Dystroglycan Patterns On The Prostate Of Non-obese Diabetic Mice Submitted To Glycaemic Control.

Dystroglycan (DG) is an adhesion protein which plays a crucial role in the maintenance of tissue integrity. Diabetes has been pointed out as a disease which causes harmful effects on prostate function. Therefore, the main objective of this work was to verify DG distribution and structure features in diabetic mice with and without glycaemic control and to relate these parameters to prostate pathogenesis. Thirty mice (Nod and BALB/c) were divided into three groups after 20 days of diabetic state: the control group received a 5 ml/kg dose of physiological saline daily for 20 days; the diabetic group had the same treatment as the control group; the diabetic-insulin group received 4-5 IU doses of Neutral Protamine Hagedorn (NPH) insulin daily for 20 days. After 20 days of treatment, all animals were killed and samples from the ventral prostate were processed for immunological and light microscopy analyses. The results showed diminished beta- and alpha-DG receptors in the diabetic group. However, there was a recovery of both beta-and alpha-DG receptor immunolocalization after insulin administration. Epithelial and stromal morphological changes were verified in the diabetic group, which also presented recovery after insulin treatment. Thus, it could be concluded that diabetes disturbed prostate structure integrity and altered the occurrence of alpha and beta-DG receptors, indicating decreased cell-matrix extracellular and cell-basal membrane attachment. However, insulin treatment could partially restore glandular homeostasis. The decrease in epithelial-stromal interaction certainly predisposes this gland in diabetic mice to be a prostate disease target.90156-6

Prostatic Angiogenic Responses In Late Life: Antiangiogenic Therapy Influences And Relation With The Glandular Microenvironment In The Transgenic Adenocarcinoma Of Mouse Prostate (tramp) Model.

Aging is considered one of the main predisposing factors for the development of prostate malignancies. Angiogenesis is fundamental for tumor growth and its inhibition represents a promising therapeutic approach in cancer treatment. Thus, we sought to determine angiogenic responses and the effects of antiangiogenic therapy in the mouse prostate during late life, comparing these findings with the prostatic microenvironment in the Transgenic Adenocarcinoma of Mouse Prostate (TRAMP) model. Male mice (52 week-old FVB) were submitted to treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c.). Finasteride was administered (20 mg/kg; s.c.), alone or in association to both inhibitors. The dorsolateral prostate was collected for VEGF, HIF-1α, FGF-2 and endostatin immunohistochemical and Western Blotting analyses and for microvessel density (MVD) count. Senescence led to increased MVD and VEGF, HIF-1α and FGF-2 protein levels in the prostatic microenvironment, similarly to what was observed in TRAMP mice prostate. The angiogenic process was impaired in all the treated groups, demonstrating significantly decreased MVD. Antiangiogenic and/or finasteride treatments resulted in decreased VEGF and HIF-1α levels, especially following TNP-470 administration, either alone or associated to SU5416. The combination of these agents resulted in increased endostatin levels, regardless of the presence of finasteride. Prostatic angiogenesis stimulation during senescence favored the development of neoplastic lesions, considering the pro-angiogenic microenvironment as a common aspect also observed during cancer progression in TRAMP mice. The combined antiangiogenic therapy was more efficient, leading to enhanced imbalance towards angiogenic inhibition in the organ. Finally, finasteride administration might secondarily upregulate the expression of pro-angiogenic factors, pointing to the harmful effects of this therapy. Prostate 75: 484-499, 2015. © 2014 Wiley Periodicals, Inc.75484-9

Upper urinary tract urothelial carcinoma experimental models

Cancer research on animals is an important complement to clinical investigations. Particularly, the use of animal models in researches on urinary tract cancer has a primary role in demonstrating that carcinogenesis is a multiple-stage process. These models are used to induce tumors in order to analyze the development of immunity, chemotherapy, and new techniques. This article discusses the role of animal models using rodents in urothelial carcinoma, the validity of animal models in carcinogen-induced tumors, the primary animal models available of transitional cell carcinoma and carcinoma of the upper urinary tract, and the advantages and disadvantages of the main experimental models in use

Hormonal Therapy In The Senescence: Prostatic Microenvironment Structure And Adhesion Molecules.

