Abstract
Researchers have found that the autonomic nervous system plays a role in the development and progression of prostate cancer, with sympathetic nerves influencing early disease development and parasympathetic nerves affecting migration and metastasis. The findings, derived from mouse models and correlated by results from human prostate tissue, may lead to novel therapies to treat the disease.
The autonomic nervous system promotes the development and progression of prostate cancer, according to a study published in Science that may help to open up neurogenesis as a frontier for cancer drug development.
Once a tumor has formed, “the tumor cells need signaling, and some signaling comes from nerve fibers,” says lead author Claire Magnon, PharmD, PhD.
Previous studies established connections between prostate cancer and the autonomic nervous system, but Magnon says she and her colleagues at the Albert Einstein College of Medicine in New York, NY, took the research to a “new level of precision” that involved close inspection of very small nerve fibers and their location within the prostate and surrounding tissue.
They used xenograft and transgenic mouse models for prostate cancer to separate the effects of the two complementary branches of the autonomic nervous system: the sympathetic system, which extends nerve fibers into the prostatic stroma, an outer layer of the organ that contains smooth muscle cells; and the parasympathetic system, whose fibers extend into the organ's inner epithelial layer.
Magnon and her colleagues concluded that parasympathetic nerve fibers invade tumors and play a predominant role in cancer cell migration and metastasis by secreting acetylcholine, which interacts with the muscarinic cholinergic receptor Chrm1, expressed on stromal cells.
Sympathetic nerve fibers play a different and surprising role, they found, nurturing the initial development of prostate cancer by releasing norepinephrine, which interacts with β2- and β3-adrenergic receptors on stromal cells.
When the sympathetic nerve fibers of the mice were snipped or chemically ablated with an injection of 6-hydroxydopamine, tumors did not develop.
A related experiment showed the flip side. Prostate cancer didn't develop in transgenic mice deficient in β-adrenergic receptors. That result is consistent with recent reports that men with prostate cancer who take β blockers have lower prostate cancer–specific mortality rates.
Kristen Austlid Taskén, PhD, a researcher at Oslo University Hospital in Oslo, Norway, who led a study of β blocker effects among a cohort of 3,561 men with high-risk or metastatic prostate cancer, describes Magnon's results as tying in “nicely” with the epidemiologic results. β blockers are inexpensive and well tolerated, she points out, and may not induce as much drug resistance as agents that target rapidly proliferating cancer cells, because they appear to target stromal cells.
Magnon and her coauthors note that existing β blockers primarily target the β1-adrenergic receptor, so one avenue for future drug development might be to develop agents that target β2- and β3-adrenergic receptors.
In addition to the mouse experiments, Magnon and her colleagues analyzed the density of autonomic nerve fibers in prostatectomy tissue from 43 men treated at the VA Medical Center in Durham, NC. They found a correlation between higher density and poorer clinical outcomes, including recurrence and dissemination. Nerve fiber density “merits exploration” as a biomarker for prostate cancer aggressiveness, they suggest.
