RESUMO
The concept of Developmental Origins of Health and Disease (DOHaD) states that exposure to malnutrition early in life increase the incidence of non-communicable chronic diseases throughout the lifespan. In this study, a reduction in serum testosterone and an increase in estrogen levels were shown in older rats born to protein malnourished dams (6% protein in the diet) during gestation and lactation. Intraprostatic levels of reduced glutathione were decreased, while tissue expression of glutathione S-transferase pi and sulfiredoxin-1 were increased in these animals. Strong immunostaining for alfametilacil CoA racemase (AMACR), vascular endothelial growth factor-A (VEGF-A), and aquaporin-1 (AQP1) was also observed. In silico analysis confirmed commonly deregulated proteins in the ventral prostate of old rats and patients with prostate cancer. In conclusion, the increase in oxidative stress associated with an imbalance of sex hormones may contribute to prostate carcinogenesis in offspring, highlighting early-life malnutrition as a key risk factor for this malignance.
Assuntos
Envelhecimento/patologia , Biomarcadores Tumorais/metabolismo , Desnutrição/complicações , Fenômenos Fisiológicos da Nutrição Materna , Estresse Oxidativo , Próstata/metabolismo , Próstata/patologia , Animais , Animais Recém-Nascidos , Feminino , Regulação Neoplásica da Expressão Gênica , Hormônios/metabolismo , Humanos , Lactação , Masculino , Gravidez , Prognóstico , Neoplasias da Próstata/genética , Neoplasias da Próstata/metabolismo , Neoplasias da Próstata/patologia , Ratos Sprague-DawleyRESUMO
The postlactational involution of the mammary gland is a complex process. It involves the collapse of the alveoli and the remodeling of the extracellular matrix, which in turn implies a complex set of interrelations between the epithelial, stromal, and extracellular matrix elements. The telocytes, a new type of CD34-positive stromal cell that differs from fibroblasts in morphological terms and gene expression, were detected in the stroma of several tissues, including the mammary gland; however, their function remains elusive. The present study employed three-dimensional reconstructions and immunohistochemical, ultrastructural, and immunofluorescence techniques in histological sections of the mammary gland of the Mongolian gerbil during lactation and postlactational involution to evaluate the presence of telocytes and to investigate a possible function for these cells. By means of immunofluorescence assays for CD34 and c-kit, major markers of telocytes, and also through morphological and ultrastructural evidences, telocytes were observed to surround the mammary ducts and collapsing alveoli. It was also found that these cells are associated with matrix metalloproteinase 9, which indicates that telocytes can play a role in extracellular matrix digestion, as well as vascular endothelial growth factor, a factor that promotes angiogenesis. Together, these data indicate that telocytes are a distinct cell type in the mammary gland and, for the first time, show that these cells possibly play a role in tissue remodeling and angiogenesis during the postlactional involution of the mammary gland.
Assuntos
Lactação/metabolismo , Glândulas Mamárias Animais/fisiologia , Telócitos/metabolismo , Animais , Antígenos CD34/metabolismo , Matriz Extracelular/metabolismo , Feminino , Expressão Gênica/genética , Gerbillinae/metabolismo , Glândulas Mamárias Animais/metabolismo , Neovascularização Patológica/metabolismo , Células Estromais/metabolismo , Telócitos/fisiologia , Fator A de Crescimento do Endotélio Vascular/metabolismoRESUMO
The incidence of prostate cancer (PCa) is increasing, and it is currently the second most frequent cause of death by cancer in men. Despite advancements in cancer therapies, new therapeutic approaches are still needed for treatment-refractory advanced metastatic PCa. Cross-species analysis presents a robust strategy for the discovery of new potential therapeutic targets. This strategy involves the integration of genomic data from genetically engineered mouse models (GEMMs) and human PCa datasets. Considering the role of antioxidant pathways in tumor initiation and progression, we searched oxidative stress-related genes for a potential therapeutic target for PCa. First, we analyzed RNA-sequencing data from Pb-Cre4; Ptenf/f mice and discovered an increase in sulfiredoxin (Srxn1) mRNA expression in high-grade prostatic intraepithelial neoplasia (PIN), well-differentiated adenocarcinoma (medium-stage tumors), and poor-differentiated adenocarcinoma (advanced-stage prostate tumors). The increase of SRXN1 protein expression was confirmed by immunohistochemistry in mouse prostate tumor paraffin samples. Analyses of human databases and prostate tissue microarrays demonstrated that SRXN1 is overexpressed in a subset of high-grade prostate tumors and correlates with aggressive PCa with worse prognosis and decreased survival. Analyses in vitro showed that SRXN1 expression is also higher in most PCa cell lines compared to normal cell lines. Furthermore, siRNA-mediated downregulation of SRXN1 led to decreased viability of PCa cells LNCaP. In conclusion, we identified the antioxidant enzyme SRXN1 as a potential therapeutic target for PCa. Our results suggest that the use of specific SRXN1 inhibitors may be an effective strategy for the adjuvant treatment of castration-resistant PCa with SRXN1 overexpression.