Hormonal replacement has been utilized to minimize the harmful effects of hormonal imbalance in elderly men. The development and progression of prostatic diseases and their relation to hormone therapy is still unclear. Thus, the aim herewith was to characterize the structure and dystroglycan molecule (DGs) reactivities in the ventral prostatic lobe from elderly rats submitted to steroid hormone replacement. Male rats (Sprague-Dawley) were divided into one Young group and six senile groups. The Young group (YNG) (4 months old) received peanut oil (5mL/kg, s.c.). The senile rats (10 months old) were submitted to the following treatments: Senile group (SEN) (5mL/kg peanut oil, s.c.); Testosterone group (TEST) (5mg/kg testosterone cipionate, s.c.); Estrogen group (EST) (25μg/kg 17β-estradiol, s.c.); Castrated group (CAS) (surgical castration); Castrated-Testosterone (CT) (surgical castration and treatment similar to TEST group); and Castrated-Estrogen (CE) (surgical castration and treatment similar to EST group). After 30 days treatment, blood samples were collected for hormonal analysis and ventral prostate samples were processed for light and transmission electron microscopies, morphometrical analysis, immunohistochemistry and Western Blotting. The results showed decreased serum testosterone levels in the senescence and increased testosterone and estrogen plasmatic levels after hormone administration in the TEST and EST groups, respectively, highlighting the therapy efficiency. Hypertrophied stroma and inflammatory cells were verified in the SEN group. After hormone replacement in the senescence or following castration, atrophic epithelium, epithelial cells with clear cytoplasmic halo around the nucleus, microacini and maintenance of hypertrophied stroma were seen. Decreased DG levels were verified in the senescence. After hormonal therapy, increased protein levels of these molecules were observed, especially in those groups which received estradiol. Thus, the occurrence of inflammatory cells, stromal hypertrophy and the presence of cells with clear halo around the nucleus after hormonal therapy probably indicated prostatic paracrine signaling imbalance, suggesting a stromal reactive microenvironment favorable to the development of glandular lesions. However, the increase of DG levels characterized positive effect of steroid hormone replacement on the prostate in the senescence. Thus, it could be concluded that despite having positive effects on important molecules involved in the maintenance of epithelial-stromal interaction and glandular cytoarchitecture, such as DGs, hormonal therapy enhanced structural changes associated with senescence, probably due to increased hormonal imbalance between androgens and estrogens in the prostatic tissue.42642-5

Experimental Alcoholism And Pathogenesis Of Prostatic Diseases In Uchb Rats.

Previous studies have shown that long-term alcohol treatment has negative effects on prostatic stromal-epithelial interaction. Thus, the aim of the present study was to analyze the histochemical, immunohistochemical and ultrastructural alterations that occur in the prostatic stroma and epithelium of rats submitted to chronic alcohol ingestion and alcohol abstinence, as well as to establish the relationship between these changes and prostatic diseases. Thirty male rats (10 Wistar and 20 UChB rats) were divided into three experimental groups: the control group received tap water, the alcoholic group received ethanol diluted to 10 degrees G.L. for 150 days, and the abstinent group received the same liquid diet as the alcoholic group up to 120 days of treatment and only tap water for 30 days thereafter. At the end of treatment, all animals were sacrificed and the ventral lobe of the prostate was removed and processed for histochemical, immunohistochemical and ultrastructural analyses. In addition, plasma testosterone levels were measured. The results showed prostatic intraepithelial neoplasia, infolding of the epithelium towards the stroma, stromal hypertrophy and the presence of inflammatory cells in alcoholic animals. In the abstinent group, alterations were noted mainly in the stromal area. In conclusion, ethanol triggers alterations in prostatic epithelial and stromal compartments, affecting the stromal microenvironment and predisposing the organ to pathological processes.31459-7

Transgenic adenocarcinoma of the mouse prostate (TRAMP) mode l : a good alternative to study PCa progression and chemoprevention approaches

The use of genetically modified animals has been studied in scientific research over time as a way to discover new treatments or even a cure for various diseases. Transgenic Adenocarcinoma of the Mouse Prostate (TRAMP) is a model for prostate cancer (PCa) that develops lesions that range from preneoplastic to metastasis. Its similarity to human PCa brings essential knowledge about disease development as well as making possible to investigate different degrees of the tumor profile. We reviewed the literature regarding five important areas relating to PCa progression in the TRAMP model. We also present some useful PCa models comparing them to TRAMP. Furthermore, we investigated the effect of some therapies related to these areas highlighting the best approaches that can delay PCa progression. The revised studies showed that TRAMP cancer stages are well established from 8 to 30 weeks of age, which makes possible to interfere in specific times of PCa development. Moreover, inflammatory and angiogenic blockage before the appearance of malignant lesions retarded PCa progression and showed better results than therapeutical approaches in other phases in TRAMP mice. Reactive stroma is less studied than other areas, although it has been showing a particular relevance in PCa as a milestone in malignant transformation through the modulation of TGF-β, vimentin, and αSMA. We concluded that even years after its creation, the TRAMP model is still one of the most essential tools for PCa study, as well as for the development of new strategies to prevent the disease21714114

Antiangiogenic Therapy Effects On Age-associated Matrix Metalloproteinase-9 (mmp-9) And Insulin-like Growth Factor Receptor-1 (igfr-1) Responses: A Comparative Study Of Prostate Disorders In Aged And Tramp Mice.

