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.

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.

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.

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.

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.