Assuntos
Terapia de Alvo Molecular , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/metabolismo , Neoplasias da Próstata/patologia , Animais , Linhagem Celular Tumoral , Sobrevivência Celular , Progressão da Doença , Regulação Neoplásica da Expressão Gênica , Humanos , Masculino , Camundongos , Gradação de Tumores , Invasividade Neoplásica , Metástase Neoplásica , Estadiamento de Neoplasias , Estresse Oxidativo/genética , Oxirredutases atuantes sobre Doadores de Grupo Enxofre/genética , Prognóstico , Próstata/patologia , Neoplasias da Próstata/genética , RNA Mensageiro/genética , RNA Mensageiro/metabolismo , Análise de SobrevidaRESUMO
This study evaluated the effect of gestational low protein diet (LPD) and/or postnatal bisphenol A (BPA) exposure on mammary gland development and carcinogenesis in female offspring. Pregnant Sprague-Dawley rats were fed a normal protein diet (NPD, 17% protein) or LPD (6% protein). At weaning, female offspring were distributed in four groups (NPD, LPD, NPD + BPA, and LPD + BPA) and received vehicle or BPA in drinking water (0.1%), during postnatal day (PND) 21 to 51. On PND 51, some female offspring were euthanized or received a single dose of 7,12-dimethylbenzoanthracene (DMBA, 30 mg/kg, i.g.) and were euthanized on PND 250. On PND 51, neither gestational LPD nor postnatal BPA exposure, individually or in combination, significantly altered the development of mammary gland tree, mean number of terminal structures or estrogen receptor beta (ER-ß), proliferating cell nuclear antigen (PCNA) or caspase-3 protein expression in the mammary tissue. A significant reduction in mammary epithelial area (%) was observed in both LPD groups and a significant increase in ER-α protein expression was detected only in LPD group. In LPD + BPA group was observed a significant increase in both fat pad area (%) and in mean number of mammary epithelial cells positive for progesterone receptor (PR). On PND 250, the groups that received BPA presented lower latency and higher tumor incidence and tumor multiplicity and LPD + BPA group more aggressive tumors. These findings suggest that postnatal BPA exposure associated with gestational LPD is able to induce morphological changes in the mammary gland and increase susceptibility to mammary carcinogenesis.
Assuntos
Compostos Benzidrílicos/toxicidade , Dieta com Restrição de Proteínas , Glândulas Mamárias Animais/efeitos dos fármacos , Neoplasias Mamárias Animais/induzido quimicamente , Fenóis/toxicidade , Animais , Carcinogênese , Receptor beta de Estrogênio/metabolismo , Feminino , Masculino , Glândulas Mamárias Animais/crescimento & desenvolvimento , Glândulas Mamárias Animais/metabolismo , Neoplasias Mamárias Animais/patologia , Gravidez , Efeitos Tardios da Exposição Pré-Natal , Antígeno Nuclear de Célula em Proliferação/metabolismo , Ratos , Ratos Sprague-Dawley , Receptores de Progesterona/metabolismoRESUMO
Telocytes are recently categorised CD34-positive interstitial cells that comprise the cells which were previously called interstitial Cajal-like cells (ICLCs). These were detected in the stroma of various organs such as the prostate, lungs, mammary glands, liver, gallbladder, and jejunum, among others. Several functions have been proposed for telocytes, such as a supportive role in smooth muscle contraction and immune function in adult organs, and tissue organisation and paracrine signalling during development, as well as others. In the jejunum, little is known about the function of telocytes in the adult organ, or is there any information about when these cells develop or if they could have an auxiliary role in the development of the jejunum. The present study employed histological, immunohistochemical and immunofluorescence techniques on histological sections of the jejunum of Mongolian gerbil pups on two different days of postnatal development of the jejunum, covering the maturation period of the organ. By immunolabelling for CD34, it was observed that telocytes are already present in the jejunum during the first week of postnatal life and exist in close association with the developing muscularis mucosae, which are therefore TGFß1-positive. The telocytes are still present at the end of the first month of life, and a portion of them present co-localisation with c-Kit. Fibroblast-like cells, which are exclusively c-Kit-positive, are also observed, which may indicate the presence of interstitial Cajal cells (ICCs). Finally, it can be hypothesised that a portion of the telocytes may give rise to ICCs, which are c-Kit-positive but CD34 negative.
Assuntos
Jejuno/crescimento & desenvolvimento , Telócitos/citologia , Animais , Antígenos CD34/genética , Antígenos CD34/metabolismo , Diferenciação Celular , Gerbillinae , Células Intersticiais de Cajal/citologia , Células Intersticiais de Cajal/metabolismo , Jejuno/citologia , Telócitos/metabolismo , Fator de Crescimento Transformador beta1/genética , Fator de Crescimento Transformador beta1/metabolismoRESUMO
Experimental data demonstrated the negative impact of maternal protein malnutrition (MPM) on rat prostate development, but the mechanism behind the impairment of prostate growth has not been well understood. Male Sprague Dawley rats, borned to dams fed a normal protein diet (CTR group, 17% protein diet), were compared with those borned from dams fed a low protein diet (6% protein diet) during gestation (GLP group) or gestation and lactation (GLLP). The ventral prostate lobes (VP) were removed at post-natal day (PND) 10 and 21, and analyzed via different methods. The main findings were low birth weight, a reduction in ano-genital distance (AGD, a testosterone-dependent parameter), and an impairment of prostate development. A delay in prostate morphogenesis was associated with a reduced testosterone levels and angiogenic process through downregulation of aquaporin-1 (AQP-1), insulin/IGF-1 axis and VEGF signaling pathway. Depletion of the microvascular network, which occurs in parallel to the impairment of proliferation and differentiation of the epithelial cells, affects the bidirectional flux between blood vessels impacting prostatic development. In conclusion, our data support the hypothesis that a reduction in microvascular angiogenesis, especially in the subepithelial compartment, is associated to the impairment of prostate morphogenesis in the offspring of MPM dams.