Age Related Differences in Responsiveness to Sildenafil and Tamsulosin are due to Myogenic Smooth Muscle Tone in the Human Prostate

Lower urinary tract symptoms (LUTS) due to Benign Prostatic Hyperplasia (BPH) are highly prevalent in older men, having a profound impact on patient quality of life. Current therapeutics for BPH/LUTS target neurogenic smooth muscle tone, but response is unpredictable and many patients fail to respond. Spontaneous myogenic tone is another component of smooth muscle contractility that is uncharacterized in human prostate. To better understand and improve the predictability of patient response, we defined myogenic contractility using human prostate specimens and examined the effect of existing therapeutics. We show that myogenic activity is present in the human prostate with the frequency of contractions in transition zone (TZ) specimens from BPH diagnosed patients approximately 160% greater than matched controls. α1-adrenoreceptor antagonists (Tamsulosin) and PDE5 inhibitors (Sildenafil) both significantly reduced myogenic contractile parameters, including frequency, with notable interpatient variability. Tamsulosin was more effective in older patients (R2 = 0.36, p < 0.01) and men with larger prostate volumes (R2 = 0.41, p < 0.05), while Sildenafil was more effective in younger men (R2 = 0.45, p < 0.05). As myogenic tone is significantly increased in BPH, therapeutics targeting this mechanism used with reference to patient characteristics could improve clinical outcomes and better predict patient response

Oxytocin receptor antagonists as a novel pharmacological agent for reducing smooth muscle tone in the human prostate

Pharmacotherapies for the treatment of Benign Prostatic Hyperplasia (BPH) are targeted at reducing cellular proliferation (static component) or reducing smooth muscle tone (dynamic component), but response is unpredictable and many patients fail to respond. An impediment to identifying novel pharmacotherapies is the incomplete understanding of paracrine signalling. Oxytocin has been highlighted as a potential paracrine mediator of BPH. To better understand oxytocin signalling, we investigated the effects of exogenous oxytocin on both stromal cell proliferation, and inherent spontaneous prostate contractions using primary models derived from human prostate tissue. We show that the Oxytocin Receptor (OXTR) is widely expressed in the human prostate, and co-localises to contractile cells within the prostate stroma. Exogenous oxytocin did not modulate prostatic fibroblast proliferation, but did significantly (p < 0.05) upregulate the frequency of spontaneous contractions in prostate tissue, indicating a role in generating smooth muscle tone. Application of atosiban, an OXTR antagonist, significantly (p < 0.05) reduced spontaneous contractions. Individual tissue responsiveness to both exogenous oxytocin (R2 = 0.697, p < 0.01) and atosiban (R2 = 0.472,p < 0.05) was greater in tissue collected from older men. Overall, our data suggest that oxytocin is a key regulator of inherent spontaneous prostate contractions, and targeting of the OXTR and associated downstream signalling is an attractive prospect in the development of novel BPH pharmacotherapies

Mast Cell‐Derived SAMD14 is a Novel Regulator of the Human Prostate Tumor Microenvironment

Mast cells (MCs) are important cellular components of the tumor microenvironment and are significantly associated with poor patient outcomes in prostate cancer and other solid cancers. The promotion of tumor progression partly involves heterotypic interactions between MCs and cancer-associated fibroblasts (CAFs), which combine to potentiate a pro-tumor extracellular matrix and promote epithelial cell invasion and migration. Thus far, the interactions between MCs and CAFs remain poorly understood. To identify molecular changes that may alter resident MC function in the prostate tumor microenvironment, we profiled the transcriptome of human prostate MCs isolated from patient-matched non-tumor and tumor-associated regions of fresh radical prostatectomy tissue. Transcriptomic profiling revealed a distinct gene expression profile of MCs isolated from prostate tumor regions, including the downregulation of SAMD14, a putative tumor suppressor gene. Proteomic profiling revealed that overexpression of SAMD14 in HMC-1 altered the secretion of proteins associated with immune regulation and extracellular matrix processes. To assess MC biological function within a model of the prostate tumor microenvironment, HMC-1-SAMD14+ conditioned media was added to co-cultures of primary prostatic CAFs and prostate epithelium. HMC-1-SAMD14+ secretions were shown to reduce the deposition and alignment of matrix produced by CAFs and suppress pro-tumorigenic prostate epithelial morphology. Overall, our data present the first profile of human MCs derived from prostate cancer patient specimens and identifies MC-derived SAMD14 as an important mediator of MC phenotype and function within the prostate tumor microenvironment

Mimicking the tumour microenvironment (TME): Angiogenesis in tumour progression

Two-dimensional (2D) substrates cannot accurately mimic the complex matrix of native TME, whereas 3D models can recapitulate the natural tumour progression in vitro. As part of the tumour stroma, fibroblasts and endothelial cells (ECs) are well-known to not only support tumour growth but also to reduce the efficacy of anti-cancer drugs. Particularly, ECs are involved in the process of tumour vascularisation which represents a crucial step in the progression of cancer. Most of the previous studies are carried out in animal models or 2D cultures; hence, a detailed evaluation of experimental data is poor. To address this issue, we aim to develop a novel 3D in vitro approach, to mimic native tumour angiogenesis in 3D and to quantify the developed vascular network

Estrogen Receptor β Activation Impairs Prostatic Regeneration by Inducing Apoptosis in Murine and Human Stem/Progenitor Enriched Cell Populations