Senescence is associated with hormonal imbalance and prostatic disorders. Angiogenesis is fundamental for the progression of malignant lesions and is a promising target for prostate cancer treatment. The aim was to characterize matrix metalloproteinase-9 (MMP-9) and insulin-like growth factor receptor-1 (IGFR-1) responses in the prostate during senescence and following antiangiogenic and/or androgen ablation therapies, comparing them to cancer progression features in TRAMP mice. Aged male mice (52-week-old FVB) were submitted to antiangiogenic treatments with SU5416 (6 mg/kg; i.p.) and/or TNP-470 (15 mg/kg; s.c). Finasteride (20 mg/kg; s.c.) was administered alone or associated to both inhibitors. Dorsolateral prostate was collected for light microscopy, and immunohistochemistry and Western blotting collected for MMP-9 and IGFR-1. Senescence led to inflammation and different proliferative lesions in the prostate, as well as to increased MMP-9 and IGFR-1, resembling TRAMP mice prostatic microenvironment. Antiangiogenic therapies promoted recovery and/or interruption of age-associated alterations, presenting differential effects on the molecules studied. SU5416 acted mainly on MMP-9, whereas TNP-470 showed its best influence on IGFR-1 levels. Finasteride administration, alone or in combination with antiangiogenic agents, also resulted in regression of inflammation and neoplastic lesions, besides having a negative modulatory effect on both MMP-9 and IGFR-1. We concluded that stimulated tissue remodeling and proliferative processes during senescence predisposed the prostate to malignant disorders. The combination of different agents was more effective to minimize prostatic imbalance during this period, probably due to the differential action of each drug on factors involved in cell proliferation and extracellular matrix remodeling, resulting in a broader spectrum of effects following the combined treatment.142269-8

Antiangiogenic and finasteride therapies: Responses of the prostate microenvironment in elderly mice

Aims The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice. Main methods 90 male FVB mice were divided into: Young (18 weeks old) and senile (52 weeks old) groups; finasteride group: finasteride (20 mg/kg); SU5416 group: SU5416 (6 mg/kg); TNP-470 group: TNP-470 (15 mg/kg,) and SU5416 + TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21 days, prostate ventral lobes were collected for morphological, immunohistochemical and Western blotting analyses. Key findings The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and endostatin reactivities, and an increase for ER-α, ER-β and VEGF, were seen in the senile group. Decreased VEGF and ER-α reactivities and increased ER-β reactivity were verified in the finasteride, SU5416 groups and especially in SU5416 + TNP-470 group. The TNP-470 group showed reduced AR and ER-β protein levels. Significance The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416 + TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-β1061-25870FUNDAÇÃO DE AMPARO À PESQUISA DO ESTADO DE SÃO PAULO - FAPESP2011/03116-4; 2012/03010-

Antiangiogenic And Finasteride Therapies: Responses Of The Prostate Microenvironment In Elderly Mice.

The aim of this study was to evaluate the structural and molecular effects of antiangiogenic therapies and finasteride on the ventral prostate of senile mice. 90 male FVB mice were divided into: Young (18 weeks old) and senile (52 weeks old) groups; finasteride group: finasteride (20mg/kg); SU5416 group: SU5416 (6 mg/kg); TNP-470 group: TNP-470 (15 mg/kg,) and SU5416+TNP-470 group: similar to the SU5416 and TNP-470 groups. After 21 days, prostate ventral lobes were collected for morphological, immunohistochemical and Western blotting analyses. The results demonstrated atrophy, occasional proliferative lesions and inflammatory cells in the prostate during senescence, which were interrupted and/or blocked by treatment with antiangiogenic drugs and finasteride. Decreased AR and endostatin reactivities, and an increase for ER-α, ER-β and VEGF, were seen in the senile group. Decreased VEGF and ER-α reactivities and increased ER-β reactivity were verified in the finasteride, SU5416 groups and especially in SU5416+TNP-470 group. The TNP-470 group showed reduced AR and ER-β protein levels. The senescence favored the occurrence of structural and/or molecular alterations suggesting the onset of malignant lesions, due to the imbalance in the signaling between the epithelium and stroma. The SU5416+TNP-470 treatment was more effective in maintaining the structural, hormonal and angiogenic factor balance in the prostate during senescence, highlighting the signaling of antiproliferation via ER-β.10658-7

Experimental Animal Model And Rna Interference: A Promising Association For Bladder Cancer Research.

Animal models are at the centre of laboratory bladder cancer (BC) research and at the same time, the bridge to the clinic. A new and very promising therapeutical approach is to silence abnormally up-regulated genes in cancer, through small interfering RNA (siRNA) molecules. Therapeutic use and success of siRNAs will largely depend on their efficient and safe in vivo delivery and on avoiding accidental off-target effects. Intravesical siRNA is a strategy which may be the best deliver option to surperficial BC like intravesical immunotherapy. Its direct action might allow a continuous intracellular exposure to effective siRNA concentrations. While the procedure of transurethral siRNA administration is promising for BC research allowing detection of new targets in BC therapy, the optimal intravesical carrier and the best target(s) to siRNA are to be determined.27353-6