Normal Development and Carcinogenesis of the Prostate (original) (raw)
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Development of the human prostate
Differentiation
This paper provides a detailed compilation of human prostatic development that includes human fetal prostatic gross anatomy, histology, and ontogeny of selected epithelial and mesenchymal differentiation markers and signaling molecules throughout the stages of human prostatic development: (a) pre-bud urogenital sinus (UGS), (b) emergence of solid prostatic epithelial buds from urogenital sinus epithelium (UGE), (c) bud elongation and branching, (d) canalization of the solid epithelial cords, (e) differentiation of luminal and basal epithelial cells, and (f) secretory cytodifferentiation. Additionally, we describe the use of xenografts to assess the actions of androgens and estrogens on human fetal prostatic development. In this regard, we report a new model of de novo DHT-induction of prostatic development from xenografts of human fetal female urethras, which emphasizes the utility of the xenograft approach for investigation of initiation of human prostatic development. These studies raise the possibility of molecular mechanistic studies on human prostatic development through the use of tissue recombinants composed of mutant mouse UGM combined with human fetal prostatic epithelium. Our compilation of human prostatic developmental processes is likely to advance our understanding of the pathogenesis of benign prostatic hyperplasia and prostate cancer as the neoformation of ductal-acinar architecture during normal development is shared during the pathogenesis of benign prostatic hyperplasia and prostate cancer.
The Role of Estrogens in Normal and Abnormal Development of the Prostate Gland
Annals of the New York Academy of Sciences, 2006
Estrogens play a physiologic role during prostate development with regard to programming stromal cells and directing early morphogenic events. However, if estrogenic exposures are abnormally high during the critical developmental period, permanent alterations in prostate branching morphogenesis and cellular differentiation will result, a process referred to as neonatal imprinting or developmental estrogenization. These perturbations are associated with an increased incidence of prostatic lesions with aging, which include hyperplasia, inflammation, and dysplasia. To understand how early estrogenic exposures can permanently alter the prostate and predispose it to neoplasia, we examined the effects of estrogens on prostatic steroid receptors and key developmental genes. Transient and permanent alterations in prostatic AR, ERα, ERβ, and RARs are observed. We propose that estrogeninduced alterations in these critical transcription factors play a fundamental role in initiating prostatic growth and differentiation defects by shifting the prostate from an androgen-dominated gland to one whose development is regulated by estrogens and retinoids. This in turn leads to specific disruptions in the expression patterns of key prostatic developmental genes that normally dictate morphogenesis and differentiation. Specifically, we find transient reductions in Nkx3.1 and permanent reductions in Hoxb-13, which lead to differentiation defects particularly within the ventral lobe. Prolonged developmental expression of Bmp-4 contributes to hypomorphic growth throughout the prostatic complex. Reduced expression of Fgf 10 and Shh and their cognate receptors in the dorsolateral lobes leads to branching defects in those specific regions in response to neonatal estrogens. We hypothesize that these molecular changes initiated early in life predispose the prostate to the neoplastic state upon aging.
Differentiation of rat neonatal ventral prostates grown in a serum‐free organ culture system
The Prostate, 1997
BACKGROUND. Organ culture methods have long been used in the study of the prostate because effects of drugs and hormones can be examined in the absence of systemic effects. METHODS. Neonatal rat ventral prostates (VP) were grown on Millipore filters floating on fluid medium composed of Dulbecco's modified Eagle's medium/Ham's F-12 supplemented with insulin, transferrin, and hydrocortisone, and in the presence or absence of testosterone (T, 10 −8 M). RESULTS. In the presence of T, ductal lumen formation occurred, ductal branching was extensive, and basal and luminal epithelial cells were identified by immunocytochemistry based on their distinctive cytokeratin profile. In the absence of T, ductal lumen formation did not occur, basal and luminal epithelial cells failed to differentiate, and there was a marked decrease in prostatic organ size relative to glands grown with T. Interestingly, DNA synthesis, as measured by counts per min (CPM) for 3 H-thymidine incorporation, showed that DNA synthesis per g DNA at 7 days of organ culture was not inhibited by lack of T. Androgen receptor expression is another marker of prostatic epithelial differentiation, and it occurred in both the presence and absence of T. CONCLUSIONS. Growth and differentiation of the neonatal rat prostate in vitro occur in a manner similar to that of the developing prostate in vivo, demonstrating that organ cultures of neonatal rat ventral prostates provide a faithful model for studying rat prostatic development and differentiation under serum-free conditions.
