Adult Prostate Research Articles

Age-related histological and zinc content changes in adult nonhyperplastic prostate glands

To clarify age-related histological and Zn content changes in nonhyperplastic adult prostate glands, a quantitative morphometric and energy-dispersive X-ray fluorescence analyses were performed. The prostates were obtained from autopsies of 63 subjects aged 21-70 years who died mainly from trauma. It was found that histologically normal prostate tissue undergoes substantial changes throughout aging. These changes are reflected in an increase of the percent volume of the glandular lumen for the third to fifth decades, reaching a maximum for the decade 41-50 years. Over the same period, the percent volume of the stroma remains steady, but the percent volume of epithelium decreases, approximately, linearly with age. The percent volume of glandular lumen (reflects the volume of prostatic fluid) in the prostate gland of men aged 41 to 50 years is 1.5-fold higher than that in men aged 21 to 30 years, but the epithelium/lumen (prostatic fluid) ratio is approximately twofold lower. This suggests that accumulation of the prostatic fluid develops from 30 to 50 years of age. This accumulation of the prostatic fluid results in an increase of the Zn mass fraction in the prostate. In turn, when the intraprostatic Zn level exceeds a certain level by the end of the fifth decade, it begins to work as a trigger for different factors, all of which increase the proliferation of stromal cells. Deductions from these results allow possible partial explanations of both relevant prostatic aging mechanisms and the effects of dietary interventions using supplementary Zn.

Stress-Response Protein RBM3 Attenuates the Stem-like Properties of Prostate Cancer Cells by Interfering with CD44 Variant Splicing

Stress-response pathways play an important role in cancer. The cold-inducible RNA-binding protein RBM3 is upregulated in several types of cancer, including prostate cancer, but its pathogenic contributions are undetermined. RBM3 is expressed at low basal levels in human fetal prostate or in CD133(+) prostate epithelial cells (PrEC), compared with the adult prostate or CD133-PrEC, and RBM3 is downregulated in cells cultured in soft agar or exposed to stress. Notably, RBM3 overexpression in prostate cancer cells attenuated their stem cell-like properties in vitro as well as their tumorigenic potential in vivo. Interestingly, either overexpressing RBM3 or culturing cells at 32°C suppressed RNA splicing of the CD44 variant v8-v10 and increased expression of the standard CD44 (CD44s) isoform. Conversely, silencing RBM3 or culturing cells in soft agar (under conditions that enrich for stem cell-like cells) increased the ratio of CD44v8-v10 to CD44s mRNA. Mechanistic investigations showed that elevating CD44v8-v10 interfered with MMP9-mediated cleavage of CD44s and suppressed expression of cyclin D1, whereas siRNA-mediated silencing of CD44v8-v10 impaired the ability of prostate cancer cells to form colonies in soft agar. Together, these findings suggested that RBM3 contributed to stem cell-like character in prostate cancer by inhibiting CD44v8-v10 splicing. Our work uncovers a hitherto unappreciated role of RBM3 in linking stress-regulated RNA splicing to tumorigenesis, with potential prognostic and therapeutic implications in prostate cancer.

Id4 deficiency attenuates prostate development and promotes PIN-like lesions by regulating androgen receptor activity and expression of NKX3.1 and PTEN

BackgroundInhibitor of differentiation 4 (Id4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer. Id4 is expressed in the normal prostate where its expression is also regulated by androgens. In this study we investigated the effect of loss of Id4 (Id4-/-) on adult prostate morphology.MethodsHistological analysis was performed on prostates from 6-8 weeks old Id4-/-, Id4+/- and Id4+/+ mice. Expression of Id1, Sox9, Myc, androgen receptor, Akt, p-Akt, Pten and Nkx3.1 was investigated by immunohistochemistry. Androgen receptor binding on NKX3.1 promoter was studied by chromatin immuno-precipitation. Id4 was either over-expressed or silenced in prostate cancer cell lines DU145 and LNCaP respectively followed by analysis of PTEN, NKX3.1 and Sox9 expression.ResultsId4-/- mice had smaller prostates with fewer tubules, smaller tubule diameters and subtle mPIN like lesions. Levels of androgen receptor were similar between wild type and Id4-/- prostate. Decreased NKX3.1 expression was in part due to decreased androgen receptor binding on NKX3.1 promoter in Id4-/- mice. The increase in the expression of Myc, Sox9, Id1, Ki67 and decrease in the expression of PTEN, Akt and phospho-AKT was associated with subtle mPIN like lesions in Id4-/- prostates. Finally, prostate cancer cell line models in which Id4 was either silenced or over-expressed confirmed that Id4 regulates NKX3.1, Sox9 and PTEN.ConclusionsOur results suggest that loss of Id4 attenuates normal prostate development and promotes hyperplasia/dysplasia with subtle mPIN like lesions characterized by gain of Myc and Id1 and loss of Nkx3.1 and Pten expression. One of the mechanisms by which Id4 may regulate normal prostate development is through regulating androgen receptor binding to respective response elements such as those on NKX3.1 promoter. In spite of these complex alterations, large neoplastic lesions in Id4-/- prostates were not observed suggesting the possibility of mechanisms/pathways such as loss of Akt that could restrain the formation of significant pre-cancerous lesions.

