RESUMO
PURPOSE: As men age, the prostate continues to grow on average 2.5% per year. While the variable growth rate of the total prostate gland is recognized, the growth rate of different prostate zones remains largely unclear. We evaluated the growth patterns of the prostate zones and identified clinical parameters contributing to the zonal growth rates. MATERIALS AND METHODS: Prostate magnetic resonance imaging (MRI) data and clinical information were obtained retrospectively on 156 patients who had at least 3 prostate MRIs between 2003 and 2018. Different prostate zonal volumes were measured and analyzed. The outcome was analyzed using linear regression. RESULTS: We observed that prostate growth rates vary depending on body mass index (BMI), transition zone index (TZI), the prostate zone and 5-alpha reductase inhibitor (5ARI) use. The peripheral zone volume growth rates increased with age and peaked at 60-70 years of age (p=0.047), while the transition zone volume demonstrates continuous growth without a peak through all ages. BMI and TZI are associated with the growth rate of the peripheral zone (p=0.026, p <0.001, respectively) but not the transition zone growth rate. 5ARI use is significantly associated with the reduction in the transition zone growth rate (p=0.033), not the peripheral zone. In addition, patients with TZI greater than 60% had the most significant reduction in the transition zone growth rate while taking 5ARI (p <0.001). CONCLUSIONS: Transition and peripheral zones of the prostate grow at variable rates. BMI and TZI affect peripheral zone growth rate, while 5ARI use reduces the transition zone growth rate.
Assuntos
Envelhecimento/fisiologia , Índice de Massa Corporal , Próstata/crescimento & desenvolvimento , Hiperplasia Prostática/tratamento farmacológico , Inibidores de 5-alfa Redutase/uso terapêutico , Idoso , Humanos , Imageamento por Ressonância Magnética , Masculino , Pessoa de Meia-Idade , Tamanho do Órgão , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Hiperplasia Prostática/patologia , Estudos RetrospectivosRESUMO
The molecular mechanisms underlying prostate development can provide clues for prostate cancer research. It has been demonstrated that MEK/ERK signaling downstream of androgen-targeted FGF10 signaling directly induces prostatic branching during development, while Rho/Rho-kinase can regulate prostate cell proliferation. MEK/ERK and Rho/Rho kinase regulate myosin light chain kinase (MLCK), and MLCK regulates myosin light chain phosphorylation (MLC-P), which is critical for cell fate, including cell proliferation, differentiation, and apoptosis. However, the roles and crosstalk of the MEK/ERK and Rho/Rho kinase signaling pathways in prostatic morphogenesis have not been examined. In the present study, we used numerical and image analysis to characterize lobe-specific rat prostatic branching during postnatal organ culture and investigated the roles of FGF10-MEK/ERK and Rho/Rho kinase signaling pathways in prostatic morphogenesis. Prostates exhibited distinctive lobe-specific growth and branching patterns in the ventral (VP) and lateral (LP) lobes, while exogenous FGF10 treatment shifted LP branching towards a VP branching pattern. Treatment with inhibitors of MEK1/2, Rho, Rho kinase, or MLCK significantly inhibited VP growth and blocked branching morphogenesis, further supporting critical roles for MEK/ERK and Rho/Rho kinase signaling pathways in prostatic growth and branching during development. We propose that MLCK-regulated MLC-P may be a central downstream target of both signaling pathways in regulating prostate morphogenesis.
Assuntos
Fator 10 de Crescimento de Fibroblastos/metabolismo , Próstata/crescimento & desenvolvimento , Quinases Associadas a rho/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Regulação da Expressão Gênica no Desenvolvimento , Sistema de Sinalização das MAP Quinases , Masculino , Morfogênese , Técnicas de Cultura de Órgãos , Próstata/metabolismo , RatosRESUMO
The prostate is vulnerable to two major age-associated diseases, cancer and benign enlargement, which account for significant morbidity and mortality for men across the globe. Prostate cancer is the most common cancer reported in men, with over 1.2 million new cases diagnosed and 350,000 deaths recorded annually worldwide. Benign prostatic hyperplasia (BPH), characterised by the continuous enlargement of the adult prostate, symptomatically afflicts around 50% of men worldwide. A better understanding of the biological processes underpinning these diseases is needed to generate new treatment approaches. Developmental studies of the prostate have shed some light on the processes essential for prostate organogenesis, with many of these up- or downregulated genes expressions also observed in prostate cancer and/or BPH progression. These insights into human disease have been inferred through comparative biological studies relying primarily on rodent models. However, directly observing mechanisms of human prostate development has been more challenging due to limitations in accessing human foetal material. Induced pluripotent stem cells (iPSCs) could provide a suitable alternative as they can mimic embryonic cells, and iPSC-derived prostate organoids present a significant opportunity to study early human prostate developmental processes. In this review, we discuss the current understanding of prostate development and its relevance to prostate-associated diseases. Additionally, we detail the potential of iPSC-derived prostate organoids for studying human prostate development and disease.
