the circulation of adult male rats (49). Te has been shown to be freely diffusible into cultured prostate explants (50). The concentration of PRL used in organ culture was approximately 10–100 times higher than the levels of PRL in male rat circulation (49, 51), because diffusion of peptide hormones in the tissue compartments of prostate explants was expected to be less efficient than that of steroid hormones. Moreover, the concentration of PRL used has been shown to be needed in rat prostate organ culture for signal transduction responses (Nevalainen and Rui, unpublished data).

Nuclear morphology
For morphological evaluation, ventral, dorsal, and lateral prostate explants were fixed in 4% formalin and embedded in paraffin. Serial sections of 7 µm were cut from each piece and stained with hematoxylin and eosin. Prostate acinar cells above the basement membranes with condensed chromatin and cytoplasm, and with intracellular apoptotic bodies with or without condensed chromatin, were considered to represent prostatic epithelial cells undergoing programmed cell death. Apoptotic indices (number of apoptotic epithelial cells per hundred epithelial cells) were determined by counting the apoptotic epithelial cells and total number of epithelial cells in sections representing each explant from every culture. Prostate epithelial cells with prominent mitotic chromosomes and mitotic spindles were counted as mitotic cells per hundred epithelial cells (mitotic indices).

In situ end-labeling (ISEL)
As a second method to detect prostate cells undergoing apoptosis, a DNA fragmentation assay (Oncogene Research Products, Calbiochem, Cambridge, MA) was applied to the paraffin-embedded tissue sections of prostate samples. Briefly, after deparaffination and rehydration of tissue sections in graded alcohol, the sections were subjected to proteinase K treatment for 20 min at room temperature (RT) to enhance the sensitivity of the DNA end-labeling. The endogenous peroxidase activity was blocked by incubating the slides in 0.3% hydrogen peroxide in water for 10 min at RT. Biotin-labeled deoxynucleotides were catalytically added to 3'-OH ends of double- or single-stranded DNA by terminal deoxynucleotidyl transferase during a 90-min incubation at 37 C. Nucleotides incorporated into fragmented DNA were detected after incubation with streptavidin-horseradish peroxidase conjugate (30 min at RT) followed by visualization with 3,3-diaminobenzidine (10 min at RT) as a chromogen and methyl green as a counterstain. Negative controls were obtained by omitting terminal deoxynucleotidyl transferase from the reaction buffer. ISEL-index (number of prostatic epithelial cells with fragmented DNA per hundred epithelial cells) was determined by counting the ISEL epithelial cells per total number of epithelial cells in sections representing each explant in every culture.

Statistics
The apoptotic indices, derived from either morphological analysis or ISEL assay, are presented as means ± SEM. In the case of in vivo analysis of castration-induced apoptosis in ventral prostates, each group represented mean values derived from ventral prostates of 3 animals (n = 3) and was based on examination of tissue corresponding to 30–50 microscopic fields from each animal. Apoptosis rates presented from in vitro organ cultures represent means ± SEM from 4 to 8 separate experiments (n = 4–8). In each experiment, tissues from 8 rats were split into small explants, pooled, and distributed evenly into the various treatment groups (10–15 explants per group per experiment). For comparisons of multiple treatment groups, one-way ANOVA was employed, followed by Sheffe’s multiple-range test (52).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Validation of methods for apoptosis detection in prostate tissue
For the present studies of apoptosis in prostate tissues, histological sections were evaluated both by analysis of nuclear morphology and ISEL of fragmented DNA. To validate the two apoptosis detection methods, ventral prostate tissues were compared from castrated rats that had been maintained for 7 days with or without androgen substitution. The apoptotic index, as determined by either method, was expressed as the number of apoptotic epithelial cells per 100 cells examined, and the two methods showed a high degree of agreement (Fig. 1Go). Specifically, analysis of apoptosis by nuclear morphology, using established criteria of chromatin condensation with or without cell shrinkage and intracellular apoptotic bodies, showed an apoptotic index of 8.4 in ventral prostates of androgen-deprived rats (Fig. 1Go, A–C). Correspondingly, analysis of apoptosis by ISEL gave a similar apoptotic index of 8.5 in androgen-deprived prostate tissue (Fig. 1Go, D and E). In prostates from androgen-substituted animals, the number of apoptotic cells was low (Fig. 1FGo), and apoptotic indices for both methods were less than 0.5 (Fig. 1Go, A and D). The number of cells undergoing apoptosis was approximately 15- to 30-fold higher in ventral prostates of androgen-deprived rats than in prostates of rats receiving androgen-substitution (Fig. 1Go, A and D), a result agreeing with previous reports (28).