INAA application in the assessment of Ag, Co, Cr, Fe, Hg, Rb, Sb, Sc, Se, and Zn mass fraction in pediatric and young adult prostate glands

The effect of age on trace element contents in intact prostate of 50 apparently healthy 0–30 year old males was investigated by neutron activation analysis with high resolution spectrometry of long-lived radionuclides. Mean values (M ± SEΜ) for mass fraction (milligram per kilogram, on dry-weight basis) of trace elements were: Ag 0.0708 ± 0.0096, Co 0.0348 ± 0.0040, Cr 0.466 ± 0.069, Fe 100 ± 10, Hg 0.0258 ± 0.0025, Rb 12.6 ± 0.8, Sb 0.0576 ± 0.0066, Sc 0.0125 ± 0.0016, Se 0.478 ± 0.031, and Zn 273 ± 31, respectively. A strongly pronounced tendency of age-related increase in Se and Zn mass fraction and of age-related decrease in Co, Cr, Fe, and Sc mass fraction was observed in period of life from 0 to 30 years.

An Integrative Review of Nursing Research on Active Surveillance in an Older Adult Prostate Cancer Population

To summarize the current state of nursing knowledge regarding the management of older adult men with prostate cancer with active surveillance as the treatment strategy. Publications of nursing research from January 2003 to March 2012 addressing patients with prostate cancer undergoing an active surveillance treatment management strategy. DATA EVALUATION AND ANALYSIS: A paradigm shift in the recommendation to consider active surveillance is apparent in the literature. Since 2003, active surveillance has become a more frequent recommendation as the management approach for low-risk, small-volume prostate cancers. Current nursing literature provides data on decision making and the uncertainty associated with active surveillance; however, minimal information is available that specifically addresses the needs of the aging adult population with prostate cancer. In addition, the trajectory of adaptation has only been preliminarily identified within the body of nursing knowledge; the actions that promote or obstruct successful adaptation to active surveillance as a treatment approach require in-depth study. PRESENTATION OF FINDINGS: Active surveillance has relevance for the aging population while providing a potential means to judiciously allocate medical resources and expenses within the healthcare delivery system. The nurse researcher, in partnership with the advanced practice nurse, should proactively address the multifaceted needs of this patient population. Active surveillance, as a program of cooperative, intentional, and prescribed monitoring of prostate cancer with a clearly defined strategy for management, is ideally suited for nursing research into the adaptation, educational needs, and management of chronic disease processes of older adult men while advancing the educator and provider roles of the advanced practice nurse. Active surveillance is an appropriate treatment option in older men with low-risk, low-volume prostate cancer. However, this treatment also is a source of uncertainty. Targeted, ongoing nursing education about active surveillance as treatment must address this uncertainty in this patient population so patients are comfortable with planned monitoring.