Assuntos
Células-Tronco Pluripotentes Induzidas/citologia , Próstata/crescimento & desenvolvimento , Hiperplasia Prostática/patologia , Neoplasias da Próstata/patologia , Diferenciação Celular , Humanos , Células-Tronco Pluripotentes Induzidas/patologia , Masculino , Organogênese , Próstata/citologia , Próstata/patologia , Técnicas de Cultura de TecidosRESUMO
Stromal androgen-receptor (AR) action is essential for prostate development, morphogenesis and regeneration. However, mechanisms underlying how stromal AR maintains the cell niche in support of pubertal prostatic epithelial growth are unknown. Here, using advanced mouse genetic tools, we demonstrate that selective deletion of stromal AR expression in prepubescent Shh-responsive Gli1-expressing cells significantly impedes pubertal prostate epithelial growth and development. Single-cell transcriptomic analyses showed that AR loss in these prepubescent Gli1-expressing cells dysregulates androgen signaling-initiated stromal-epithelial paracrine interactions, leading to growth retardation of pubertal prostate epithelia and significant development defects. Specifically, AR loss elevates Shh-signaling activation in both prostatic stromal and adjacent epithelial cells, directly inhibiting prostatic epithelial growth. Single-cell trajectory analyses further identified aberrant differentiation fates of prostatic epithelial cells directly altered by stromal AR deletion. In vivo recombination of AR-deficient stromal Gli1-lineage cells with wild-type prostatic epithelial cells failed to develop normal prostatic epithelia. These data demonstrate previously unidentified mechanisms underlying how stromal AR-signaling facilitates Shh-mediated cell niches in pubertal prostatic epithelial growth and development.
Assuntos
Androgênios/metabolismo , Proteínas Hedgehog/metabolismo , Próstata/crescimento & desenvolvimento , Nicho de Células-Tronco , Animais , Diferenciação Celular , Linhagem da Célula , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Proteínas Hedgehog/genética , Masculino , Camundongos , Próstata/citologia , Próstata/metabolismo , RNA-Seq , Receptores Androgênicos/genética , Receptores Androgênicos/metabolismo , Transdução de Sinais , Análise de Célula Única , Transcriptoma , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
The brominated flame retardants (BFRs), 1,2-dibromo-4-(1,2 dibromoethyl)cyclohexane (TBECH) and 2,3-dibromopropyl-2,4,6-tribromophenyl ether (DPTE) bind to the androgen receptor (AR). in vitro bioassays have shown that TBECH is a potent androgen agonist while DPTE is a potent AR antagonist. Both TBECH and DPTE alter gene expression associated with AR regulation. However, it remains to be determined if TBECH and DPTE can affect the prostate. For this reason, we exposed CD1 mice to a 1:1 mixture of TBECH diastereomers α and ß, a 1:1 mixture of γ and δ, and to DPTE, and tested their effects on prostate growth, histology and gene expression profiles. Castrated mice were used to study the androgenic effects of TBECHαß and TBECHγδ while the antagonistic effects of DPTE were studied in non-castrated mice. We observed that testosterone and TBECHγδ increased body and prostate weights while TBECHαß affected neither of them; and that DPTE had no effect on body weight but reduced prostate weight drastically. Histomorphometric analysis of the prostate revealed epithelial and glandular alterations in the TBECHγδ group comparable to those in testosterone group while alterations in the TBECHαß group were less pronounced. DPTE displayed androgen antagonist activity reminiscent of castration. The transcription profile of the prostate was altered by castration and exposure to testosterone and to TBECHγδ reversed several of these changes. Testosterone and TBECHγδ also regulated the expression of several androgen responsive genes implicated in prostate growth and cancer. While DPTE resulted in a drastic reduction in prostate weight, it only affected a small number of genes. The results indicate that TBECHγδ and DPTE are of high human health concern as they may contribute to changes in prostate growth, histology and function.
Assuntos
Cicloexanos/toxicidade , Disruptores Endócrinos/toxicidade , Retardadores de Chama/toxicidade , Hidrocarbonetos Bromados/toxicidade , Próstata/efeitos dos fármacos , Antagonistas de Androgênios , Antagonistas de Receptores de Andrógenos , Androgênios , Animais , Linhagem Celular Tumoral , Disruptores Endócrinos/metabolismo , Expressão Gênica/efeitos dos fármacos , Halogenação , Humanos , Masculino , Camundongos , Organogênese/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Receptores Androgênicos/metabolismoRESUMO
Fibroblast growth factors (FGFs) are a family of proteins possessing paracrine, autocrine, or endocrine functions in a variety of biological processes, including embryonic development, angiogenesis, tissue homeostasis, wound repair, and cancer. Canonical FGFs bind and activate tyrosine kinase FGF receptors (FGFRs), triggering intracellular signaling cascades that mediate their biological activity. Experimental evidence indicates that FGFs play a complex role in the physiopathology of the prostate gland that ranges from essential functions during embryonic development to modulation of neoplastic transformation. The use of ligand- and receptor-deleted mouse models has highlighted the requirement for FGF signaling in the normal development of the prostate gland. In adult prostate, the maintenance of a functional FGF/FGFR signaling axis is critical for organ homeostasis and function, as its disruption leads to prostate hyperplasia and may contribute to cancer progression and metastatic dissemination. Dissection of the molecular landscape modulated by the FGF family will facilitate ongoing translational efforts directed toward prostate cancer therapy.
