Abstract 507: Autonomic intratumoral neo-nerves drive prostate cancer development and metastasis

Abstract

Abstract Cancer cells seize and shape the healthy tissue microenvironment to promote their growth, invasion and metastasis. While multiple tumor-stroma interactions have been examined, the role of nerves in cancer progression remains unclear. Here, we show that autonomic intratumoral nerve development at the primary cancer site is a pivotal event that regulates prostate cancer initiation and its dissemination. We established an orthotopic luciferase-expressing (PC3luc) xenogeneic tumor model to track serially tumor initiation and dissemination. In addition, we used transgenic mice expressing c-Myc under the probasin promoter (AAR2/Pbsn-MYC) to evaluate the role of intratumor nerves in cancer progression from prostatic intraepithelial neoplasia (PIN) to invasive adenocarcinomas. Immunofluorescence analyses revealed that PC3luc tumors were invaded by numerous nerve fibers from the sympathetic (SNS) and parasympathetic nervous system (PNS). To investigate the role of SNS nerves in cancer progression, prostate glands were sympathectomized either chemically or surgically. Unexpectedly, adrenergic nerve ablation jeopardized PC3luc tumor cell survival at the primary site and delayed the emergence of PIN. In addition, we found that tumor formation was severely impaired in nu/nu mice lacking both β2-and β3-adrenergic receptors whereas it was slightly delayed in littermates deficient in a single adrenergic receptor. These results suggest that adrenergic signals delivered by intratumor nerve fibers are critical role for prostate cancer initiation. In the course of immunofluorescence analyses, we have noted a strong correlation between cholinergic fiber densities at the primary site and prostate cancer dissemination, suggesting a potential role for the PNS in tumor cell migration. To test this possibility, we mimicked endogenous cholinergic signal by treatment of mice with the non-selective cholinergic agonist carbachol, either alone or in combination with muscarinic receptor antagonists. Carbachol administration markedly increased invasion of lymph nodes and triggered tumor cell dissemination to distant organs (p < 0.05). This process was mediated specifically by M1R (encoded by Chrm1) since invasion and metastasis were inhibited after pharmacological blockade or genetic disruption of M1R in the stroma using nu/nu Chrm1-/- mice (p=0.05) or AAR2/Pbsn-MYC Chrm1-/- mice (p = 8 × 10-14). Consistent with a potential role of neo-nerve development in prostate cancer, quantitative immunofluorescence analyses revealed that human prostate invasive adenocarcinoma from primary biopsies exhibited robust infiltration of SNS and PNS nerve fibers by comparison with benign human prostatic hyperplasia. This study uncovers a dual role for the autonomic nervous system in cancer where SNS neo-nerves critically regulate the early-stage cancer development and, by contrast, PNS fibers promote cancer dissemination. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 507. doi:10.1158/1538-7445.AM2011-507