Postnatal growth of the ventral prostate in Wistar rats: A stereological and morphometrical study
The Anatomical Record Part A: Discoveries in Molecular, Cellular, and Evolutionary Biology, 2006
Morphological and stereological analyses were used to characterize the growth kinetics of the Wistar rat ventral prostate (VP). Volume density and absolute volume of the epithelium, lumen, smooth muscle cells (SMCs), and nonmuscular stroma were determined by stereology and paired with plasma testosterone levels and different morphometric measurements. The VP shows an initial growth within the first 3 weeks, a resting phase, and the puberal growth. The puberal growth was coincident with the raise in plasma testosterone. Lumen formation occurred within the 3 postnatal weeks. After an expected increase during puberty, the lumen showed a further increase at the 12th week. The volume density of the nonmuscular stroma and of the SMCs decreased slowly postnatally. Absolute volume of the luminal compartment showed three phases of growth (weeks 1-3, 6 -9, and 11-12). On the other hand, the increase in the absolute volume of the epithelium was steady up to the 8th week and then showed a marked increase up the 10th week. The increase in epithelial volume was characterized morphologically by the presence of epithelial infoldings and sprouts. The growth of the epithelium showed a 2-week delay as compared to the lumen and occurred only until the 10th week. The epithelial height was variable but could be related to the synthetic activity of the epithelium. In conclusion, the postnatal growth of the VP results from a combination of epithelial proliferation/differentiation and synthesis/accumulation of the secretory products in the lumen. Anat Rec Part A, 288A:885-892, 2006.
Evidence That Estrogens Directly Alter Androgen-Regulated Prostate Development*
Endocrinology, 2000
Neonatal exposure to high doses of estrogen results in permanent suppression of prostate growth and reduced sensitivity to androgens in adulthood. It is unclear whether alterations in prostate growth are due to a direct effect of estrogens on the gland or are the result of hypothalamic-pituitary-gonadal axis suppression and a subsequent reduction in androgen levels. Therefore, the aim of this study was to determine whether estrogens have a direct effect on the prostate using a defined method of culturing neonatal prostates. Newborn rat ventral prostates were microdissected and cultured in the presence of testosterone, which resulted in branching morphogenesis and ductal canalization. Solid cords of epithelium differentiated into acini lined by tall columnar epithelial cells; these acini were surrounded by stromal cells, expressing smooth muscle ␣-actin. When cultured in the presence of 17-estradiol or diethylstilbestrol in addition to testosterone, androgen-induced prostatic growth was reduced, and differentiation was altered. Although Materials and Methods Animals and tissue collection Newborn Sprague Dawley male rats were obtained from Central Animal Services, Monash University (Clayton, Australia), and killed on
The Anatomical record, 1973
Standard tissue culture and epithelio-mesenchymd separation and recombination techniques were applied to the question of sex determination of the male urogenital sinus of embryonic mice. Explants of urogenital sinuses from 12-to 17day old embryos were cultured in an androgen-free environment to a gestational age equivalency of 18 to 20 days. The developmental response of these explants led to the following conclusions: (1) Androgens are necessary for initiation of prostatic bud outgrowth; (2) The effect of androgens can be demonstrated at the stage when the fetal testis begins to secrete androgens; and (3) Prior to the appearance of prostatic buds, the urogenital sinus has the capacity to pursue that developmental end-point independently of further androgen stimulation. In addition, the developmental response of recombinants composed of androgen-treated and untreated epithelium and mesenchyme from the urogenital sinus has shown that it is the epithelium which is primarily determined by androgens during prostatic morphogenesis.
Molecular Signaling Pathways That Regulate Prostate Gland Development
Differentiation, 2008
Prostate gland development is a complex process that involves coordination of multiple signaling pathways including endocrine, paracrine, autocrine, juxtacrine and transcription factors. To put this into proper context, the present manuscript will begin with a brief overview of the stages of prostate development and a summary of androgenic signaling in the developing prostate, which is essential for prostate formation. This will be followed by a detailed description of other transcription factors and secreted morphogens directly involved in prostate formation and branching morphogenesis. Except where otherwise indicated, results from rodent models will be presented since studies that examine molecular signaling in the developing human prostate gland are sparse at the present time.