Oxidative stress signalling in the apoptosis of Jurkat T-lymphocytes

Within the first 24 h after castration of an adult male rat, the vascular system of the ventral prostate gland undergoes a degenerative process that drastically reduces blood flow to the tissue. Since the vascular degeneration precedes the loss of the prostatic epithelium (by apoptosis), we have proposed that the onset of epithelial cell apoptosis in this tissue is caused by an ischemic/hypoxic environment resulting from the loss of blood flow. In order to further evaluate the extent to which ischemia/hypoxia might be a factor in apoptosis of the prostate epithelium after castration, we analyzed for biomarkers of cellular hypoxia in rat ventral prostates during the first 3 days following castration. Ventral prostate tissues removed from hypoxyprobe-1-treated adult male rats (uncastrated controls; surgically castrated for 24, 48 or 72 h, or sham-castrated for equivalent times) were directly analyzed for evidence of hypoxia by in situ immunohistochemical evaluation of hypoxyprobe-1 adduct formation in the prostate cells. Protein extracts from these tissues were also tested for expression of the 120 kDa hypoxia-inducible factor-1-alpha (HIF-1-alpha) protein as well as for expression of mitogen-activated protein kinase (MAPK) and c-Jun N-terminal kinase (JNK) proteins using a Western blot assay. The tyrosine phosphorylation status of the latter signaling molecules was also evaluated by Western blotting using anti-tyrosine phosphate antibodies. Our results showed that epithelial cells of the rat ventral prostate stained positively for hypoxyprobe-1 adducts at all times after castration, whereas cells in control tissues were unstained by this procedure. In addition, the prostatic expression of HIF-1-alpha protein was increased approximately 20-fold at 48 h after castration compared to control tissues. Finally, although prostatic MAPK and JNK protein expression was unaltered during the early period after castration, phosphorylation of the JUN kinase protein was significantly elevated, indicating that this stress-activated cellular signaling pathway becomes more active subsequent to castration. These results support our proposal that early castration-induced degeneration and constriction of the vascular system of the rat ventral prostate gland leads to reduced oxygenation of prostatic epithelial cells and the activation of hypoxic cellular signaling in these cells through upregulation of HIF-1-alpha expression and stimulation of the JUN kinase signaling pathway.     

The effect of androgen deprivation on branching morphogenesis in the mouse prostate

Androgen-induced prostatic development encompasses many individual processes such as ductal branching morphogenesis, cellular proliferation, and secretory cytodifferentiation. Previous studies of ductal morphogenesis (Y. Sugimura, G.R. Cunha, and A.A. Donjacour, 1986, Biol. Reprod. 34, 961-971) demonstrated that the majority (approximately 70%) of ductal tips and branchpoints in the mouse prostate is generated before 15 days of age. Since circulating androgen levels are low during this neonatal period, it is possible that ductal branching morphogenesis may not require the continuous presence of androgens. To test this hypothesis mice were castrated within 24 hr of birth, and prostates from these mice were microdissected at various ages from 5 to 120 days of age to assess the number of ductal tips and branchpoints; wet weight and DNA content were also determined. In intact males wet weight and DNA content increased rapidly between 15 and 60 days of age, after most of the prostatic ductal architecture had been laid down. Neonatal castration considerably reduced the number of tips and branchpoints in both the ventral and dorsolateral prostate, yet both lobes still underwent significant branching morphogenesis in the absence of testes. The administration of anti-androgens to neonatal castrates did not suppress ductal branching to any greater extent than did neonatal castration alone. Androgen replacement immediately following neonatal castration resulted in precocious attainment of the adult number of tips and branchpoints, but caused only modest increases in wet weight. In contrast, when androgen replacement was delayed until adulthood, prostatic wet weight increased to normal adult levels, but the number of ductal tips and branchpoints did not. These experiments show that neonatal prostatic ductal morphogenesis is sensitive to, but does not require, chronic androgen stimulation.     

