Histological modifications of the rat prostate following transection of somatic and autonomic nerves

Diaz, Rosaura; García, Luis I.; Locia, Jose; Silva, Milagros; Rodrı́guez, Sara; Perez, Cesar A.; Aranda-Abreu, Gonzálo Emiliano; Manzo, Jorge; Toledo, Rebeca; Hernández, Marı́a Elena

doi:10.1590/s0001-37652010000200015

Cited by 13 publications

(12 citation statements)

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“…Similar findings have been reported in other neurotrophic cancer such as pancreatic cancer(13). Studies in rats have shown that denervation of the prostate leads to almost complete loss of epithelium (14), indicating a strong trophic effect of nerves on normal prostate epithelium. Similarly, men with complete spinal cord injury had significantly smaller prostates than controls(15).…”

Section: Introductionmentioning

confidence: 99%

RET Signaling in Prostate Cancer

Ban

Feng

Shao

et al. 2017

Clinical Cancer Research

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Purpose Large diameter perineural prostate cancer is associated with poor outcomes. GDNF, with its co-receptor GFRα1, binds RET and activates downstream pro-oncogenic signaling. Since both GDNF and GFRα1 are secreted by nerves, we examined the role of RET signaling in prostate cancer. Experimental Design Expression of RET, GDNF and/or GFRα1 was assessed. The impact of RET signaling on proliferation, invasion and soft agar colony formation, perineural invasion and growth in vivo was determined. Cellular signaling downstream of RET was examined by Western blotting. Results RET is expressed in all prostate cancer cell lines. GFRα1 is only expressed in 22Rv1 cells, which is the only line that responds to exogenous GDNF. In contrast, all cell lines respond to GDNF plus GFRα1. Conditioned medium from dorsal root ganglia contains secreted GFRα1 and promotes transformation related phenotypes, which can be blocked by anti-GFRα1 antibody. Perineural invasion in the dorsal root ganglion assay is inhibited by anti-GFRα antibody and RET knockdown. In vivo, knockdown of RET inhibits tumor growth. RET signaling activates ERK or AKT signaling depending on context, but phosphorylation of p70S6 kinase is markedly increased in all cases. Knockdown of p70S6 kinase markedly decreases RET induced transformed phenotypes. Finally, RET is expressed in 18% of adenocarcinomas and all three small cell carcinomas examined. Conclusions RET promotes transformation associated phenotypes, including perineural invasion in prostate cancer via activation of p70S6 kinase. GFRα1, which is secreted by nerves, is a limiting factor for RET signaling, creating a perineural niche where RET signaling can occur.

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Section: Introductionmentioning

confidence: 99%

RET Signaling in Prostate Cancer

Ban

Feng

Shao

et al. 2017

Clinical Cancer Research

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“…The optimized direct administration protocol was applied to the rat hypogastric nerve and aortic plexus, which served as surgically accessible autonomic nerves that model the composition and smaller size of the cavernous nerves as compared to the brachial plexus and sciatic nerves used for murine studies 51 , 58 , 59 . The rat doses of Oxazine 4 and Nile Red for both direct and systemic administration were scaled from the murine studies by body surface area equivalence 65 .…”

Section: Resultsmentioning

confidence: 99%

“…The optimized direct administration method using Oxazine 4 alone and in combination with Nile Red was scaled to rat imaging studies to facilitate imaging of surgically available autonomic nerves that were in close anatomical proximity to the prostate with similar composition to the cavernous nerves 51 , 58 , 66 . The aortic plexus and hypogastric nerves were selected for direct administration studies where the hypogastric nerves were larger and more easily visualized than the aortic plexuses.…”

Section: Discussionmentioning

confidence: 99%

“…Rat hypogastric nerves and aortic plexuses were stained using the optimized direct administration methodology developed in murine models. The hypogastric nerves and aortic plexus were selected as representative autonomic nerves with close proximity to the prostatic nerves that were surgical accessible in the peritoneal cavity of rats 51 , 58 , 59 . Nerve SBR in the hypogastic nerves and aortic plexuses after direct administration was compared to nerve SBR in these same nerve structures following systemic administration.…”

Section: Methodsmentioning

confidence: 99%

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Direct Administration of Nerve-Specific Contrast to Improve Nerve Sparing Radical Prostatectomy

