313 INFLUENCE OF THE NEURAL MICROENVIRONMENT IN PROSTATE CANCER

You have accessJournal of UrologyProstate Cancer: Basic Research II1 Apr 2012313 INFLUENCE OF THE NEURAL MICROENVIRONMENT IN PROSTATE CANCER Jason K. Au, Diego Florentin, Yi Ding, Dandan He, Chad J. Creighton, Anna Frolov, Olga Dakhova, Yiqun Zhang, Christopher Smith, Dov Kadmon, Brian Miles, Michael Ittmann, David Rowley, and Gustavo Ayala Jason K. AuJason K. Au Houston, TX More articles by this author , Diego FlorentinDiego Florentin Houston, TX More articles by this author , Yi DingYi Ding Houston, TX More articles by this author , Dandan HeDandan He Houston, TX More articles by this author , Chad J. CreightonChad J. Creighton Houston, TX More articles by this author , Anna FrolovAnna Frolov Houston, TX More articles by this author , Olga DakhovaOlga Dakhova Houston, TX More articles by this author , Yiqun ZhangYiqun Zhang Houston, TX More articles by this author , Christopher SmithChristopher Smith Houston, TX More articles by this author , Dov KadmonDov Kadmon Houston, TX More articles by this author , Brian MilesBrian Miles Houston, TX More articles by this author , Michael IttmannMichael Ittmann Houston, TX More articles by this author , David RowleyDavid Rowley Houston, TX More articles by this author , and Gustavo AyalaGustavo Ayala Houston, TX More articles by this author View All Author Informationhttps://doi.org/10.1016/j.juro.2012.02.373AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookTwitterLinked InEmail INTRODUCTION AND OBJECTIVES Nerves exhibit inductive and trophic functions in development and adult tissues. They are important for wound repair and tissue homeostasis. Cancer cells induce neurogenesis and perineural invasion results in a survival advantage for cancer cells. METHODS To address the functional significance of neural input to tumorigenesis, the major pelvic ganglion (MPG) of male NIH-Foxn1rnu nude rats was excised, sham operated, or injected with Botox or vehicle, and the anterior prostate glands were inoculated with VCaP-luc human prostate cancer cells (2 × 106) for 7 weeks. As a second model we used VCaP-luc orthotopically in nu-nu mice that underwent the same procedures except MPG dissection. Chemical denervation was used to eliminate the potential confounding factors of affecting blood vessels. Laser captured epithelium, stroma and tumor was used for gene array analysis. We next evaluated the gene expression profiles in laser-captured material obtained from prostate cancer patients with spinal cord injuries. RESULTS Quantitative histologic image analysis demonstrated that bilateral denervation (Botox injection, MPG dissection or spinal cord injury) resulted in a significant reduction in tumor size, both in the rat and mouse experiments. Gene expression profiling analysis revealed that both chemical and physical denervation produced similar expression profiles that self-clustered in each compartment, confirming that both act through similar mechanisms. The gene profile of tumors shared similarities with tumors in patients with spinal cord injuries, confirming an effect through denervation. Normal, non-neoplastic epithelium exhibited variable atrophic histology, but alterations in gene expression are extensive with a total of 1231 unique genes differentially expressed at a high significance threshold (2237 gene probes, ANOVA p<0.01, SD>0.2, true positive rate, ∼83%). Gene Ontology (GO) analysis of genes downregulated in denervated epithelium compared to intact prostates include translational elongation, ribosome, structural constituent of ribosome, translation, cytosolic small and large ribosomal subunit, RNA binding, ribonucleoprotein complex, and protein binding. CONCLUSIONS These studies suggest that nerves exert trophic effects on epithelium and prostate cancer cells and are paramount for cancer progression. The studies have lead to new therapeutic approaches to target the neural niche in cancer, including a human neoadjuvant clinical trial with botox. © 2012 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 187Issue 4SApril 2012Page: e127 Advertisement Copyright & Permissions© 2012 by American Urological Association Education and Research, Inc.Metrics Author Information Jason K. Au Houston, TX More articles by this author Diego Florentin Houston, TX More articles by this author Yi Ding Houston, TX More articles by this author Dandan He Houston, TX More articles by this author Chad J. Creighton Houston, TX More articles by this author Anna Frolov Houston, TX More articles by this author Olga Dakhova Houston, TX More articles by this author Yiqun Zhang Houston, TX More articles by this author Christopher Smith Houston, TX More articles by this author Dov Kadmon Houston, TX More articles by this author Brian Miles Houston, TX More articles by this author Michael Ittmann Houston, TX More articles by this author David Rowley Houston, TX More articles by this author Gustavo Ayala Houston, TX More articles by this author Expand All Advertisement Advertisement PDF downloadLoading ...