In vivo time course of morphological changes and DNA degradation during the degeneration of castration-induced apoptotic prostate cells

The in vivo time course of the morphological changes and DNA degradation in castration-induced apoptotic prostate cells was studied from the earliest to the latest stage of the degeneration process. To study this problem, we first induced apoptotic prostate cells in rats by castration for 3 days and then promptly and continuously blocked the death of healthy prostatic cells in the castrated rats by in vivo testosterone replacement. Because testosterone replacement could not stop the irreversible lysis of already damaged prostate cells, apoptotic cells at different stages of the degeneration process were eliminated sequentially from the prostate after the healthy prostate cells had been protected. Prostate cells at the earliest stage of apoptosis at the time when the castrated rats received testosterone replacement disappeared last. By tracing the morphological and DNA degradation of apoptotic cells after hormone treatment, we estimated the time course of prostate cell death from the early to the final stage. In the morphological evolution of apoptotic prostate cells, the clumping of nuclear chromatin, the degeneration of cytoplasm and the involution of the cell surface occurred and progressed simultaneously, resulting in the rapid formation of apoptotic bodies that were gradually digested by other cells. The DNA ladders of apoptotic cells were progressively cleaved into a mononucleosomal subunit that was further degraded at an additional site, generating a heterogeneous population of small nucleotides. The final digestion of DNA fragments occurred within the apoptotic bodies. The whole course of prostate cell death after castration took about 44 h.     

Internucleosomal DNA fragmentation is not obligatory for castration induced rat ventral prostate cell apoptosis in vivo

Castrated male rats were treated with the reversible S1-phase cell cycle blocking drug, mimosine, and the effects of this drug on prostate cell apoptosis was characterized. At a single dose of mimosine (25 mg/kg/day), we found that the internucleosomal DNA fragmentation associated with apoptosis was partially suppressed in the rat ventral prostate at all early time points (24, 48 and 72 h) analyzed post-castration. This suppression was dose-dependent, and treatment with mimosine up to 150 mg/kg/day was sufficient to reduce the internucleosomal DNA fragmentation in the prostate by 90% at 72 h post-castration. Intriguingly, this drug did not suppress the induction of mRNAs for several apoptosis-associated gene products in the ventral prostate gland (bcl-2, p53, TGF-beta and SGP-2/clusterin). Moreover, this treatment did not suppress the histological appearance of apoptotic bodies in the ventral prostate detectable by fast green staining of thin sections of tissue. The apoptotic bodies present in mimosine-treated regressing ventral prostate tissues, however, were refractory to labeling by the in situ gap labeling method, further demonstrating lack of nuclear DNA fragmentation in the condensed nuclei of apoptotic cells. In summary, the cell cycle-blocking drug mimosine does not appear to affect the rate of apoptosis in the regressing rat ventral prostate gland. However, this drug was capable of suppressing the nuclear DNA fragmentation associated with androgen-regulated prostate cell apoptosis. These results support the concept that nuclear DNA fragmentation is not obligatory for apoptosis. Additionally, they imply that cell cycle movement from the G1/S-phase boundary might be important for the terminal DNA degradation associated with androgen-regulated prostate cell apoptosis.     

The bio/immuno ratio of serum luteinizing hormone increases after orchiectomy in prostatic cancer patients and is associated with decreased molecular weight and appearance of isohormones with alkaline pI values