Barth

Gibbs

2017

Theranostics

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Nerve damage remains a major morbidity following nerve sparing radical prostatectomy, significantly affecting quality of life post-surgery. Nerve-specific fluorescence guided surgery offers a potential solution by enhancing nerve visualization intraoperatively. However, the prostate is highly innervated and only the cavernous nerve structures require preservation to maintain continence and potency. Systemic administration of a nerve-specific fluorophore would lower nerve signal to background ratio (SBR) in vital nerve structures, making them difficult to distinguish from all nervous tissue in the pelvic region. A direct administration methodology to enable selective nerve highlighting for enhanced nerve SBR in a specific nerve structure has been developed herein. The direct administration methodology demonstrated equivalent nerve-specific contrast to systemic administration at optimal exposure times. However, the direct administration methodology provided a brighter fluorescent nerve signal, facilitating nerve-specific fluorescence imaging at video rate, which was not possible following systemic administration. Additionally, the direct administration methodology required a significantly lower fluorophore dose than systemic administration, that when scaled to a human dose falls within the microdosing range. Furthermore, a dual fluorophore tissue staining method was developed that alleviates fluorescence background signal from adipose tissue accumulation using a spectrally distinct adipose tissue specific fluorophore. These results validate the use of the direct administration methodology for specific nerve visualization with fluorescence image-guided surgery, which would improve vital nerve structure identification and visualization during nerve sparing radical prostatectomy.

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“…On the other hand, while GDNF signalling is important for kidney development and spermatogenesis (Sariola & Saarma 2003), the role of other GDNF families of neurotrophic factors outside the nervous system is not well understood. In humans and rodents, the prostate gland has a rich sympathetic and parasympathetic innervation (Vaalasti & Hervonen 1979, 1980, and previous rodent studies of autonomic denervation have suggested significant (Martinez-Pineiro et al 1993, Lujan et al 1998, Diaz et al 2010) but complex and ill-defined roles of autonomic nerves in the regulation of glandular structure and function. Therefore, the original aim of this study was to utilise transgenic mouse models lacking either a ligand (NTNKO) or a receptor (GFRa2KO) for the NTN signalling pathway to characterise the role and signalling mechanisms of parasympathetic nerves in prostate development.…”

Section: Discussionmentioning

confidence: 99%

Evidence for increased tissue androgen sensitivity in neurturin knockout mice

Simanainen

Gao

Desai

et al. 2013

Journal of Endocrinology

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Neurturin (NTN) is a member of the glial cell line-derived neurotrophic factor (GDNF) family and signals through GDNF family receptor alpha 2 (GFRa2). We hypothesised that epithelial atrophy reported in the reproductive organs of Ntn (Nrtn)-and Gfra2 (Gfra2)-deficient mice could be due to NTN affecting the hormonal environment. To investigate this, we compared the reproductive organs of Ntn-and Gfra2-deficient male mice in parallel with an analysis of their circulating reproductive hormone levels. There were no significant structural changes within the organs of the knockout mice; however, serum and intratesticular testosterone and serum LH levels were very low. To reconcile these observations, we tested androgen sensitivity by creating a dihydrotestosterone (DHT) clamp (castration plus DHT implant) to create fixed circulating levels of androgens, allowing the evaluation of androgen-sensitive endpoints. At the same serum DHT levels, serum LH levels were lower and prostate and seminal vesicle weights were higher in the Ntn knockout (NTNKO) mice than in the wild-type mice, suggesting an increased response to androgens in the accessory glands and hypothalamus and pituitary of the NTNKO mice. Testicular and pituitary responsiveness was unaffected in the NTNKO males, as determined by the response to the human chorionic gonadotrophin or GNRH analogue, leuprolide, respectively. In conclusion, our results suggest that NTN inactivation enhances androgen sensitivity in reproductive and neuroendocrine tissues, revealing a novel mechanism to influence reproductive function and the activity of other androgen-dependent tissues. Key Words" glial cell line-derived neurotrophic factor (GDNF) family " TGFb family " neurotrophic " hypothalamic-pituitarytesticular axis " urogenital tract

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Histological modifications of the rat prostate following transection of somatic and autonomic nerves

Cited by 13 publications

References 24 publications

RET Signaling in Prostate Cancer

RET Signaling in Prostate Cancer

Direct Administration of Nerve-Specific Contrast to Improve Nerve Sparing Radical Prostatectomy

Evidence for increased tissue androgen sensitivity in neurturin knockout mice

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