Assuntos
Fatores de Crescimento de Fibroblastos/fisiologia , Próstata/fisiologia , Próstata/fisiopatologia , Doenças Prostáticas/fisiopatologia , Neoplasias da Próstata/fisiopatologia , Receptores de Fatores de Crescimento de Fibroblastos/fisiologia , Animais , Humanos , Peptídeos e Proteínas de Sinalização Intercelular/fisiologia , Masculino , Próstata/crescimento & desenvolvimentoRESUMO
Hypercholesterolemia has been found to be closely linked with a significant increase in both cancer incidence and mortality. However, the exact correlation between serum cholesterol levels and cancer has not been completely deciphered. Here we analyzed the effect of low-density lipoprotein (LDL) cholesterol on prostate and pancreatic cancer cells. We noted that LDL induced a substantial STAT3 activation and JAK1, JAK2, Src activation in diverse prostate and pancreatic tumor cells. Moreover, LDL promoted cancer cell proliferation, migration, and invasion as well as upregulated the expression of diverse oncogenic gene products. However, deletion of LDL-activated STAT3 in LNCaP and PANC-1 cells and reduced LDL-induced cell viability. Simvastatin (SV) treatment also alleviated LDL-induced cell viability and migration ability in both the prostate and pancreatic tumor cells. These results demonstrate that LDL-induced STAT3 activation may exert a profound effect on the proliferation and survival of tumor cells.
Assuntos
Carcinogênese/patologia , LDL-Colesterol/metabolismo , Neoplasias Pancreáticas/patologia , Neoplasias da Próstata/patologia , Fator de Transcrição STAT3/metabolismo , Anticolesterolemiantes/farmacologia , Carcinogênese/genética , Linhagem Celular Tumoral , Movimento Celular/fisiologia , Proliferação de Células/fisiologia , Sobrevivência Celular/fisiologia , Regulação Neoplásica da Expressão Gênica/genética , Humanos , Janus Quinase 1/metabolismo , Janus Quinase 2/metabolismo , Masculino , Pâncreas/citologia , Pâncreas/crescimento & desenvolvimento , Pâncreas/patologia , Próstata/citologia , Próstata/crescimento & desenvolvimento , Próstata/patologia , Interferência de RNA , RNA Interferente Pequeno/genética , Fator de Transcrição STAT3/genética , Transdução de Sinais/fisiologia , Sinvastatina/farmacologiaRESUMO
Androgen receptor (AR) plays a fundamental role in most aspects of adult prostate homeostasis, and anti-androgen therapy represents the cornerstone of prostate cancer treatment. However, early prostate organogenesis takes place during pre-pubertal stages when androgen levels are low, raising the possibility that AR function is more limited during prostate development. Here, we use inducible AR deletion and lineage tracing in genetically engineered mice to show that basal and luminal epithelial progenitors do not require cell-autonomous AR activity during prostate development. We also demonstrate the existence of a transient bipotent luminal progenitor that can generate luminal and basal progeny, yet is also independent of AR function. Furthermore, molecular analyses of AR-deleted luminal cells isolated from developing prostates indicate their similarity to wild-type cells. Our findings suggest that low androgen levels correlate with luminal plasticity in prostate development and may have implications for understanding how AR inhibition promotes lineage plasticity in prostate cancer.