<div><p>Androgen depletion is the primary treatment for prostate disease; however, it fails to target residual castrate-resistant cells that are regenerative and cells of origin of prostate cancer. Estrogens, like androgens, regulate survival in prostatic cells, and the goal of this study was to determine the advantages of selective activation of estrogen receptor β (ERβ) to induce cell death in stem cells that are castrate-resistant. Here we show two cycles of short-term ERβ agonist (8β-VE2) administration this treatment impairs regeneration, causing cystic atrophy that correlates with sustained depletion of p63+ basal cells. Furthermore, agonist treatment attenuates clonogenicity and self-renewal of murine prostatic stem/progenitor cells and depletes both murine (Lin⁻Sca1⁺CD49f^hi) and human (CD49f^hiTrop2^hi) prostatic basal cells. Finally, we demonstrate the combined added benefits of selective stimulation of ERβ, including the induction of cell death in quiescent post-castration tissues. Subsequent to castration ERβ-induces further apoptosis in basal, luminal and intermediate cells. Our results reveal a novel benefit of ERβ activation for prostate disease and suggest that combining selective activation of ERβ with androgen-deprivation may be a feasible strategy to target stem cells implicated in the origin of prostatic disease.</p> </div

Двухмоўны слоўнік метафар псіхалагічнай сферы чалавека / В.Ю. Шыманская

Двухмоўны слоўнік метафар псіхалагічнай сферы чалавека адлюстроўвае субстантыўныя сродкі рэпрэзентацыі псіхалагічнай сферы чалавека ў беларускай і англійскай мовах. Аб’ект слоўнікавай сістэматызацыі – субстантыўныя метафары, які ўжываюцца для намінацыі і характарызацыі псіхічных працэсаў, станаў і ўласцівасцей асобы. Слоўнік з’яўляецца даведачнай крыніцай пры вызначэнні семантыкі, ужывальнасці, сінанімічных варыянтаў і перакладу метафар, а таксама пры выбары сродкаў метафарычнай рэпрэзентацыі псіхалогіі чалавека. Рэестр слоўніка складаюць беларускія і англійскія метафары, змешчаныя ў алфавітным парадку. У слоўніку пададзена 490 беларускіх і 548 англійскіх метафар псіхалагічнай сферы чалавека, да кожнай з якіх прыведзена да 25 сінанімічных і эквівалентных метафар. У агульны рэестр слоўніка, а таксама ў рэестр сінанімічных і эквівалентных метафар уключаны 142 беларускія і 105 англійскіх патэнцыяльных моўных метафар. Слоўнік арыентаваны на шырокае кола карыстальнікаў – філолагаў, выкладчыкаў, пісьменнікаў, перакладчыкаў, усіх, хто вывучае беларускую і англійскую мовы, цікавіцца вобразнымі сродкамі рэпрэзентацыі псіхалагічнай сферы чалавека ў мове

ERβ treatment after castration induces a second wave of apoptosis in castrate-resistant cells, including basal, luminal and intermediate cells.

<p>(<b>A</b>) Time course of total levels of prostatic apoptosis after 14 days of Cx followed sequentially by 3 days of vehicle (circles) or 8β-VE2 (triangles). Following treatment, groups are coloured green (vehicle) or red (8β-VE2) for clarity (n = 7/group). Representative micrographs show basal cell apoptosis (black arrows indicate apoptag⁺ staining) in 8β-VE2 treated tissues that is absent in vehicle controls. Breakdown of apoptotic levels in individual cell types following sequential treatment (<b>B–D</b>). (<b>B</b>) Stereological analysis (n≥7/group) showing levels of apoptosis in individual cell types in the prostates of mice treated with 14 day Cx +3 day vehicle (14dCx+3dV) or 14 day Cx +3 day 8β-VE2 (14dCx+3dβ). (<b>C</b>) Representative micrograph of immunofluorescent dual labeling in mouse ventral prostate with CKHMW (basal cell marker, green) and CK18 (luminal cell marker, red) used to identify intermediate cells (dual stained in yellow and indicated by white arrow) for quantitation in sequentially treated tissues. (<b>D</b>) Relative numbers of intermediate cells following 14 days of Cx and 3 days of vehicle (grey bars) or 8β-VE2 (open bars) (n≥5/group). (nd; non-detectable, <i>*P</i>&lt;0.05, <i>**P</i>&lt;0.01, ***<i>P</i>&lt;0.005 by Mann Whitney test (B) or students t-test (D)). (Scale A = 20 µm, C = 10 µm).</p

ERβ induces apoptosis in regenerative murine and human prostatic basal cells.

<p>(<b>A</b>) Representative flow cytometry plots showing live, dead and apoptotic cells following vehicle or 8β-VE2 treatment of digested mouse prostate. (<b>B</b>) Percent apoptotic cells following vehicle (grey bar) or 8β-VE2 (open bar) treatment of digested mouse prostate (n = 3 with 3 mice/group/experiment). (<b>C</b>) Representative flow cytometry plots showing gating for regenerative murine LSC cells. (<b>D</b>) Changes in the regenerative murine LSC population following vehicle (grey bar) or 8β-VE2 treatment (open bar) (n = 3 with 3 mice/group). (<b>E</b>) Representative flow cytometry plots following vehicle or 8β-VE2 treatment of human prostatic epithelial cells. (<b>F</b>) Changes in the regenerative CD49f^hiTrop2^hi population following vehicle (grey bars) or 8β-VE2 treatment (open bars). (n = 3 patients), <i>**P&lt;</i>0.01 by students t-test.</p