Twenty-five Cases of Adult Prostate Sarcoma Treated at a High-volume Institution From 1989 to 2009

To analyze the clinical characteristics, treatment modalities, and outcomes of adult prostate sarcoma treated at our institution. The medical records of 25 adult patients with prostate sarcoma were obtained from January 1989 to December 2009. The clinicopathologic parameters were evaluated to determine their effect on survival. The median age was 37 years (range 18-81). The median tumor size was 9.5 cm (range 4-25). The median serum prostate-specific antigen level was 1.39 ng/mL (range 0.39-33.20). The most common symptom was dysuria (72%). Transrectal ultrasound-guided needle biopsy was used to diagnose 22 sarcomas, transurethral resection of the prostate to diagnose 2, and open surgery to diagnose 1. The predominant histologic subtype was leiomyosarcoma (40%); 21 (88%) were high grade and 6 patients had metastatic disease. Surgical resection of curative intent was performed in 14 patients, with negative margins in 10. After a median follow-up of 21 months (range 5-63), 2 patients were disease free, 4 were alive with disease, and 19 had died of their disease. Overall, the 1-, 2-, 3-, and 5-year survival rate was 80.0%, 47.4%, 22.6%, and 11.3%, respectively, and the median survival time was 23 months. The median survival time after recurrence was 20 months (range 9-39) and that after metastasis was 10 months (range 3-23). Age >50 years, metastasis at presentation, and a lack of surgery with curative intent were independently predictive of an unfavorable outcome. Adult prostate sarcoma accounted for 0.7% of primary prostate malignancies and carried a poor prognosis. Early diagnosis and surgical resection with curative intent offer patients the best chance of survival.

Abstract 1355: Biospecimen preferences of African-American cancer survivors for cancer genetic research.

Abstract Background: Research based on large population-based biobanks has potential to ameliorate health disparities attributed to biological and genetic differences. Study goals were to identify associations of cancer survivors’ sample preferences with sociodemographic characteristics and familiarity with genetic research and testing. Methods: Information was analyzed on a convenience sample of 158 adult African-American breast, colon or prostate cancer survivors who expressed a willingness to provide a biospecimen for cancer genetic research. Information was collected from a self-directed instrument that measured: 1) demographics, 2)familiarity with genetic research and testing, and 3)willingness to provide a variety of sample types. Descriptive statistics and bivariate chi-square analyses were utilized. Results: Sample preference variation (N=158) consisted of: 65%, 62% and 18% willing to donate blood, saliva and tissue, respectively. One third (n= 53) endorsed willingness to provide only one form of biological sample (blood, saliva, or tissue). Significant associations were detected between willingness to provide tissue and individuals < 50 years of age (p=0.04). Sample preferences were not otherwise related to age at cancer diagnosis, gender, income, educational status, or familiarity with genetic testing or genetic research. Conclusions/Impact: Providing options of acceptable biological sample types may yield increased donation from minorities. Inadvertently, this may introduce quality control challenges in obtaining sufficient or multiple forms of biological samples. Identifying additional predictive factors for samples preferences may lead to improvements in methods used to obtain biospecimens from minority populations. Citation Format: Altovise T. Ewing, Lori AH Erby, Luisel J. Ricks-Santi, Nnenna Kalu, Denise M. Scott. Biospecimen preferences of African-American cancer survivors for cancer genetic research. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 1355. doi:10.1158/1538-7445.AM2013-1355 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

A Novel Model of Urinary Tract Differentiation, Tissue Regeneration, and Disease: Reprogramming Human Prostate and Bladder Cells into Induced Pluripotent Stem Cells

BackgroundPrimary culture and animal and cell-line models of prostate and bladder development have limitations in describing human biology, and novel strategies that describe the full spectrum of differentiation from foetal through to ageing tissue are required. Recent advances in biology demonstrate that direct reprogramming of somatic cells into pluripotent embryonic stem cell (ESC)-like cells is possible. These cells, termed induced pluripotent stem cells (iPSCs), could theoretically generate adult prostate and bladder tissue, providing an alternative strategy to study differentiation. ObjectiveTo generate human iPSCs derived from normal, ageing, human prostate (Pro-iPSC), and urinary tract (UT-iPSC) tissue and to assess their capacity for lineage-directed differentiation. Design, setting, and participantsProstate and urinary tract stroma were transduced with POU class 5 homeobox 1 (POU5F1; formerly OCT4), SRY (sex determining region Y)-box 2 (SOX2), Kruppel-like factor 4 (gut) (KLF4), and v-myc myelocytomatosis viral oncogene homolog (avian) (MYC, formerly C-MYC) genes to generate iPSCs. Outcome measurements and statistical analysisThe potential for differentiation into prostate and bladder lineages was compared with classical skin-derived iPSCs. The student t test was used. Results and limitationsSuccessful reprogramming of prostate tissue into Pro-iPSCs and bladder and ureter into UT-iPSCs was demonstrated by characteristic ESC morphology, marker expression, and functional pluripotency in generating all three germ-layer lineages. In contrast to conventional skin-derived iPSCs, Pro-iPSCs showed a vastly increased ability to generate prostate epithelial-specific differentiation, as characterised by androgen receptor and prostate-specific antigen induction. Similarly, UT-iPSCs were shown to be more efficient than skin-derived iPSCs in undergoing bladder differentiation as demonstrated by expression of urothelial-specific markers: uroplakins, claudins, and cytokeratin; and stromal smooth muscle markers: α-smooth-muscle actin, calponin, and desmin. These disparities are likely to represent epigenetic differences between individual iPSC lines and highlight the importance of organ-specific iPSCs for tissue-specific studies. ConclusionsIPSCs provide an exciting new model to characterise mechanisms regulating prostate and bladder differentiation and to develop novel approaches to disease modelling. Regeneration of bladder cells also provides an exceptional opportunity for translational tissue engineering.

