Nerves may play key role in triggering prostate cancer and its spread

Nerves play a critical role in both the development and spread of prostate tumors. These findings, which used both a mouse model and human prostate tissue, may lead to new ways to predict the aggressiveness of prostate cancer and to novel therapies for preventing and treating the disease.

The body's autonomic nervous system, which governs functions that we do not consciously control, such as heart rate, is divided into two branches. The sympathetic nervous system (SNS) modulates the body's "fight or flight response" by, for example, revving up the heart rate and constricting blood vessels. The parasympathetic nervous system (PNS) generally acts in opposition to the SNS to keep bodily functions in balance.

Earlier research by the study's lead author, Paul Frenette, MD, of Albert Einstein College of Medicine of Yeshiva University in New York, New York, had found that the sympathetic nervous system regulates hematopoietic stem cell niches, which are the sites in the bone marrow where red blood cells are formed.

Nerves are commonly found around tumors, but their role in the growth and progression of cancer has not been clear. "Since there might be similarities between the hematopoietic stem cell niche and the stem cell niches found in cancer, we thought that sympathetic nerves might also have a role in tumor development," said Dr. Frenette. "It turns out that in prostate cancer, not only are sympathetic nerves involved, but so too are parasympathetic nerves."

The researchers discovered the role of nerves in prostate cancer by first injecting human prostate cancer cells into mice and then systematically disabling various parts of the SNS and PNS and observing how the cells fared. A control group of mice were administered the cancer cells but underwent no further interventions.

The study, published in Science (2013; doi: 10.1126/science.1236361), found that the autonomic nervous system's two branches have complementary functions in the development and spread of prostate cancer. The SNS helps initiate the early phases of the disease, while the PNS is involved in the later stages when the cancer spreads.

More specifically, the researchers found that the SNS promotes tumor growth by producing the neurotransmitter norepinephrine, which then binds to and stimulates two types of adrenergic receptors on the surface of the stromal cells in the tumor. "This is consistent with recent epidemiological studies showing that the use of beta-blockers, which lower blood pressure by blocking beta-adrenergic receptors, is associated with improved survival of prostate cancer patients," said Dr. Frenette.

PNS affects tumor progression because it makes tumor cells invade other tissues and travel to distant parts of the body when its nerve fibers release acetylcholine, which activates a signaling pathway in the connective stromal cells of the tumor microenvironment.

In analyses of patient samples, patients with aggressive prostate cancers were found to have a higher density of nerve fibers within tumors and in normal prostate tissue surrounding their tumors compared with patients who had less aggressive tumors.
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