Sympathetic nerve fibers (in green) are interlaced with blood vessels (in white) in an early-stage prostate cancer tumor.
Image credit: Albert Einstein College of Medicine
Dr. Paul Frenette, of the Departments of Medicine and Cell Biology at the Albert Einstein College of Medicine in New York City, NY, led the study. The findings from the new research are published in the journal Science.
"Solid tumors depend on an expanding blood supply to thrive," says Dr. Frenette. "Here we show that nerves stimulate the new blood vessels that encourage prostate tumor growth and that we can short-circuit nerve stimulation to prevent new vessels from forming."
"This opens up an entirely new strategy for treating prostate cancer — one that we may be able to pursue using existing drugs," he adds.
Every single year, more than 172,000 men in the United States are diagnosed with prostate cancer, and more than 28,000 people die from the disease. Aside from skin cancer, prostate cancer is the most common form of cancer among U.S. men.
Earlier research by Dr. Frenette and colleagues discovered that nerves play a primary role in the development and spread of prostate tumors.
Norepinephrine triggers metabolic switch
More specifically, the team found that the nerves of the sympathetic nervous system — which controls the body's "fight-or-flight" response — drive the growth of tumors by producing the neurotransmitter norepinephrine.
Norepinephrine promotes tumor growth by "binding to and stimulating" receptors on the surface of tumor connective tissue cells. Now, using a mouse model of prostate cancer, researchers reveal how the nerves in connective tissue fuel tumor growth.
Once the nerve fibers release norepinephrine, it binds to receptors on endothelial cells that line the inside of blood vessels. The binding of norepinephrine to the receptors activates an "angio-metabolic switch," which alters the way in which the cells metabolize glucose.
Endothelial cells ordinarily get energy to produce new blood vessels from glucose using oxidative phosphorylation. However, the cells were instead using glycolysis to metabolize glucose — a phenomenon that has been detected in cancer cells.
Oxidative phosphorylation prevents tumors
The researchers set out to confirm the role of norepinephrine in triggering the metabolic switch. To do this, they deleted a gene in their mouse model that looks for norepinephrine's receptor on vessel cells, which "eliminat[ed] norepinephrine's binding target."
As predicted, cells that lacked the receptor used oxidative phosphorylation to metabolize glucose rather than glycolysis, thus inhibiting the formation of new vessels.
"Oxidative phosphorylation generates more energy than glycolysis. It may seem counter-intuitive, but this energy boost provided by oxidative phosphorylation diminishes endothelial cell function and inhibits angiogenesis — the formation of new blood vessels that sustains tumor growth."
Dr. Paul Frenette
Dr. Frenette and colleagues showed through their mouse model of prostate cancer that stimulation from the release of norepinephrine by the nerves maintained the use of glycolysis by the endothelial cells.
This enabled prostate cancer to escalate from "a low-grade precancerous stage to a high-grade malignant stage."
"While we need to learn more about the role that norepinephrine-releasing nerves play in prostate cancer," explains Dr. Frenette, "it's certainly worth exploring whether beta-blockers can improve disease outcomes."
Beta-blockers block norepinephrine's effects, and studies have indicated that these drugs lower metastasis rates and boost survival in individuals with prostate cancer, he concludes.