Serum concentrations of bioactive (B) and immunoreactive (I) luteinizing hormone (LH) were determined in six patients with prostatic cancer before castration and at frequent intervals after the operation up to 6 mo. B-LH increased in 6 mo from 11 +/- 1 to 90 +/- 9 (mean +/- SEM, n = 6) IU/liter (p less than 0.01), and I-LH from 9 +/- 1 to 37 +/- 5 IU/liter (p less than 0.01). Accordingly, a significant increase in the B/I ratio of LH occurred at the same time, from 1.3 +/- 0.1 to 2.4 +/- 0.2 (p less than 0.01). To elucidate the molecular basis of the B/I ratio change, serum samples obtained before and 2-6 mo after orchiectomy were fractionated by gel filtration and chromatofocusing, and the eluted fractions were analyzed for B-LH and I-LH. In gel filtration, the fractions with the highest B-LH and I-LH contents were eluted later in the post-castration samples than in the pretreatment samples (mean Ve/Vo 1.31-1.32 vs. 1.26-1.28; p less than 0.02-0.01), indicating a small reduction in the average Mr of the circulating LH after castration. In chromatofocusing, a single major peak of immunoreactivity with a pI value of 7.4 was identified before castration, but in post-castration samples, a significantly large proportion of the immunoreactivity was eluted in the alkaline pI range 7.4-9 (22.2 +/- 2.4% before, 56.5 +/- 5.2% after castration, p less than 0.05). These findings indicate that after castration, the increased B/I ratio of serum LH is explained by a preferential increase in isohormones with slightly reduced molecular weights and alkaline pI values.     

Androgen regulation of FLICE-like inhibitory protein gene expression in the rat prostate

In hope of eventually identifying defects in human prostatic neoplasias that render them insensitive to anti-androgen therapy, we have examined the regulation of components of ligand-induced cell death pathways during castration-induced regression of the prostate. Rat prostates were obtained after surgical castration with or without subsequent androgen replacement. The mRNA levels of genes encoding components of the apoptotic pathway were measured from individual prostates. Whole prostates 1-10 days after castration did not show a significant change in mRNA levels encoding either Fas or FasL, which some studies suggest are necessary for regression to occur. However, the mRNA encoding a catalytically inactive cysteinyl aspartate-specific protease (caspase) analog, FLICE-like inhibitor protein (FLIP), decreases during the first day following castration. In the most apoptotically responsive ventral lobe of the rat prostate, the reduction in FLIP mRNA levels is evident within 12 h of castration. The mRNA levels of the principal target of FLIP inhibition, caspase-8, do not change during the period preceding the onset of detectable DNA fragmentation. Androgen administration to castrated rats reverses prostate regression, and restores FLIP mRNA to normal levels. By acting as an inhibitor of caspase-8, FLIP may protect prostatic epithelium from apoptosis. Androgen withdrawal, by reducing FLIP mRNA levels, might leave the cells vulnerable to as yet unidentified cell death signals.     

Estrogen receptor β activation impairs prostatic regeneration by inducing apoptosis in murine and human stem/progenitor enriched cell populations

Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin(-)Sca1(+)CD49f(hi)) and human (CD49f(hi)Trop2(hi)) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERβ, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERβ-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERβ activation for prostate disease and suggest that combining selective activation of ERβ with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.     

Estrogen uptake capacity of individual pituitary cell types from male and female rats one, fourteen and fifty days after castration

A quantitative autoradiographic technique was combined with immunocytochemical staining to compare 3H-estrogen uptake in individual pituitary cell types 1, 14 or 50 days after castration in both male and female rats. Silver grains were counted over nuclei of immunocytochemically stained cells and means were computed for each cell type. The order of labelling intensity for all groups was gonadotropes greater than or equal to lactotropes = somatotropes greater than thyrotropes = corticotropes. In male rats 3H-estrogen uptake capacity in all of these cell types remained unchanged over the post-castration interval. Only gonadotropes from female rats demonstrated a significant change in estrogen uptake capacity over the intervals examined. Uptake in these cells increased by 137% between 1 and 50 days after ovariectomy. At both 14 and 50 days post-ovariectomy, gonadotropes concentrated significantly more radioactive label than either lactotropes or somatotropes. One day after castration, gonadotropes from females concentrated less 3H-estrogen than males while at 50 days after castration they concentrated significantly more than gonadotropes from male rats.     