Assuntos
Organogênese , Próstata/crescimento & desenvolvimento , Receptores Androgênicos/fisiologia , Células-Tronco/fisiologia , Animais , Animais Geneticamente Modificados , Diferenciação Celular , Plasticidade Celular , Proliferação de Células , Células Epiteliais/citologia , Células Epiteliais/fisiologia , Regulação da Expressão Gênica , Genótipo , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Próstata/citologia , Deleção de Sequência , Células-Tronco/citologiaRESUMO
Several techniques have been employed for deletion of the NKX3.1 gene, resulting in developmental defects of the prostate, including alterations in ductal branching morphogenesis and prostatic secretions as well as epithelial hyperplasia and dysplasia. To investigate whether the CRISPR/Cas9-mediated technique can be applied to study prostate carcinogenesis through exon I deletion of NKX3.1 gene, alterations in the prostatic intraepithelial neoplasia (PIN) and their regulatory mechanism were observed in the prostate of NKX3.1 knockout (KO) mice produced by the CRISPR/Cas9-mediated NKX3.1 mutant gene, at the ages of 16 and 24 weeks. The weight of dorsal-lateral prostate (DLP) and anterior prostate (AP) were observed to be increased in only the 24 weeks KO mice, although morphogenesis was constant in all groups. Obvious PIN 1 and 2 lesions were frequently detected in prostate of the 24 weeks KO mice, as compared with the same age wild type (WT) mice. Ki67, a key indicator for PIN, was densely stained in the epithelium of prostate in the 24 weeks KO mice, while the expression of p53 protein was suppressed in the same group. Also, both the 16 and 24 weeks KO mice reveal inhibition of the PI3K/AKT/mTOR pathway in the prostate. However, prostate specific antigen (PSA) levels and Bax/Bcl-2 expressions were decreased in the prostate of 16 weeks KO mice, and were increased in only the 24 weeks KO mice. Taken together, the results of the present study provide additional evidence that CRISPR/Cas9-mediated exon 1 deletion of the NKX3.1 gene successfully induces PIN lesions, along with significant alterations of Ki67 expression, EGFR signaling pathway, and cancer-regulated proteins.
Assuntos
Proteínas de Homeodomínio/genética , Morfogênese/genética , Neoplasia Prostática Intraepitelial/genética , Fatores de Transcrição/genética , Proteína Supressora de Tumor p53/genética , Animais , Sistemas CRISPR-Cas/genética , Receptores ErbB/genética , Humanos , Antígeno Ki-67/genética , Masculino , Camundongos , Camundongos Knockout , Próstata/crescimento & desenvolvimento , Próstata/patologia , Neoplasia Prostática Intraepitelial/patologiaRESUMO
The characterization of prostate epithelial hierarchy and lineage heterogeneity is critical to understand its regenerative properties and malignancies. Here, we report that the transcription factor RUNX1 marks a specific subpopulation of proximal luminal cells (PLCs), enriched in the periurethral region of the developing and adult mouse prostate, and distinct from the previously identified NKX3.1+ luminal castration-resistant cells. Using scRNA-seq profiling and genetic lineage tracing, we show that RUNX1+ PLCs are unaffected by androgen deprivation, and do not contribute to the regeneration of the distal luminal compartments. Furthermore, we demonstrate that a transcriptionally similar RUNX1+ population emerges at the onset of embryonic prostate specification to populate the proximal region of the ducts. Collectively, our results reveal that RUNX1+ PLCs is an intrinsic castration-resistant and self-sustained lineage that emerges early during prostate development and provide new insights into the lineage relationships of the prostate epithelium.
The prostate is part of the reproductive organs in male mammals. Many of the cells lining the inside of the prostate known as 'luminal cells' need hormones to survive. Certain treatments for prostate cancer, including surgical and chemical castration, lead to fewer hormones reaching the prostate, which shrinks as luminal cells die. But some of these luminal cells are able to survive the damaging effects of castration, rebuilding the prostate upon treatment with hormones, which can lead to the cancer reappearing. It is unclear which type of luminal cells survive during periods without hormones and are responsible for regenerating the prostate. RUNX1 is a protein responsible for switching genes on and off, and is usually found in blood cells, which it helps to mature and perform their roles, but has also been detected in tissues that depend on hormones. Since the luminal cells of the prostate rely on hormones, could RUNX1 also be present in these cells? To answer this question, Mével et al. used mice to determine where and when RUNX1 is found in prostate cells. Mével et al. detected high levels of RUNX1 in a patch of luminal cells at the base of the prostate. Samples of these cells were taken for further testing from developing mouse embryos, healthy adult mice and mice in which the prostate was regenerating after surgical castration. Mével et al. found that these cells were a distinct subtype of luminal cells that were able to resist the effects of castration they survived without hormones. Though these cells were present during the early stages of prostate embryonic development and in healthy adult prostate tissue, they were not responsible for rebuilding the prostate after castration. Mével et al.'s results indicate that, in mice, RUNX1 may act as a marker for a subset of luminal cells that can survive after castration. Further probing the roles of these castration-resistant luminal cells in normal and cancerous prostate tissue may improve the outcome of patients with prostate cancer treated with hormone deprivation therapy.
