Research Article

Autonomic Nerve Development Contributes to Prostate Cancer Progression

Science  12 Jul 2013:
Vol. 341, Issue 6142,
DOI: 10.1126/science.1236361

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Structured Abstract

Introduction

Cancer cells usurp the healthy tissue microenvironment to promote their survival, proliferation, and dissemination. The role of angiogenesis, the formation of new blood vessels, in solid tumor growth is well established. Whether neurogenesis, the formation of new nerve fibers, likewise contributes to tumor development and progression remains unclear. Here, studying mouse models and human tumor samples, we examined the role of the autonomic nervous system in prostate cancer growth and dissemination.

Embedded Image

The parasympathetic nervous system promotes prostate cancer dissemination in mice. Image shows bone metastases (arrowheads) detected by Na18F-PET scanning of Hi-Myc mice, a model of prostate cancer. Such metastases are not detected when the Hi-Myc mice are genetically deficient in muscarinic cholinergic receptor type 1, an essential signaling component of the parasympathetic branch of the autonomic nervous system.

Methods

To track tumor growth and dissemination, we studied (i) mice bearing PC-3 prostate tumor xenografts that expressed luciferase and (ii) transgenic mice expressing the c-Myc oncogene under the control of the probasin promoter (Hi-Myc mice), which develop prostatic intraepithelial neoplasia that progresses to invasive adenocarcinoma. Tumors were monitored by bioluminescence, positron emission tomography (PET), and histological analyses. Sympathetic (adrenergic) and parasympathetic (cholinergic) nerve functions were assessed using chemical or surgical neural ablation, pharmacological agonists or antagonists, and genetically engineered mice. We also determined the adrenergic and cholinergic nerve densities in radical prostatectomy tissues from a cohort of 43 patients with prostate cancer.

Results

Quantitative bioluminescence and immunofluorescence analyses, combined with histological examinations, revealed that sympathetic adrenergic nerve outgrowth was critical in the early phases of cancer development. Prostate tumor xenografts developed poorly in mice that had been pretreated by chemical or surgical sympathectomy of the prostate gland, or when stromal β2- and β3-adrenergic receptors were genetically deleted. Prostate tumors were also infiltrated by parasympathetic cholinergic fibers that promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis in mice were inhibited by pharmacological blockade or genetic disruption of the stromal type 1 muscarinic receptor. Quantitative confocal microscopy analysis of radical prostatectomy specimens from patients with low-risk (n = 30) or high-risk (n = 13) prostate adenocarcinoma revealed higher overall nerve densities in high-risk tumors relative to low-risk tumors. Adrenergic fibers were increased in normal prostate tissues surrounding the human tumors, whereas cholinergic fibers infiltrated the tumor tissue. Higher densities of adrenergic and cholinergic nerve fibers were associated with poor clinical outcome, including higher preoperative levels of prostate-specific antigen (PSA), extension beyond the prostatic capsule, and biochemical recurrence.

Discussion

These results suggest that the formation of new nerve fibers within and around prostate tumors can alter tumor behavior. The autonomic nervous system appears to exert dual functions in prostate cancer: Sympathetic neonerves promote early stages of tumorigenesis, whereas parasympathetic nerve fibers promote cancer dissemination. Conceivably, drugs targeting both branches of the autonomic nervous system could provide therapeutic benefit.

Cancer Hits a Nerve

Solid tumors sculpt their microenvironment to maximize their growth and metastatic potential. This concept is illustrated most famously by tumor angiogenesis, a process whereby tumors induce the growth of new blood vessels to boost their supply of oxygen and blood-borne nutrients. Magnon et al. (p. 10.1126/science.1236361; see the Perspective by Isaacs) now highlight the important contribution made by another microenvironmental component—developing autonomic nerve fibers—to tumor growth and metastasis. In mouse models of prostate cancer, surgical or chemical destruction of sympathetic nerves prevented early-stage growth of tumors, whereas pharmacological inhibition of parasympathetic nerves inhibited tumor dissemination. In a small study of human prostate cancer specimens, the presence of a high density of nerve fibers in and around the tumor tissue was found to correlate with poor clinical outcome. These results raise the possibility that drugs targeting the autonomic nervous system may have therapeutic potential for prostate cancer.

Abstract

Nerves are a common feature of the microenvironment, but their role in tumor growth and progression remains unclear. We found that the formation of autonomic nerve fibers in the prostate gland regulates prostate cancer development and dissemination in mouse models. The early phases of tumor development were prevented by chemical or surgical sympathectomy and by genetic deletion of stromal β2- and β3-adrenergic receptors. Tumors were also infiltrated by parasympathetic cholinergic fibers that promoted cancer dissemination. Cholinergic-induced tumor invasion and metastasis were inhibited by pharmacological blockade or genetic disruption of the stromal type 1 muscarinic receptor, leading to improved survival of the mice. A retrospective blinded analysis of prostate adenocarcinoma specimens from 43 patients revealed that the densities of sympathetic and parasympathetic nerve fibers in tumor and surrounding normal tissue, respectively, were associated with poor clinical outcomes. These findings may lead to novel therapeutic approaches for prostate cancer.

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