Prostatic ductal system in rats: regional variation in morphological and functional activities

The rat prostate is a complex ductal system with branches and subbranches extending from one end to another. Owing to the relative distance of various regions of the duct from the urethra, the entire length of the ductal system can be arbitrarily divided into three segments, i.e., the proximal, intermediate, and distal segments. The present study was carried out to assess the regional variation in cellular activities in this ductal system. Ventral prostates from adult Sprague-Dawley rats were dissected so that an individual ductal system was mechanically isolated and longitudinally sectioned to reveal various segments. Epithelial cells lining distal segments were tall-columnar type and were actively engaging in mitotic activity. Cells in intermediate segments were also tall-columnar type. However, they were mitotically quiescent, but able to produce secretory proteins. Evidence of programmed cell death was not observed in either of these two segments. Cells in proximal segments, on the other hand, were low-columnar or cuboidal in shape and were stained heavily for cathepsin D, a marker associated with late manifestation of cell death. Following castration in adult rats, there was a reversal in the site of programmed death in cells lining the ductal system. By Day 4 post-castration, distal segments contained many epithelial cells with intense cytoplasmic staining for cathepsin D while proximal segments showed a reduction in number of positively stained cells. By Day 7 post-castration, cells in proximal segments, though atrophied, were devoid of staining for cathepsin D.(ABSTRACT TRUNCATED AT 250 WORDS)     

The influence of nitric oxide on basal and cholecystokinin-8-induced proliferation and apoptosis in the rat pancreas

Nitric oxide (NO) is formed by different cell types in the pancreas. In this study, inhibition of endogenous nitric oxide by N(omega)-nitro-L-arginine (L-NNA) reduced the urinary excretion of NO(2)/NO(3) and raised serum L-arginine and the NO donator S-nitroso-N-acetylpenicillamine (SNAP) increased the urinary excretion of NO(2)/NO(3). The peptide cholecystokinin-8 (CCK-8) has a strong influence on exocrine pancreatic proliferation. Rat pancreas was excised and studied with regard to tissue weight, protein and DNA contents after 3 days of treatment with saline, L-NNA or SNAP given separately or combined with CCK-8. Further, proliferation of different pancreatic cells was studied with [3H]-thymidine incorporation and apoptotic activity was studied by analysing caspase-3 activity and histone-associated DNA fragments. The effects of L-NNA indicate that endogenous nitric oxide formation has a tonic inhibition on apoptosis in the pancreas during both basal condition and growth stimulation by CCK-8. In CCK-induced hyperplasia, NO inhibits the proliferation of acinar cells but stimulates ductal cells. Endogenous NO may regulate the balance between proliferation and apoptosis and in a situation of growth stimulation by CCK-8, it has a tonic inhibition on both mitogenesis and apoptosis thus slowing down the acinar cell turnover in the pancreas.     

Flt3 ligand expands dendritic cell numbers in normal and malignant murine prostate

We have developed a murine model that facilitates the structural and functional analysis in vivo of dendritic cell (DC)-mediated phagocytosis of prostate epithelial cells. Recombinant human Flt3 ligand (rhFL) expands the number of dendritic cells in lymphoid and non-lymphoid tissues of mice. We show that rhFL also induced the ingress of dendritic cells into murine prostate, which involutes via epithelial apoptosis after surgical castration. Intact or castrated C57BL/6 and syngeneic transgenic adenocarcinoma of mouse prostate (TRAMP) mice were treated with rhFL or PBS control. Prostate and spleen were then studied by flow cytometry and immunohistochemistry.The number of prostatic CD11c+ and CD11b+ dendritic cells increased significantly in rhFL-treated mice compared with PBS-treated control mice and this effect was greatly augmented by castration of the mice. The immunophenotype of rhFL-mobilized prostatic cells was consistent with that of Langerhans cells (MHC class II+, CD11c+,CD11b+, DEC-205+, CD8 alpha-).MHC class II+ and CD11c+ dendritic cells that were present in the prostate glands of rhFL-treated and castrated C57BL/6 mice were intimately associated with TUNEL+ inclusions, which suggests that Langerhans-type dendritic cells in prostate participated in the clearance of apoptotic cells. Expression of MHC class II, CD54, CD80 and CD86 by prostatic dendritic cells was not up-regulated after castration and freshly isolated rhFL-induced prostate cells were unable to prime allogeneicT cells unless they were activated by culture either on plastic or with recombinant soluble CD40 ligand. Our data suggest that rhFL-mobilized prostatic dendritic cells resemble the functionally immature dendritic cells, which reside in peripheral tissues and contribute to the maintenance of peripheral tolerance.     

