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Introduction: Radium-223 dichloride is the first alpha-particle emitting therapeutic agent approved by FDA and EMA for bone metastatic castration-resistant prostate cancer. We studied its age-dependent biodistribution in mice, and compared it with [ 99m Tc]Tc-MDP and [ 18 F]NaF aiming to identify a potential imaging surrogate to predict [ 223 Ra]RaCl 2 whole-body localization., Methods: Male C57Bl/6 mice dosed with [ 223 Ra]RaCl 2 were sacrificed at different time points to explore [ 223 Ra]RaCl 2 whole-body distribution. In another experiment, mice at different ages were dosed with [ 223 Ra]RaCl 2 to evaluate the aging impact. Finally, [ 99m Tc]Tc-MDP and [ 18 F]NaF were administered to mice, and we compared their biodistributions with [ 223 Ra]RaCl 2 . Detailed micro-localization of each tracer was visualized using autoradiography and histochemical staining., Results: [ 223 Ra]RaCl 2 uptake in bone was rapid and stable. We observed persistent localization at bone epiphyses, as well as the red pulp of the spleen, while its uptake in most soft tissues cleared within 24 h. [ 223 Ra]RaCl 2 distribution in soft tissues is similar in all age groups tested, while bone activity significantly decreased with aging. Although the diagnostic tracers cleared much faster from soft tissues than the therapeutic radionuclide, [ 99m Tc]Tc-MDP and [ 18 F]NaF both co-localized with [ 223 Ra]RaCl 2 in the skeletal compartment., Conclusions: Radium-223 localization to the bone is dependent on age-varying factors, which implies that radium-223 dosimetry should take patient age into account. [ 99m Tc]Tc-MDP shows a different biodistribution from [ 223 Ra]RaCl 2 , both in soft tissues and in bone. [ 18 F]NaF presents a high similarity with [ 223 Ra]RaCl 2 in skeletal uptake, which validates the potential of [ 18 F]NaF as an imaging surrogate to predict radium-223 radiotherapeutic distribution in bone., (Copyright © 2018 The Authors. Published by Elsevier Inc. All rights reserved.)

Urinary complications resulting from benign prostatic hyperplasia and bladder outlet obstruction continue to be a serious health problem. Novel animal model systems and imaging approaches are needed to understand the mechanisms of disease initiation, and to develop novel therapies for benign prostatic hyperplasia. Long-term administration of both estradiol and testosterone in mice can result in prostatic enlargement and recapitulate several clinical components of lower urinary tract symptoms. Herein, we use longitudinal magnetic resonance imaging and histological analyses to quantify changes in prostatic volume, urethral volume, and genitourinary vascularization over time in response to estradiol-induced prostatic enlargement. Our data demonstrate significant prostatic enlargement by 12 weeks after treatment, with no detectable immune infiltration by macrophages or T- or B-cell populations. Importantly, the percentage of cell death, as measured by terminal deoxynucleotidyl transferase dUTP nick-end labeling, was significantly decreased in the prostatic epithelium of treated animals as compared to controls. We found no significant change in prostate cell proliferation in treated mice when compared to controls. These studies highlight the utility of magnetic resonance imaging to quantify changes in prostatic and urethral volumes over time. In conjunction with histological analyses, this approach has the high potential to enable mechanistic studies of initiation and progression of clinically relevant lower urinary tract symptoms. In addition, this model is tractable for investigation and testing of therapeutic interventions to ameliorate or potentially reverse prostatic enlargement., (Copyright © 2017 American Society for Investigative Pathology. Published by Elsevier Inc. All rights reserved.)

Androgens initiate a complex network of signals within the UGS that trigger prostate lineage commitment and bud formation. Given its contributions to organogenesis in other systems, we investigated a role for canonical Wnt signaling in prostate development. We developed a new method to achieve complete deletion of beta-catenin, the transcriptional coactivator required for canonical Wnt signaling, in early prostate development. Beta-catenin deletion abrogated canonical Wnt signaling and yielded prostate rudiments that exhibited dramatically decreased budding and failed to adopt prostatic identity. This requirement for canonical Wnt signaling was limited to a brief critical period during the initial molecular phase of prostate identity specification. Deletion of beta-catenin in the adult prostate did not significantly affect organ homeostasis. Collectively, these data establish that beta-catenin and Wnt signaling play key roles in prostate lineage specification and bud outgrowth., (Copyright © 2012 Elsevier Inc. All rights reserved.)

Prostatic branching morphogenesis is an intricate event requiring precise temporal and spatial integration of numerous hormonal and growth factor-regulated inputs, yet relatively little is known about the downstream signaling pathways that orchestrate this process. In this study, we use a novel mesenchyme-free embryonic prostate culture system, newly available mTOR inhibitors and a conditional PTEN loss-of-function model to investigate the role of the interconnected PI3K and mTOR signaling pathways in prostatic organogenesis. We demonstrate that PI3K levels and PI3K/mTOR activity are robustly induced by androgen during murine prostatic development and that PI3K/mTOR signaling is necessary for prostatic epithelial bud invasion of surrounding mesenchyme. To elucidate the cellular mechanism by which PI3K/mTOR signaling regulates prostatic branching, we show that PI3K/mTOR inhibition does not significantly alter epithelial proliferation or apoptosis, but rather decreases the efficiency and speed with which the developing prostatic epithelial cells migrate. Using mTOR kinase inhibitors to tease out the independent effects of mTOR signaling downstream of PI3K, we find that simultaneous inhibition of mTORC1 and mTORC2 activity attenuates prostatic branching and is sufficient to phenocopy combined PI3K/mTOR inhibition. Surprisingly, however, mTORC1 inhibition alone has the reverse effect, increasing the number and length of prostatic branches. Finally, simultaneous activation of PI3K and downstream mTORC1/C2 via epithelial PTEN loss-of-function also results in decreased budding reversible by mTORC1 inhibition, suggesting that the effect of mTORC1 on branching is not primarily mediated by negative feedback on PI3K/mTORC2 signaling. Taken together, our data point to an important role for PI3K/mTOR signaling in prostatic epithelial invasion and migration and implicates the balance of PI3K and downstream mTORC1/C2 activity as a critical regulator of prostatic epithelial morphogenesis., (Copyright © 2011 Elsevier Inc. All rights reserved.)