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  		Figure 1. Castration-induced apoptosis in rat prostate quantified by analysis of nuclear morphology (A, B, and C) or ISEL of fragmented DNA (D, E, and F). For validation of histological apoptosis detection methods, rat ventral prostates were used from rats castrated for 7 days (castr.) (A, B, C, D, and E) and from rats castrated for 7 days and treated daily for 6 days with Te (castr. + Te) (A, D, and F). Arrowheads (B and C) indicate the typical morphology of apoptotic prostate epithelial cells with condensed chromatin and cell shrinkage and with intracellular apoptotic bodies. The numbers of apoptotic cells are presented per hundred epithelial cells (apoptotic index). Columns represent means ± SEM of counts from ventral prostates of three rats in each treatment group (A). Cells with fragmented DNA were evaluated by ISEL of the 3'OH-ends of DNA strands by biotin-coupled deoxynucleotides. Biotin-streptavidin amplified peroxidase-antiperoxidase reaction visualizes clear positive staining (arrowheads) in a number of nuclei of epithelial cells of ventral prostates of rats castrated for 7 days (E), in contrast to ventral prostates of rats castrated for 7 days and treated with Te (F). Columns represent means ± SEM of ISEL prostate epithelial cells per hundred epithelial cells (ISEL-index) in ventral prostates from three rats in each treatment group (D). A total of 10–20 visual fields were examined per prostate (A and D). B: Magnification, x390; bar, 17.5 µm; C, E, and F: magnification, x97.5; bar, 70 µm. ***, P < 0.001.

 
Determination of apoptosis rates in rat ventral, dorsal, and lateral prostate organ cultures in the absence of androgen
To establish the time-dependent induction of apoptosis in separate rat prostate lobes maintained as organ cultures in the absence of androgen, rat ventral, dorsal, and lateral prostate explants were cultured for up to 10 days in basal medium supplemented with only I and corticosterone. The number of apoptotic cells of prostate explants was determined at the onset of organ culture (day 0) and on days 2, 3, 4, 5 or 7, and 10. Using the ISEL method, peak apoptosis levels were detected on day 2 in rat ventral prostates (Fig. 2AGo), whereas dorsal and lateral lobes reached peak apoptosis levels on day 3 (Fig. 2BGo). The more rapid induction of programmed cell death in ventral lobe, compared with dorsal and lateral, prostate might reflect the differences in androgen responsiveness in distinct rat prostate lobes, as shown previously (36, 37, 38). After this initial surge of apoptosis, the number of apoptotic cells in each of the prostate cultures essentially returned to the day 0 rate by culture day 10. Parallel analysis of apoptosis by nuclear morphology showed highest levels on day 3 (Fig. 2AGo) and 4 (data not shown) in ventral and dorsolateral prostate cultures, respectively, a day later than the peak observed with ISEL (Fig. 2AGo). This modest shift could be attributable to an extended appearance of morphological apoptotic features in cells undergoing apoptosis, relative to a more narrow window of ISEL-detectable DNA fragments. Regardless of the exact cause of this minor difference between the two methods, this initial characterization established that in dorsal, lateral, and ventral prostates that were cultured in the absence of androgen, elevated levels of apoptosis occurred during days 2–4 of culture.



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  		Figure 2. Time course of induction of apoptosis in rat ventral, dorsal, and lateral prostate cultured in the absence of androgens, during a 10-day period, in organ culture. Rat ventral (A), dorsal (DP), and lateral prostate (LP) (B) explants were cultured for 2, 3, 4, 5 or 7, and 10 days in basal medium containing I (0.08 IU/ml) and corticosterone (10-7 M). The apoptotic epithelial cells were quantified by examining nuclear morphology and by ISEL of fragmented DNA of the apoptotic nuclei at various timepoints of organ cultures, as indicated. The number of apoptotic cells per hundred epithelial cells, as counted by either method, are shown on the y-axis. The datapoints represent mean counts (±SEM) of 4–8 separate experiments, each based on a total of 40–150 explants examined.