Factors influencing prostatic 5 alpha-reductase activity in possum (Trichosurus vulpecula)

1. There were marked differences in prostatic wts among individual possums, but no evidence of a seasonally related change in wt could be established. It was concluded that the wt differences are mainly due to the changes in secretory activities. After castration the prostate wts fell while after administration of testosterone or oestradiol partially reversed this process. 2. Seven steroid conversion products were isolated from prostatic homogenates incubated with [3H] testosterone; 5 alpha-androstane-3 beta,17 beta-diol forming the highest yield. 3. While the 5 alpha-reductase activity of prostates from intact possums was very low (approx. 8% of the total yield), it increased to over 50% after castration. 4. Administration of testosterone or oestradiol partially reversed the post-castration rise in 5 alpha-reductase, while 17 beta-hydroxy-5 alpha-androstane-3-one (DHT) was ineffective. Administration of porcine FSH-NIH-P2 to both intact or castrated possums caused a marked rise in prostatic 5 alpha-reductase activity. 5. It was concluded that in possum, FSH may have a direct stimulatory effect on prostatic 5 alpha-reductase activity. The results are discussed in relation to placental mammals.     

Neuropeptides bombesin and calcitonin induce resistance to etoposide induced apoptosis in prostate cancer cell lines

BACKGROUND: Neuroendocrine differentiation in prostatic carcinoma has been related to regulation of proliferation and metastatic potential and correlated with prognosis. More than 80% of prostate carcinomas initially respond to androgen ablation, but most relapse, due to the heterogeneous presence of androgen-dependent and independent clones. The pathways of cellular proliferation and apoptosis are inexorably linked to minimize the occurrence of neoplasia, and disfunction of apoptosis is proposed as a pathogenic process in malignant tumors. Androgen-dependent prostatic cancer cells undergo apoptosis after androgen deprivation, but not androgen-independent ones due to a defect in the initiation step. Anyway, they retain the basic cellular machinery to undergo apoptosis. We suggest a possible role of neuroendocrine differentiation in the onset and regulation of apoptosis in prostatic neoplasia. METHODS: LNCaP, PC-3 and DU 145 prostatic cancer cell lines were induced to undergo apoptosis after treatment with etoposide alone or plus androgen ablation. We tested the role of neuropeptides bombesin and calcitonin at modulating etoposide induced apoptosis. RESULTS: Etoposide-induced apoptosis in all cancer cell lines was achieved. In LNCaP androgen ablation was also required. Apoptosis is prevented in all three lines when bombesin was added. Calcitonin addition prevents apoptosis in PC-3, LNCaP and in an etoposide dose-dependent way in DU 145. CONCLUSION: Neuropeptides bombesin and calcitonin can modulate the apoptotic response of prostate cancer cells by inducing resistance to etoposide-induced apoptosis, suggesting that neuropeptides can be used as a target of therapeutical approach in prostatic carcinoma.     

Escherichia coli induces apoptosis and proliferation of mammary cells

Mammary cell apoptosis and proliferation were assessed after injection of Escherichia coli into the left mammary quarters of six cows. Bacteriological analysis of foremilk samples revealed coliform infection in the injected quarters of four cows. Milk somatic cell counts increased in these quarters and peaked at 24 h after bacterial injection. Body temperature also increased, peaking at 12 h postinjection. The number of apoptotic cells was significantly higher in the mastitic tissue than in the uninfected control. Expression of Bax and interleukin-1beta converting enzyme increased in the mastitic tissue at 24 h and 72 h postinfection, whereas Bcl-2 expression decreased at 24 h but did not differ significantly from the control at 72 h postinfection. Induction of matrix metalloproteinase-9, stromelysin-1 and urokinase-type plasminogen activator was also observed in the mastitic tissue. Moreover, cell proliferation increased in the infected tissue. These results demonstrate that Escherichia coli-induced mastitis promotes apoptosis and cell proliferation.     