Assuntos
Subunidade alfa 2 de Fator de Ligação ao Core/fisiologia , Próstata/crescimento & desenvolvimento , Animais , Linhagem da Célula , Subunidade alfa 2 de Fator de Ligação ao Core/metabolismo , Epitélio/metabolismo , Masculino , Camundongos , Orquiectomia , Próstata/citologia , Próstata/metabolismoRESUMO
BACKGROUND: Epithelial stem cells (ESCs) demonstrate a capacity to maintain normal tissues homeostasis and ESCs with a deregulated behavior can contribute to cancer development. The ability to reprogram normal tissue epithelial cells into prostate or mammary stem-like cells holds great promise to help understand cell of origin and lineage plasticity in prostate and breast cancers in addition to understanding normal gland development. We previously showed that an intracellular chemokine, CXCL12γ induced cancer stem cells and neuroendocrine characteristics in both prostate and breast adenocarcinoma cell lines. However, its role in normal prostate or mammary epithelial cell fate and development remains unknown. Therefore, we sought to elucidate the functional role of CXCL12γ in the regulation of ESCs and tissue development. METHODS: Prostate epithelial cells (PNT2) or mammary epithelial cells (MCF10A) with overexpressed CXCL12γ was characterized by quantitative real-time polymerase chain reaction, Western blots, and immunofluorescence for lineage marker expression, and fluorescence activated cell sorting analyses and sphere formation assays to examine stem cell surface phenotype and function. Xenotransplantation animal models were used to evaluate gland or acini formation in vivo. RESULTS: Overexpression of CXCL12γ promotes the reprogramming of cells with a differentiated luminal phenotype to a nonluminal phenotype in both prostate (PNT2) and mammary (MCF10A) epithelial cells. The CXCL12γ-mediated nonluminal type cells results in an increase of epithelial stem-like phenotype including the subpopulation of EPCAMLo /CD49fHi /CD24Lo /CD44Hi cells capable of sphere formation. Critically, overexpression of CXCL12γ promotes the generation of robust gland-like structures from both prostate and mammary epithelial cells in in vivo xenograft animal models. CONCLUSIONS: CXCL12γ supports the reprogramming of epithelial cells into nonluminal cell-derived stem cells, which facilitates gland development.
Assuntos
Quimiocina CXCL12/biossíntese , Glândulas Mamárias Humanas/crescimento & desenvolvimento , Próstata/crescimento & desenvolvimento , Animais , Reprogramação Celular/fisiologia , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Feminino , Xenoenxertos , Humanos , Masculino , Glândulas Mamárias Humanas/citologia , Glândulas Mamárias Humanas/metabolismo , Camundongos , Próstata/citologia , Próstata/metabolismo , Isoformas de ProteínasRESUMO
"Consortium Linking Academic and Regulatory Insights on BPA Toxicity" (CLARITY-BPA) was a comprehensive "industry-standard" Good Laboratory Practice (GLP)-compliant 2-year chronic exposure study of bisphenol A (BPA) toxicity that was supplemented by hypothesis-driven independent investigator-initiated studies. The investigator-initiated studies were focused on integrating disease-associated, molecular, and physiological endpoints previously found by academic scientists into an industry standard guideline-compliant toxicity study. Thus, the goal of this collaboration was to provide a more comprehensive dataset upon which to base safety standards and to determine whether industry-standard tests are as sensitive and predictive as molecular and disease-associated endpoints. The goal of this report is to integrate the findings from the investigator-initiated studies into a comprehensive overview of the observed impacts of BPA across the multiple organs and systems analyzed. For each organ system, we provide the rationale for the study, an overview of methodology, and summarize major findings. We then compare the results of the CLARITY-BPA studies across organ systems with the results of previous peer-reviewed studies from independent labs. Finally, we discuss potential influences that contributed to differences between studies. Developmental exposure to BPA can lead to adverse effects in multiple organs systems, including the brain, prostate gland, urinary tract, ovary, mammary gland, and heart. As published previously, many effects were at the lowest dose tested, 2.5µg/kg /day, and many of the responses were non-monotonic. Because the low dose of BPA affected endpoints in the same animals across organs evaluated in different labs, we conclude that these are biologically - and toxicologically - relevant.
Assuntos
Compostos Benzidrílicos/toxicidade , Disruptores Endócrinos/toxicidade , Troca Materno-Fetal , Fenóis/toxicidade , Efeitos Tardios da Exposição Pré-Natal/induzido quimicamente , Animais , Comportamento Animal/efeitos dos fármacos , Metilação de DNA , Feminino , Regulação da Expressão Gênica no Desenvolvimento/efeitos dos fármacos , Coração/efeitos dos fármacos , Coração/crescimento & desenvolvimento , Masculino , Glândulas Mamárias Animais/efeitos dos fármacos , Glândulas Mamárias Animais/crescimento & desenvolvimento , Ovário/efeitos dos fármacos , Ovário/crescimento & desenvolvimento , Gravidez , Efeitos Tardios da Exposição Pré-Natal/genética , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Ratos Sprague-Dawley , Reprodutibilidade dos Testes , Glândula Tireoide/efeitos dos fármacos , Glândula Tireoide/crescimento & desenvolvimento , Uretra/efeitos dos fármacos , Uretra/crescimento & desenvolvimentoRESUMO
The prostate development has an important postnatal period where cell proliferation begins at the first days after birth and is related to gland growth and ramification. Any metabolic and/or hormonal changes occurring during the postnatal period can interfere with prostate branching. Hyperglycemia is a common condition in low-weight preterm babies at neonatal period and also a disorder found in the offspring of obese mothers. Thus, this study aimed to investigate the in vitro effects of a glucose-rich environment during prostate postnatal development. Wistar rats prostate were removed at birth and cultured for 1, 2 and 3 days in DMEM under normal (5.5 mM) or elevated (7 and 25 mM) glucose concentrations. Samples were processed for morphological analysis, PCNA and smooth muscle α-actin immunohistochemistry, evaluation of active caspase-3, ERK1/2 and Wnt5a gene expression. High glucose concentrations reduced the number of prostatic buds and proliferating cells. The natural increase in smooth muscle cells and collagen deposition observed in control prostates during the first 3 days of development was reduced by elevated glucose concentrations. The amount of active caspase-3 was higher in prostates incubated at 7 mM and TGF-ß levels also increased sharply after both glucose concentrations. Additionally, high glucose environment decreased ERK 1/2 activation and increased Wnt5a expression. These data show that high levels of glucose during the first postnatal days affected prostate development by inhibiting cell proliferation which impairs bud branching and this was associated with anti-proliferative signals such as decreased ERK1/2 activation and increased Wnt5a expression.