A CONSORT Clinical Trial Reporting Compliance Audit of the Oncology Randomized Controlled Trial Literature

Introduction: The Consolidated Standards for Reporting Trials (CONSORT) checklist has been formulated to improve the reporting of randomized controlled trials (RCTs). This investigation aims to determine predictors of CONSORT checklist compliance in the oncology literature. Methods: Eight-hundred and fifty articles assessing interventions in adult breast, prostate, colorectal, and lung cancer between 1992-2010 were identified by a systematic search. Exclusion criteria included investigations reporting interim/secondary/long-term update analyses, pilot/phase 2/non-parallel design studies. After full article review, 408 RCTs were eligible for inclusion. RCT descriptive variables including number of authors/study patients, 2009 journal impact factor/journal classification, type of cancer and therapeutic intervention, publication year, primary study country, and cooperative group involvement were captured for all trials. Two qualified auditors assessed all manuscripts in order to generate average and difference CONSORT checklist scores related to the observers. Results: Mean average CONSORT score was 16.6 (SD 3, max 25) and median difference score was two (interquartile range one to three). Kappa agreement for each checklist item ranged from (0.02-0.92) with an overall two-way intra-class correlation coefficient of 0.71 (95% Cl: 0.61-0.78) for comparison of overall CONSORT score between raters. Recent year of publication, increasing author number, and higher impact factor were associated with higher average CONSORT scores (p<0.0001). Conclusions: Improvements in RCT reporting have been observed over time. Further work in the assessment of the inter-observer reliability of individual CONSORT items is warranted.

Effect of neonatal administration of estrogen, antiestrogen, and testosterone on the histological picture and estrogen receptor pattern of the adult rat prostate

Background Normal sexual development and functioning of the male reproductive organs are primarily controlled by androgens. However, estrogen also plays a role in the normal development, although this is not well defined. Aim The aim of this study was to assess the effect of neonatal administration of estrogen (E), antiestrogen (AE), and testosterone (T) on the histological picture and estrogen receptor (ER) pattern of the adult rat prostate. Materials and methods In all, 40 male albino rats at the age of 2 days were divided into four equal groups: untreated controls, rats that received E, those that received AE, and those that received T orally for 5 days starting from the second day. All rats were euthanized at the age of 6 weeks, after which specimens from the ventral lobe of the prostate were obtained. Main outcome measures Histopathological and immunohistochemical analysis of the investigated sections. Results In the E-treated rats, the diameter of the prostatic acini was reduced with increased fibromuscular stroma and epithelial hyperplasia. AE-treated or T-treated rats showed no histological changes compared with controls. The prostate of E-treated rats exhibited strong immunoreactivity against the ER compared with that of AE-treated or T-treated rats. The mean area percentage of ER immunoreactivity showed significant increase in E-treated rats compared with the controls, AE-treated rats, and T-treated rats. Conclusion The prostate, despite being an androgen-dependant gland, on exposure to E early in life could undergo structural disturbances that might lead to the development of prostatic disorders later.