Ultrastructural and biochemical observations on the early changes in apoptotic epithelial cells of the rat prostate induced by castration

The present study describes the sequential ultrastructural changes in the apoptotic cells of the rat ventral and dorsal prostates during the early period of 1-3 days postcastration. The major morphological changes include: (1) condensation of heterochromatin along the nuclear envelope and fragmentation into crescent-shaped micronuclei; (2) formation of membrane-bound cytoplasmic spherical bodies, which contain various organelles and micronuclei, within the apoptotic cells; (3) formation of non-membrane-bound autolytic vacuoles by autolysis of cytoplasm; (4) focal rupture of outer mitochondrial membrane; and (5) phagocytosis of the fragmented cytoplasmic spherical bodies and apoptotic cells by macrophages. The occurrence of both cytoplasmic apoptotic bodies and autolytic vacuoles in apoptotic cells suggests that the cytoplasm of the apoptotic cells could be destroyed by different means. The responsiveness of different prostatic lobes to androgen withdrawal and the time course of the transitory apoptotic activity in different lobes were analyzed by counting the indices of the TUNEL-labeled apoptotic cells against the postcastration periods. The results showed that the ventral lobe responded more rapidly to castration than the lateral and dorsal lobes. The dorsal lobe was the slowest in response to castration among the three lobes. Analysis of protease activities by zymography has identified two Ca(2+)-independent proteases of apparent MW 20 and 24 kDa (expressed in both ventral and dorsolateral lobes), and one Ca(2+)-dependent protease of MW 66.5 kDa (expressed only in the dorsolateral lobe) which became activated at day 3 postcastration. Their expression patterns were different from that of CPP-3 in the castrated prostates, suggesting that the activated proteases were enzymes other than CPP-3. The association of their highest activities with the maximum apoptotic activity at day 3 postcastration and also their loss of activity at day 15 suggest that these protease activities might be related to apoptosis or glandular involution.     

Glyceraldehyde-3-phosphate dehydrogenase expression during apoptosis and proliferation of rat ventral prostate.

Glyceraldehyde-3-phosphate dehydrogenase (GAPDH) is a multifunctional enzyme known to play a critical role in neuronal apoptosis. We undertook the current studies to determine whether GAPDH also plays a role in prostate epithelial cell apoptosis in response to androgen deprivation. To do so, we analyzed GAPDH staining by immunohistochemistry during castration-induced involution and androgen-induced regeneration of rat ventral prostate. We found that GAPDH was undetectable in secretory epithelial cells at baseline and that staining did not increase in the epithelium during the period of peak apoptosis from 1 to 3 days after castration. However, GAPDH levels did increase within nuclei of some basal epithelial cells 5 days after castration and within the cytoplasm of all secretory epithelial cells 7 days after castration. GAPDH was also abundant within the cytoplasm of secretory epithelial cells during the period of maximal cell proliferation from 2 to 3 days after androgen replacement and was clearly apparent within nuclei of some epithelial cells 4 days after androgen replacement. Our studies suggest that GAPDH plays multiple roles during prostate epithelial cell apoptosis and proliferation.     