Assuntos
Regulação da Expressão Gênica/efeitos dos fármacos , Glucose/toxicidade , Próstata/patologia , Transdução de Sinais , Animais , Animais Recém-Nascidos , Proliferação de Células , Técnicas In Vitro , Masculino , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Ratos , Ratos Wistar , Edulcorantes/toxicidadeRESUMO
The aim of this study was to evaluate the impact of prenatal testosterone exposure on prostate development in male and female neonatal gerbils. Pregnant females were exposed to subcutaneous injections of testosterone cypionate (500 µg/animal) at gestational days 20 and 22. Male and female pups were then euthanized at postnatal day 1. Morphological analysis showed that females were severely affected by androgen exposure. We also observed that male and female urogenital sinus (UGS) responded differentially to testosterone treatment, demonstrating heterogeneous immunostaining for the androgen receptor (AR), estrogen receptor alpha (ERα), and proliferating cell nuclear antigen (PCNA). Smooth muscle α-actin (α-SMA) analysis showed that testosterone delays the myodifferentiation, allowing buds to reach the ectopic mesenchymes of the female UGS. Our data showed that abnormal testosterone exposure disrupted prostate organogenesis, altered the expression patterns of important markers, and demonstrated that female UGS was particularly influenced by androgen exposure during a critical window in the developmental period.
Assuntos
Organogênese/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Testosterona/farmacologia , Animais , Receptor alfa de Estrogênio/metabolismo , Feminino , Gerbillinae , Imageamento Tridimensional , Masculino , Antígeno Nuclear de Célula em Proliferação/metabolismo , Próstata/anatomia & histologia , Próstata/diagnóstico por imagem , Próstata/efeitos dos fármacos , Receptores Androgênicos/metabolismo , Testosterona/sangueRESUMO
The development and maintenance of prostate function depend on a fine balance between oestrogen and androgen levels. Finasteride inhibits 5α-reductase, which is responsible for the conversion of testosterone into its most active form, dihydrotestosterone. Enzymes that metabolize these hormones have a highly relevant role in both the normal prostate metabolism and in the occurrence of pathological conditions. There are few studies on the impact of finasteride on male prostate development and fewer studies on the female prostate and possible intersexual differences. Therefore, we treated male and female gerbils from 7 to 14 days in postnatal life with a high dose of finasteride (500 µg/kg/day); the prostate complexes were then removed and submitted to immunohistochemistry, immunofluorescence and three-dimensional reconstruction. In addition, hormonal serum dosages were administered. Treatment with finasteride resulted in an increased thickness of the periductal smooth musculature in the prostate of both male and female gerbils, such as well as a reduction in the thickness of developing prostate alveoli in both sexes. In addition, intersexual differences were observed as increased epithelial proliferation and decreases in the number of developing alveoli in females. Together, the data indicate that postnatal exposure to finasteride causes greater changes in the female gerbil prostate than in the male.
Assuntos
Finasterida/toxicidade , Gerbillinae/crescimento & desenvolvimento , Próstata , Animais , Feminino , Masculino , Próstata/efeitos dos fármacos , Próstata/crescimento & desenvolvimento , Receptores Androgênicos/metabolismo , Testosterona/sangueRESUMO
Prostate development depends on balanced cell proliferation and differentiation, and acetylated KLF5 is known to alter epithelial proliferation. It remains elusive whether post-translational modifications of transcription factors can differentially determine adult stem/progenitor cell fate. Here we report that, in human and mouse prostates, Klf5 is expressed in both basal and luminal cells, with basal cells preferentially expressing acetylated Klf5. Functionally, Klf5 is indispensable for maintaining basal progenitors, their luminal differentiation, and the proliferation of their basal and luminal progenies. Acetylated Klf5 is also essential for basal progenitors' maintenance and proper luminal differentiation, as deacetylation of Klf5 causes excess basal-to-luminal differentiation; attenuates androgen-mediated organoid organization; and retards postnatal prostate development. In basal progenitor-derived luminal cells, Klf5 deacetylation increases their proliferation and attenuates their survival and regeneration following castration and subsequent androgen restoration. Mechanistically, Klf5 deacetylation activates Notch signaling. Klf5 and its acetylation thus contribute to postnatal prostate development and regeneration by controlling basal progenitor cell fate.
