@article{e92aa5b2a95440bea9514adb8183fd6a,
title = "Influence of the neural microenvironment on prostate cancer",
abstract = "Background: Nerves are key factors in prostate cancer (PCa), but the functional role of innervation in prostate cancer is poorly understood. PCa induced neurogenesis and perineural invasion (PNI), are associated with aggressive disease. Method: We denervated rodent prostates chemically and physically, before orthotopically implanting cancer cells. We also performed a human neoadjuvant clinical trial using botulinum toxin type A (Botox) and saline in the same patient, before prostatectomy. Result: Bilateral denervation resulted in reduced tumor incidence and size in mice. Botox treatment in humans resulted in increased apoptosis of cancer cells in the Botox treated side. A similar denervation gene array profile was identified in tumors arising in denervated rodent prostates, in spinal cord injury patients and in the Botox treated side of patients. Denervation induced exhibited a signature gene profile, indicating translation and bioenergetic shutdown. Nerves also regulate basic cellular functions of non-neoplastic epithelial cells. Conclusion: Nerves play a role in the homeostasis of normal epithelial tissues and are involved in prostate cancer tumor survival. This study confirms that interactions between human cancer and nerves are essential to disease progression. This work may make a major impact in general cancer treatment strategies, as nerve/cancer interactions are likely important in other cancers as well. Targeting the neural microenvironment may represent a therapeutic approach for the treatment of human prostate cancer.",
keywords = "Botox, cancer, denervation, nerves, neurogenesis, prostate",
author = "Christian Coarfa and Diego Florentin and Putluri, {Nagi Reddy} and Yi Ding and Jason Au and Dandan He and Ahmed Ragheb and Anna Frolov and George Michailidis and Lee, {Min Jae} and Dov Kadmon and Brian Miles and Christopher Smith and Michael Ittmann and David Rowley and Arun Sreekumar and Creighton, {Chad J.} and Gustavo Ayala",
note = "Funding Information: This work was supported by National Institutes of Health grant RO1 CA140734-03 (GA); TMEN U54CA126568-01 (GA, MI and DR), RO1CA133458 (ASK), RP120092 (ASK), W81XWH-12-1-0130 (ASK), U01 CA167234 (ASK), funds from Alkek Center for Molecular Discovery (ASK). and a PCa Foundation Creativity Award (GA). We acknowledge the joint participation of the Diana Helis Henry Medical Research Foundation. DF, AR, and JA contributed to the design of the study, the animal experiments, laboratory examinations, collection and analysis of data, discussion, and writing of the manuscript. DH contributed the pathological and immunohistochemical analysis of mice and rat tissues, discussion, and writing of the manuscript. CJC, AF, GM, and YZ contributed the bioinformatics analysis, discussion, and writing of the manuscript. CC, NP, and AS contributed in the metabolomics study design and performance, discussion, and writing of the manuscript. OD contributed the microarray experiment of mice and humans, discussion, and writing of the manuscript. MM contributed in the design and discussion and writing of the manuscript. YD contributed the microarray experiment of mice, and humans, the in vitro experiments, discussion, and writing of the manuscript. CS, DK, and BM contributed in the design and execution of the human clinical trial, discussion and writing of the manuscript. MI contributed the coordination of pathological evaluation of humans, discussion, and writing of the manuscript. DR contributed the design of the study, the writing of the manuscript, obtaining funding, and discussion, and writing of the manuscript. GA contributed the idea and hypothesis, conception and design of the study, development of the experimental mouse models, collection, analysis and interpretation of data, drafting of the manuscript, obtaining funding, and study supervision and coordination. Funding Information: This work was supported by National Institutes of Health grant RO1 CA140734-03 (GA); TMEN U54CA126568-01 (GA, MI and DR), RO1CA133458 (ASK), RP120092 (ASK), W81XWH-12-1-0130 (ASK), U01 CA167234 (ASK), funds from Alkek Center for Molecular Discovery (ASK). and a PCa Foundation Creativity Award (GA). We acknowledge the joint participation of the Diana Helis Henry Medical Research Foundation. Publisher Copyright: {\textcopyright} 2017 The Authors. The Prostate Published by Wiley Periodicals, Inc.",
year = "2018",
month = feb,
day = "1",
doi = "10.1002/pros.23454",
language = "English (US)",
volume = "78",
pages = "128--139",
journal = "Prostate",
issn = "0270-4137",
publisher = "Wiley-Liss Inc.",
number = "2",
}