Vitamin A deficiency inhibits intestinal adaptation by modulating apoptosis,proliferation, and enterocyte migration

In a prior study, vitamin A-deficient rats subjected to submassive small bowel resections did not mount a normal intestinal adaptive response by 10 days postoperatively, although adaptive increases in crypt cell proliferation were not attenuated and there were no differences in apoptotic indexes. The present study was designed to address the mechanisms by which vitamin A status effects adaptation by analyzing proliferation, apoptosis, and enterocyte migration in the early postoperative period (16 and 48 h) in vitamin A-sufficient, -deficient, and partially replenished sham-resected and resected rats. At 16 h postresection, apoptosis was significantly greater in the remnant ileum of resected vitamin A-deficient rats compared with the sufficient controls. Crypt cell proliferation was increased by resection in all dietary groups at both timepoints. However, at 48 h postresection, proliferation was significantly decreased in the vitamin A-deficient and partially replenished rats. By 48 h after resection, vitamin A deficiency also reduced enterocyte migration rates by 44%. This occurred in conjunction with decreased immunoreactive collagen IV at 48 h and 10 days postoperation. Laminin expression was also reduced by deficiency at 10 days postresection, whereas fibronectin and pancadherin were unchanged at 48 h and 10 days. These studies indicate that vitamin A deficiency inhibits intestinal adaptation following partial small bowel resection by reducing crypt cell proliferation, by enhancing early crypt cell apoptosis, and by markedly reducing enterocyte migration rates, which may be related to changes in the expression of collagen IV and other extracellular matrix components.     

Stromal-epithelial interactions and heterogeneity of proliferative activity within the prostate

Growth and functional activity within the prostate gland is known to be regulated by androgens whose effects are thought to be mediated via androgen receptors. This concept has been derived in large part through analysis of whole organ homogenates, an approach which ignores potential heterogeneity of biological activity within the gland and the importance of cell-cell interactions. In this review recent findings are summarized which demonstrate that growth of the prostatic ductal network during prepubertal periods, as well as during prostatic regeneration in androgen-treated adult castrates, is nonuniform, with ductal growth being highest at the ductal tips and much lower in proximal ducts closer to the urethra. Androgen dependency for maintenance of ductal architecture following castration follows a similar pattern in that castration results in total destruction of distal ductal architecture, while proximal ducts are maintained albeit in an atrophic state. Thus, striking differences in biological properties are found in distal versus proximal prostatic ducts. Morphogenesis, growth, and secretory cytodifferentiation within the developing prostate is elicited by androgens which act via mesenchymal-epithelial interactions. Through analysis of chimeric prostates constructed with androgen-receptor-positive wild-type mesenchyme and androgen-receptor-negative Tfm (testicular feminization) bladder epithelium, it is now evident that androgenic effects can be elicited in androgen-receptor-deficient (androgen-insensitive) Tfm prostatic epithelium, provided that the connective tissue component of the chimeric prostate is wild type. This observation has been made for both the developing and adult prostate. From this data it is evident that certain androgenic effects (ductal morphogenesis, epithelial growth, and secretory cytodifferentiation) do not require the presence of intraepithelial androgen receptors.(ABSTRACT TRUNCATED AT 250 WORDS)     

Morphological and histological study of castration-induced degeneration and androgen-induced regeneration in the mouse prostate

Degenerative and regenerative changes in the ductal architecture of the ventral and dorsolateral prostates (VP and DLP) of the adult mouse were investigated in microdissected specimens over a time-course of 14 days following castration and subsequently during 14 days of administration of testosterone propionate. After castration, about 35% of the ductal tips and branch-points were lost in distal regions (usually near the capsule) in both prostatic lobes. By contrast, in more proximal regions of the prostate (closer to the urethra), the ducts survived in an atrophic condition. The ductal morphology that had been lost in the distal regions completely regenerated after testosterone propionate was administered to the castrated males. In the VP, androgen replacement simply returned the gland to its former size with moderate ductal distension; in the DLP, excessive epithelial infoldings and ductal distension were elicited in the distal regions of the ducts after 14 days of treatment with testosterone propionate. These results suggest that androgenic responsiveness and dependency are different in distal versus proximal ducts. Distal ducts are exquisitely androgen-dependent and androgen-sensitive; in proximal regions, androgen-dependency is not as strict.