Assuntos
Fatores de Transcrição Kruppel-Like/metabolismo , Próstata/crescimento & desenvolvimento , Próstata/metabolismo , Acetilação , Androgênios/metabolismo , Animais , Diferenciação Celular , Proliferação de Células , Humanos , Fatores de Transcrição Kruppel-Like/deficiência , Fatores de Transcrição Kruppel-Like/genética , Masculino , Camundongos , Camundongos Endogâmicos C57BL , Camundongos Knockout , Orquiectomia , Organoides/citologia , Organoides/metabolismo , Próstata/citologia , Regeneração , Transdução de Sinais , Células-Tronco/citologia , Células-Tronco/metabolismoRESUMO
The androgen receptor (AR) is a critical therapeutic target in prostate cancer that responds to antagonists in primary disease, but inevitably becomes reactivated, signaling onset of the lethal castration-resistant prostate cancer (CRPC) stage. Epigenomic investigation of the chromatin environment and interacting partners required for AR transcriptional activity has uncovered three pioneer factors that open up chromatin and facilitate AR-driven transcriptional programs. FOXA1, HOXB13, and GATA2 are required for normal AR transcription in prostate epithelial development and for oncogenic AR transcription during prostate carcinogenesis. AR signaling is dependent upon these three pioneer factors both before and after the clinical transition from treatable androgen-dependent disease to untreatable CRPC. Agents targeting their respective DNA binding or downstream chromatin-remodeling events have shown promise in preclinical studies of CRPC. AR-independent functions of FOXA1, HOXB13, and GATA2 are emerging as well. While all three pioneer factors exert effects that promote carcinogenesis, some of their functions may inhibit certain stages of prostate cancer progression. In all, these pioneer factors represent some of the most promising potential therapeutic targets to emerge thus far from the study of the prostate cancer epigenome.
Assuntos
Cromatina/metabolismo , Fator de Transcrição GATA2/metabolismo , Fator 3-alfa Nuclear de Hepatócito/metabolismo , Proteínas de Homeodomínio/metabolismo , Neoplasias de Próstata Resistentes à Castração/genética , Receptores Androgênicos/genética , Antineoplásicos/farmacologia , Antineoplásicos/uso terapêutico , Carcinogênese/genética , Montagem e Desmontagem da Cromatina/efeitos dos fármacos , Montagem e Desmontagem da Cromatina/genética , Progressão da Doença , Epigênese Genética/efeitos dos fármacos , Fator de Transcrição GATA2/antagonistas & inibidores , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Fator 3-alfa Nuclear de Hepatócito/antagonistas & inibidores , Proteínas de Homeodomínio/antagonistas & inibidores , Humanos , Masculino , Próstata/crescimento & desenvolvimento , Próstata/patologia , Neoplasias de Próstata Resistentes à Castração/tratamento farmacológico , Neoplasias de Próstata Resistentes à Castração/patologia , Receptores Androgênicos/metabolismo , Transdução de Sinais/efeitos dos fármacos , Transdução de Sinais/genética , Transcrição Gênica/efeitos dos fármacosRESUMO
Prostate embryonic development, pubertal and adult growth, maintenance, and regeneration are regulated through androgen signaling-mediated mesenchymal-epithelial interactions. Specifically, the essential role of mesenchymal androgen signaling in the development of prostate epithelium has been observed for over 30 years. However, the identity of the mesenchymal cells responsible for this paracrine regulation and related mechanisms are still unknown. Here, we provide the first demonstration of an indispensable role of the androgen receptor (AR) in sonic hedgehog (SHH) responsive Gli1-expressing cells, in regulating prostate development, growth, and regeneration. Selective deletion of AR expression in Gli1-expressing cells during embryogenesis disrupts prostatic budding and impairs prostate development and formation. Tissue recombination assays showed that urogenital mesenchyme (UGM) containing AR-deficient mesenchymal Gli1-expressing cells combined with wildtype urogenital epithelium (UGE) failed to develop normal prostate tissue in the presence of androgens, revealing the decisive role of AR in mesenchymal SHH responsive cells in prostate development. Prepubescent deletion of AR expression in Gli1-expressing cells resulted in severe impairment of androgen-induced prostate growth and regeneration. RNA-sequencing analysis showed significant alterations in signaling pathways related to prostate development, stem cells, and organ morphogenesis in AR-deficient Gli1-expressing cells. Among these altered pathways, the transforming growth factor ß1 (TGFß1) pathway was up-regulated in AR-deficient Gli1-expressing cells. We further demonstrated the activation of TGFß1 signaling in AR-deleted prostatic Gli1-expressing cells, which inhibits prostate epithelium growth through paracrine regulation. These data demonstrate a novel role of the AR in the Gli1-expressing cellular niche for regulating prostatic cell fate, morphogenesis, and renewal, and elucidate the mechanism by which mesenchymal androgen-signaling through SHH-responsive cells elicits the growth and regeneration of prostate epithelium.