Role of CEACAM1 and CEACAM20 in an In Vitro Model of Prostate Morphogenesis

CEACAM20, a novel member of the CEACAM1 gene family with expression limited to the lumen of small intestine, testes, and prostate, is co-expressed with CEACAM1 in adult prostate tissue and down-regulated to the same extent as CEACAM1 in prostate cancer. Since prostate cancer often involves loss of epithelial lumen formation, we hypothesized that CEACAM20 and CEACAM1 play important roles in lumen formation of normal prostate epithelium. When prostate cells were grown on Matrigel as a source of extracellular matrix (ECM), they differentiated into acinar structures with single tubules and well-defined lumina closely resembling embryonic prostate organoids. Confocal microscopic analysis revealed restriction of CEACAM20 to acini and CEACAM1 to tubule structures, respectively. Inhibition of CEACAM1 with antibodies or soluble CEACAM1 or antisense oligonucleotides inhibited tubule formation by over 50% while the remaining tubules were stunted. Inhibition of CEACAM20 with antisense oligonucleotides completely inhibited tubule formation and stunted the growth of acini. We conclude that CEACAM20 and CEACAM1 not only mark the lumina of adult prostate tissue but also play a critical role in the vitro generation of prostate organoids.

Recent advances in prostate development and links to prostatic diseases

The prostate is a branched ductal-acinar gland that is part of the male reproductive tract. Prostate development depends upon the integration of steroid hormone signals, paracrine interactions between the stromal and epithelial tissue layers, and the actions of cell autonomous factors. Several genes and signaling pathways are known to be required for one or more steps of prostate development including epithelial budding, duct elongation, branching morphogenesis, and/or cellular differentiation. Recent progress in the field of prostate development has included the application of genome-wide technologies including serial analysis of gene expression, expression profiling microarrays, and other large-scale approaches to identify new genes and pathways that are essential for prostate development. The aggregation of experimental results into online databases by organized multilab projects including the Genitourinary Developmental Molecular Atlas Project has also accelerated the understanding of molecular pathways that function during prostate development and identified links between prostate anatomy and molecular signaling. Rapid progress has also recently been made in understanding the nature and role of candidate stem cells in the developing and adult prostate. This has included the identification of putative prostate stem cell markers, lineage tracing, and organ reconstitution studies. However, several issues regarding their origin, precise nature, and possible role(s) in disease remain unresolved. Nevertheless, several links between prostatic developmental mechanisms and the pathogenesis of prostatic diseases including benign prostatic hyperplasia and prostate cancer have led to recent progress on targeting developmental pathways as therapeutic strategies for these diseases.

Androgen Signaling Disruption during Fetal and Postnatal Development Affects Androgen Receptor and Connexin 43 Expression and Distribution in Adult Boar Prostate

To date, limited knowledge exists regarding the role of the androgen signaling during specific periods of development in the regulation of androgen receptor (AR) and connexin 43 (Cx43) in adult prostate. Therefore, in this study we examined mRNA and protein expression, and tissue distribution of AR and Cx43 in adult boar prostates following fetal (GD20), neonatal (PD2), and prepubertal (PD90) exposure to an antiandrogen flutamide (50 mg/kg bw). In GD20 and PD2 males we found the reduction of the luminal compartment, inflammatory changes, decreased AR and increased Cx43 expression, and altered localization of both proteins. Moreover, enhanced apoptosis and reduced proliferation were detected in the prostates of these animals. In PD90 males the alterations were less evident, except that Cx43 expression was markedly upregulated. The results presented herein indicate that in boar androgen action during early fetal and neonatal periods plays a key role in the maintenance of normal phenotype and functions of prostatic cells at adulthood. Furthermore, we demonstrated that modulation of Cx43 expression in the prostate could serve as a sensitive marker of hormonal disruption during different developmental stages.

Cytokeratin 18 Is Not Required for Morphogenesis of Developing Prostates but Contributes to Adult Prostate Regeneration

Cytokeratin 18 (CK18) is a key component of keratin-containing intermediate filaments and has long been used as a classic luminal cell marker in prostatic tissue. However, the in vivo function of CK18 in prostate is not known so far. We reported in this study, unexpectedly, that deletion of CK18 in a mouse model did not affect the morphological or the histological structures of adult prostate, as the CK18 knockout prostate displayed a normal glandular ductal structure, branching pattern, and composition of both luminal and basal cells. However, CK18 loss compromised the regenerative tubular branching in dorsolateral prostate after castration and androgen replacement. Therefore, in contrast to its importance as luminal cell marker, CK18 is dispensable for the prostate morphogenesis but contributes to adult prostate regeneration.