 
Mitotic indices in lateral and dorsal prostates during long-term organ culture in the absence of androgen
Parallel examination of mitosis rates in dorsal and lateral prostates, during the same long-term cultures, revealed a coinciding peak of epithelial cell division during days 2–4 (Fig. 3AGo). The analysis was based on the number of prostate epithelial cells with prominent mitotic chromosomes and mitotic spindles expressed per 100 cells counted. Interestingly, the increased levels of mitotic activity observed in lateral and dorsal prostate explants on day 4 could not be further stimulated by the presence of either Te or PRL in the culture medium (Fig. 3BGo). However, continued incubation of prostate explants in the presence of PRL, for 7 days, revealed a significant stimulatory effect of PRL in both lateral and dorsal prostates (Fig. 3CGo). Te treatment for 7 days also had a significant mitotic effect in lateral, but not in dorsal, prostates (Fig. 3CGo). The mechanism underlying the hormone-independent elevation of mitotic cells, observed during days 2–4 of culture, is unclear, but the process may reflect remodeling and repair of epithelial cell surfaces damaged during preparation of tissue for explant culture. However, the observation of increased mitotic activity in PRL-treated cultures on day 7 supports a role of PRL as a mitogen for prostate epithelial cells (12). These studies led us to hypothesize that PRL might also protect against apoptosis in prostate epithelium.



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  		Figure 3. Mitotic indices of rat dorsal and lateral prostate epithelium during 10 days in organ culture. A, Rat DP and LP explants were cultured for 2, 3, 4, 7, and 10 days in basal medium containing insulin (I) (0.08 IU/ml) and corticosterone (C) (10-7 M). Mitotic epithelial cells of cultured prostate explants were counted per hundred epithelial cells (mitotic indices; y-axis) at various times of organ culture, as indicated (x-axis). The datapoints represent the mean values from 4–8 separate experiments representing a total of 150–200 explants. B, Lack of hormone effects on proliferation on the culture day 4 of prostate organ culture. C, Positive regulation of proliferation by Te and PRL on day 7 of prostate organ culture. Columns represent means ± SEM from 4 separate experiments representing a total of 30–50 explants (B and C). The data were analyzed by one-way ANOVA, followed by Scheffé’s multiple-range test. *, P < 0.05; **, P < 0.01; ***, P < 0.001 vs. IC (B and C). The hormones are I (0.08 IU/ml), corticosterone (10-7 M), PRL (100 nM), and Te (10-7 M).

 
PRL prevents apoptosis in androgen-deprived prostate epithelium in organ culture
We specifically investigated whether PRL would antagonize the surge of apoptosis that we had observed during days 2–4 of androgen-deprived rat prostate organ cultures. Dorsal, lateral, and ventral prostate tissue explants were cultured either in basal medium containing I and corticosteroid alone or supplemented with either PRL or Te for up to 4 days. Corresponding to peak apoptosis rates, explants from 4-day (dorsal and lateral prostate) and 3-day (ventral prostate) cultures were examined for apoptotic cells, by nuclear morphology, whereas 3-day cultures (dorsal and lateral prostate) were used for apoptosis detection by ISEL. The general morphology is shown for dorsal prostate cultures (Fig. 4Go, A–C) and for lateral prostates (Fig. 4Go, D–F) after 4 days of treatment in organ culture. In brief, maintenance of polarized, tall columnar secretory epithelial cells required Te, as previously established (12, 32), whereas either Te or PRL supplementation inhibited epithelial cell apoptosis, when compared with control tissue, of both dorsal and lateral prostate.



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  		Figure 4. Maintenance of morphology and antiapoptotic effect of PRL on rat dorsal and lateral prostate explants cultured for 4 days in organ culture. Morphology of rat DP and LP, cultured for 4 days in basal medium containing I (0.08 IU/ml) and corticosterone (10-7 M) [DP (A); LP (D)] and with 100 nM PRL [DP (B); LP (E)] or with Te (10-7 M) [DP (C); LP (F)]. Arrowheads indicate apoptotic cells (A, D) with cell shrinkage, condensed chromatin, and intracellular apoptotic bodies in explants cultured in basal medium. Magnification, x195; bar, 35 µm.