Assuntos
Proteínas Hedgehog/metabolismo , Morfogênese , Próstata/metabolismo , Receptores Androgênicos/metabolismo , Regeneração , Transdução de Sinais , Animais , Células Cultivadas , Células Epiteliais/citologia , Células Epiteliais/metabolismo , Masculino , Células-Tronco Mesenquimais/citologia , Células-Tronco Mesenquimais/metabolismo , Camundongos , Próstata/citologia , Próstata/crescimento & desenvolvimento , Próstata/fisiologia , Fator de Crescimento Transformador beta/metabolismo , Proteína GLI1 em Dedos de Zinco/genética , Proteína GLI1 em Dedos de Zinco/metabolismoRESUMO
BACKGROUND: To compare the growth of the prostate in anencephalic, prune belly syndrome (PBS) and control fetuses. METHODS: We studied 35 prostates from normal human fetuses aged 11-22â¯weeks postconception (WPC); 15 from anencephalic fetuses aged 13-19 WPC; and 6 from PBS fetuses aged 13-31WPC. After prostate dissection, we evaluated the prostate length, width and thickness with the aid of a computer program (Image Pro and Image J). The fetal prostate volume (PV) was calculated using the ellipsoid formula: PVâ¯=â¯[length × thickness × width] × 0.523. The prostates were dissected and the PV was measured with the aid of the same computer program. Means were statistically compared using the unpaired t-test and linear regression was performed. RESULTS: In 2 PBS fetuses we observed prostatic atresia. We did not observe significant differences in PV when comparing the control group (PV: 6.1 to 313.81â¯mm, meanâ¯=â¯70.85â¯mm: SDâ¯=â¯71.43â¯mm) with anencephalic fetuses: pâ¯=â¯0.3575 (PV: 5.1 to 159.11â¯mm, meanâ¯=â¯42.94â¯mm; SDâ¯=â¯40.11â¯mm) and PBS fetuses: pâ¯>â¯0.999 (PV: 10.89 to 148.71â¯mm, meanâ¯=â¯55.4â¯mm; SDâ¯=â¯63.64â¯mm). The linear regression analysis indicated that the PV in the control group (r2â¯=â¯0.3096; pâ¯=â¯0.0004), anencephalic group (r2â¯=â¯0.3778; pâ¯=â¯0.0148) and PBS group (r2â¯=â¯0.9821; pâ¯<â¯0.009) increased significantly and positively with fetal age (pâ¯<â¯0.0001). CONCLUSIONS: We did not observe significant differences in development of the prostate in fetuses with anencephaly and in 2/3 of fetuses with PBS during the fetal period studied. In 1/3 of the PBS fetuses, the prostate had important atresia. LEVEL OF EVIDENCE: Level III.
Assuntos
Anencefalia/embriologia , Próstata/embriologia , Próstata/crescimento & desenvolvimento , Síndrome do Abdome em Ameixa Seca/embriologia , Feto/embriologia , Idade Gestacional , Humanos , Masculino , Tamanho do ÓrgãoRESUMO
Chlorocholine chloride (CCC), a plant growth retardant, may act as an endocrine disruptor. Our previous study showed that pubertal CCC exposure in rats might decrease testosterone (T) synthesis. This study observed the changes in pubertal development and reproduction of male rats exposed to CCC and its underlying mechanisms. Rats were exposed to CCC (0, 75, 137.5 and 200 mg/kg bw/day) from postnatal day 23 to 60. The results showed that CCC treatment delayed the onset of puberty and reduced the relative organ weight of prostate. Seminiferous tubules with deciduous spermatogenic cells were observed in the 200 mg/kg bw/day group. Sexual behavior was inhibited in the 137.5 and 200 mg/kg bw/day groups. Sperm motility, litter size and normalized anogenital distance (AGD) of male pups were decreased in the 137.5 and 200 mg/kg bw/day groups. Serum kisspeptin level and serum and testicular levels of T were reduced in all CCC treated groups. Crucial hormones in hypothalamic-pituitary-testicular (HPT) axis were reduced subsequently after CCC treatment. Collectively, our results demonstrated that CCC might disturb HPT axis through suppressing the secretion of kisspeptin and subsequently lead to delayed puberty onset and impaired reproductive functions.