Use of Neutron Activation Analysis and Inductively Coupled Plasma Mass Spectrometry for the Determination of Trace Elements in Pediatric and Young Adult Prostate

The questions about the androgen control and the involvement of trace elements in prostatic reproductive function still remain unanswered. One valuable way to elucidate the situation is to compare the values for the prostatic mass fractions of trace elements in pre-and post-pubertal boys. The effect of age on the mass fraction of 54 trace elements in intact prostate of 50 apparently healthy 0-30 years old males was investigated by neutron activation analysis and inductively coupled plasma mass spectrometry. Mean values (M ± SΕΜ) for mass fraction (milligram per kilogram, on dry-weight basis) of trace elements were: Ag 0.062 ± 0.008, Al 80 ± 18, Au 0.0092 ± 0.0024, B 5.9 ± 3.5, Be 0.0034 ± 0.0009, Bi 0.018 ± 0.010, Br 26 ± 3, Cd 0.26 ± 0.05, Ce 0.049 ± 0.012, Co 0.035 ± 0.004, Cr 0.49 ± 0.07, Cs 0.036 ± 0.005, Dy 0.0072 ± 0.0018, Er 0.0040 ± 0.0011, Fe 100 ± 10, Gd 0.0065 ± 0.0018, Hg 0.031 ± 0.004, Ho 0.0013 ± 0.0004, La 0.034 ± 0.007, Li 0.064 ± 0.009, Mn 1.69 ± 0.15, Mo 0.54 ± 0.13, Nb 0.013 ± 0.004, Nd 0.025 ± 0.006, Ni 4.1 ± 0.6, Pb 1.3 ± 0.2, Pr 0.0058 ± 0.0015, Rb 14.5 ± 0.8, Sb 0.051 ± 0.006, Sc 0.013 ± 0.002, Se 0.54 ± 0.03, Sm 0.0055 ± 0.0015, Sn 0.22 ± 0.05, Tb 0.0012 ± 0.0004, Th 0.0076 ± 0.0020, Ti 2.8 ± 0.5, Tl 0.0032 ± 0.0009, Tm 0.00064 ± 0.00017, U 0.0025 ± 0.0004, Y 0.036 ± 0.010, Yb 0.0037 ± 0.0012, Zn 281 ± 32, and Zr 0.16 ± 0.04. The upper limit of mean mass fraction of As, Eu, Ga, Hf, Ir, Lu, Pd, Pt, Re, and Ta were: As ≤ 0.069, Eu ≤ 0.0012, Ga ≤ 0.071, Hf ≤ 0.049, Ir ≤ 0.00054, Lu ≤ 0.00063, Pd ≤ 0.014, Pt ≤ 0.0029, Re ≤ 0.0048, and Ta ≤ 0.010. This work revealed that there is a significant tendency for the mass fractions of Cd, Se and Zn in the prostate tissue of healthy individuals to increase with age from the time of birth up to 30 years. It was also shown that high levels of Al, Au, B, Br, Cr, Ga, Li, and Ni mass fraction in prostate tissue do not indicate a direct involvement of these elements in the reproductive function of prostate.

Prostate Stem Cells in the Development of Benign Prostate Hyperplasia and Prostate Cancer: Emerging Role and Concepts

Benign Prostate hyperplasia (BPH) and prostate cancer (PCa) are the most common prostatic disorders affecting elderly men. Multiple factors including hormonal imbalance, disruption of cell proliferation, apoptosis, chronic inflammation, and aging are thought to be responsible for the pathophysiology of these diseases. Both BPH and PCa are considered to be arisen from aberrant proliferation of prostate stem cells. Recent studies on BPH and PCa have provided significant evidence for the origin of these diseases from stem cells that share characteristics with normal prostate stem cells. Aberrant changes in prostate stem cell regulatory factors may contribute to the development of BPH or PCa. Understanding these regulatory factors may provide insight into the mechanisms that convert quiescent adult prostate cells into proliferating compartments and lead to BPH or carcinoma. Ultimately, the knowledge of the unique prostate stem or stem-like cells in the pathogenesis and development of hyperplasia will facilitate the development of new therapeutic targets for BPH and PCa. In this review, we address recent progress towards understanding the putative role and complexities of stem cells in the development of BPH and PCa.