 
The quantitative results of apoptosis, as measured by nuclear morphology, are shown for dorsal, lateral, and ventral prostate (Fig. 5Go). As determined by nuclear morphology, PRL significantly inhibited apoptosis, in both dorsal and lateral prostate, more than 50% (P < 0.001) but had no effect on apoptosis in ventral prostate tissue. Te was used as a positive control, and it inhibited apoptosis in each prostate lobe. We also examined epithelial cell apoptosis in rat dorsal and lateral prostate at day 3 of culture, using ISEL (Figs. 6Go and 7Go). This histochemical detection method revealed a similar significant reduction in apoptosis rates in individual PRL- or Te-treated cultures (Fig. 6Go), as quantified based on analysis of explants from eight separate experiments (Fig. 7Go). Specifically, PRL significantly inhibited apoptosis by more than 40% in dorsal prostate (P < 0.01) and lateral prostate (P < 0.05), by this method, on day 3 (Fig. 7Go). As expected, Te also effectively inhibited apoptosis, as determined by ISEL. We conclude, from these experiments on organ cultures of individual rat prostate lobes, that PRL can function as an androgen-independent survival factor for normal rat dorsal and lateral prostate epithelium.



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  		Figure 5. Apoptotic indices of rat dorsal, lateral, and ventral prostate in organ culture. DP (A) and LP (B) explants were cultured for 4 days, and ventral prostate (VP) (C) explants were cultured for 3 days in basal medium containing I (0.08 IU/ml) and corticosterone (C) (10-7 M) in the presence or absence of 100 nM PRL. Apoptotic cells were counted per hundred epithelial cells, according to the criteria of nuclear morphology of apoptotic cells. Protection from apoptosis by androgen (Te; 10-7 M) was used as a positive control. Columns represent means ± SEM from 8 (dorsal and lateral prostate) and 5 (ventral prostate) separate experiments representing a total of 50–100 explants. The statistical analysis used was one-way ANOVA, followed by Scheffé’s multiple-range test. ***, P < 0.001.

 


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  		Figure 6. The survival effect of PRL on rat dorsal and lateral prostate epithelium in organ culture, shown by detection of cells with fragmented DNA. The nuclei of epithelial cells with fragmented DNA were visualized in tissue explants of rat dorsal and lateral prostate cultured for 3 days in basal medium containing I (0.08 IU/ml) and corticosterone (10-7 M) in the absence [DP (A); LP (D)] or presence [DP (B); LP (E)] of 100 nM PRL. The DNA ISEL was performed as described in Figs. 1Go and 2Go. Cells with fragmented DNA gave clear positive staining in a number of nuclei of epithelial cells of dorsal and lateral prostate tissue explants cultured without PRL [DP (A); LP (D)] (arrowheads) when compared with explants cultured with PRL or with Te (10-7 M) [DP (C); LP (F)]. Explants cultured with Te were used as a control of presence of androgen regulation of apoptosis in organ culture. Magnification, x195; bar, 35 µm.

 


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  		Figure 7. Quantification of ISEL-positive cells in rat dorsal and lateral prostate explants grown as organ cultures. ISEL cells of DP (A) and LP (B) explants, cultured for 3 days in basal medium I (0.08 IU/ml) and corticosterone (C) (10-7 M) in the presence or absence of 100 nM PRL, were counted per hundred epithelial cells. Protection from apoptosis by androgen (Te; 10-7 M) was used as a positive control. Columns represent means ± SEM from 8 separate experiments representing a total of 50–100 explants. The statistical analysis used was one-way ANOVA, followed by Scheffé’s multiple-range test. *, P < 0.05; **, P < 0.01.

 

   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
In this study, we demonstrate that PRL is a survival factor for rat dorsal and lateral prostate epithelium. This antiapoptotic effect of PRL on prostate epithelial cells adds an important new facet to the regulatory role of PRL in promotion of prostate growth. Previously, PRL had been shown to regulate differentiation and proliferation of rat and human prostate epithelium in organ cultures (12, 13). Using morphologic quantifying of mitotic cells, the present study also demonstrated a mitogenic effect of PRL in androgen-deprived dorsal and lateral prostate, thus extending our previous observation of PRL-stimulated DNA synthesis in prostate tissue explants (12).

A role of PRL as an androgen-independent mitogen and antiapoptotic factor for normal prostate epithelium in organ culture has important implications for understanding the involvement of PRL in regulating growth of benign and malignant prostate. Compelling growth-promoting effects of PRL in rodent prostate was recently demonstrated in transgenic mice overexpressing PRL (11). In these mice, chronic hyperprolactinemia led to marked hyperplasia and a dramatic 20-fold increase in size of dorsolateral prostates. This effect of chronic hyperprolactinemia was prostate-specific and not associated with generally increased organ sizes, supporting the notion that the prostate is a central target organ for PRL in the male. Moreover, in estrogenized male rats, pharmacological suppression of the accompanying hyperprolactinemia completely counteracted the associated prostate epithelial dysplasia (53).