A developmental stage-dependent switch of the mechanisms for prostate epithelial maintenance

A developmental stage-dependent switch of the mechanisms for prostate epithelial maintenance

Growth kinetics of CD133‐positive prostate cancer cells

In the adult human prostate CD133 expression is thought to mark rare prostate epithelial stem cells and malignant tumor stem/initiating cells. Such putative stem cell populations are thought to proliferate slowly, but possess unlimited proliferative potential. Based on this, we hypothesized that CD133(pos) prostate cancer cells proliferate slower than CD133(neg) cells. Human prostate cancer cell lines were analyzed for CD133 expression and DNA content using flow cytometry. Rates of cell division and DNA synthesis were determined using CFSE cell tracing and BrdU uptake, respectively. Changes in cell cycle distribution and the percentage of CD133(pos) cells were assayed under conditions of different cell density and AR-pathway modulation. Lastly, we over-expressed lentiviral CD133 to measure whether CD133 regulates the cell cycle. The cell cycle distribution differs between CD133(pos) and CD133(neg) cells in all three human prostate cancer cell lines studied. CD133(pos) cells have a greater proportion of cells in G2 and proliferate faster than CD133(neg) cells. High cell density increases the percentage of CD133(pos) cells without changing CD133(pos) cell cycle progression. Treatment with the AR agonist R1881, or the anti-androgen MDV3100, significantly changed the percentage and proliferation of CD133(pos) cells. Finally, ectopic over-expression of CD133 had no effect on cell cycle progression. Contrary to our hypothesis, we demonstrate that CD133(pos) cells proliferate faster than CD133(neg) cells. This association of CD133 expression with increased cell proliferation is not directly mediated by CD133, suggesting that surface CD133 is a downstream target gene of an undefined pathway controlling cell proliferation.

Subcellular Localization of p44/WDR77 Determines Proliferation and Differentiation of Prostate Epithelial Cells

The molecular mechanism that controls the proliferation and differentiation of prostate epithelial cells is currently unknown. We previously identified a 44-kDa protein (p44/wdr77) as an androgen receptor-interacting protein that regulates a set of androgen receptor target genes in prostate epithelial cells and prostate cancer. In this study, we found that p44 localizes in the cytoplasm of prostate epithelial cells at the early stage of prostate development when cells are proliferating, and its nuclear translocation is associated with cellular and functional differentiation in adult prostate tissue. We further demonstrated that cytoplasmic p44 protein is essential for proliferation of prostate epithelial cells, whereas nuclear p44 is required for cell differentiation and prostate- specific protein secretion. These studies suggest a novel mechanism by which proliferation and differentiation of prostate epithelial cells are controlled by p44’s location in the cell.

Human α2β1HI CD133+VE Epithelial Prostate Stem Cells Express Low Levels of Active Androgen Receptor

Stem cells are thought to be the cell of origin in malignant transformation in many tissues, but their role in human prostate carcinogenesis continues to be debated. One of the conflicts with this model is that cancer stem cells have been described to lack androgen receptor (AR) expression, which is of established importance in prostate cancer initiation and progression. We re-examined the expression patterns of AR within adult prostate epithelial differentiation using an optimised sensitive and specific approach examining transcript, protein and AR regulated gene expression. Highly enriched populations were isolated consisting of stem (α2β1 HI CD133+VE), transiently amplifying (α2β1 HI CD133–VE) and terminally differentiated (α2β1 LOW CD133–VE) cells. AR transcript and protein expression was confirmed in α2β1 HI CD133+VE and CD133–VE progenitor cells. Flow cytometry confirmed that median (±SD) fraction of cells expressing AR were 77% (±6%) in α2β1 HI CD133+VE stem cells and 68% (±12%) in α2β1 HI CD133–VE transiently amplifying cells. However, 3-fold lower levels of total AR protein expression (peak and median immunofluorescence) were present in α2β1 HI CD133+VE stem cells compared with differentiated cells. This finding was confirmed with dual immunostaining of prostate sections for AR and CD133, which again demonstrated low levels of AR within basal CD133+VE cells. Activity of the AR was confirmed in prostate progenitor cells by the expression of low levels of the AR regulated genes PSA, KLK2 and TMPRSS2. The confirmation of AR expression in prostate progenitor cells allows integration of the cancer stem cell theory with the established models of prostate cancer initiation based on a functional AR. Further study of specific AR functions in prostate stem and differentiated cells may highlight novel mechanisms of prostate homeostasis and insights into tumourigenesis.