In the human, PRL receptors are also physiologically activated by GH (54), and it is therefore of direct relevance that a study of patients with acromegaly showed a striking degree of prostate hyperplasia, as revealed by ultrasound (55). Even though PRL has been shown to stimulate in vitro growth of primary prostate epithelial cells (56, 57) and the androgen refractory prostate cancer cell lines DU145 and PC-3 (58), there is a lack of a clear correlation between serum PRL levels and prostate cancer risk or disease progression (59). Likewise, in clinical trials of prostate cancer patients, adjuvant treatment with inhibitors of pituitary PRL secretion has only had limited success (60, 61, 62). However, the recent demonstration of local production of PRL in normal and malignant prostate epithelium has suggested an autocrine loop (13, 14). It is therefore possible that autocrine PRL production may obscure the correlation between circulating PRL levels and risk for prostate cancer or disease prognosis, as well as limit the clinical effect of pharmacological suppression of pituitary PRL production in prostate cancer patients. The present study may therefore stimulate further research on PRL promotion of benign and malignant prostate growth, as well as breast tumors, because a similar autocrine PRL loop has been demonstrated in mammary epithelial cells and breast cancer (63, 64, 65).

The long-term prostate organ culture model, applied in the present study, demonstrated its usefulness for in vitro studies of regulation of apoptosis in intact prostate tissue explants. The hormone responsiveness and tissue-specific functions of both rat and human prostate are well preserved in this experimental prostate model (12, 13, 14, 16, 30, 31, 32), which is probably attributable to the maintenance of intact epithelial and stromal compartments and autocrine/paracrine interactions (33, 34, 35). In this study, several fundamental characteristics of apoptosis and mitosis rates in prostate organ culture model were established. When explants from rat ventral, dorsal, or lateral prostates were cultured in basal medium without androgens, a surge of epithelial apoptosis occurred in the prostate tissues during days 2–4 of the 10-day culture period. Parallel to this initial wave of apoptosis, a burst of epithelial mitotic activity was also evident during the first days of culture. This increased mitotic activity during the early phase of organ culture could not be further enhanced by androgen and may represent regeneration and repair after tissue explant cutting. In contrast, apoptosis during this early phase was, to a large extent, blocked by androgen replacement, suggesting that the epithelial apoptosis response was induced by androgen withdrawal. PRL alone could also partly mimic androgen protection against apoptosis. The fact that apoptosis rates in this in vitro model reversed toward low, normal levels within 5–10 days corresponded well with an in vivo tissue response to castration. Long-term prostate organ cultures will therefore also be useful for future studies of endogenous factors that are responsible for restoring normal cell turnover in the residual androgen-deprived epithelial cell population.

Currently, little is known about the signal transduction mechanisms used by PRL in prostate. The effects of PRL on prostate are mediated through the signal transduction pathways triggered by the short and long PRL receptors (15), which we have demonstrated to be expressed in both rat and human prostate (13, 16). Based on studies of mammary gland and hematopoietic cells (66, 67, 68, 69), the Stat5 transcription factor may critically mediate key effects of PRL also in prostate. Interestingly, PRL and Stat5 have recently been associated with antiapoptotic action in a number of cell types (70, 71, 72, 73, 74). Prostate organ culture provides an excellent model to study the signal transduction molecules used by PRL in prostate tissue.

In conclusion, PRL can act as an androgen-independent antiapoptotic factor for normal prostate epithelium, as demonstrated in organ cultures. Factors that stimulate survival of normal prostate epithelial cells during androgen-deprivation may have particular relevance to progression of hormone-refractory prostate cancer. Furthermore, the physiological sensitivity of prostate tissue in organ culture to androgen withdrawal suggests that this experimental in vitro model will be useful for identifying additional androgen-independent survival factors. Finally, this model should also prove useful for studies of prostate epithelial signal transduction mechanisms used by PRL and other factors to keep residual epithelial cells viable during long-term androgen deprivation.


   Acknowledgments
 
The authors thank Ms. Leena Simola for technical assistance.


   Footnotes
 
1 This work was financially supported by the Academy of Finland, the Finnish Cancer Societies, and the Cancer Societies of South-Western Finland, and National Institutes of Health Grant R01-DK-52013. Back

Received March 2, 1999.


   References
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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