Nerves and prostate cancer
BRONX, N.Y.—New research out of the Albert Einstein College of Medicine, part of Montefiore Medicine, has shown that some nerves trigger prostate cancer progression by flipping a switch that leads to an increase in tumor blood vessels. The work appeared in Science in a paper titled "Adrenergic nerves activate an angio-metabolic switch in prostate cancer."
"Solid tumors depend on an expanding blood supply to thrive," said Dr. Paul Frenette, study leader. Frenette is a professor of medicine and cell biology and director of the Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research at Einstein, as well as a member of the NCI-designated Albert Einstein Cancer Center. "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."
This new research builds off of previous work. A 2013 Science paper by Frenette and colleagues reported that nerves play a pivotal role in the progression of prostate tumors—specifically, that nerves of the sympathetic nervous system promote tumor growth via the production of norepinephrine. As noted in an Albert Einstein College of Medicine press release at the time, "The study found that the autonomic nervous system's two branches have complementary functions in the development and spread of prostate cancer. The [sympathetic nervous system] helps initiate the early phases of the disease, while the [parasympathetic nervous system] is involved in the later stages when the cancer spreads."
The 2017 study looked at mouse models of prostate cancer to understand how select nerves can drive tumor growth. What they found was that after norepinephrine is released by nerve fibers, it binds to receptors on endothelial cells that line blood vessels. This binding flips an “angio-metabolic switch” that alters how the cells metabolize glucose—following the switch, rather than using oxidative phosphorylation to derive energy from glucose, the endothelial cells use glycolysis almost exclusively, something seen in cancer cells. The mouse model showed that thanks to the norepinephrine binding that caused cells to switch to glycolysis, prostate cancer quickly progressed from a low-grade precancerous state to a high-grade malignant one.
In an effort to confirm their findings, the team deleted a gene that codes for the norepinephrine receptor on blood vessel cells. The cells without the binding target continued to use oxidative phosphorylation as opposed to glycolysis, and the growth of new blood vessels was inhibited.
The authors noted in their abstract that, “Endothelial cells typically rely on aerobic glycolysis for angiogenesis. We found that the loss of endothelial Adrb2, the gene encoding the β2-adrenergic receptor, leads to inhibition of angiogenesis through enhancement of endothelial oxidative phosphorylation. Codeletion of Adrb2 and Cox10, a gene encoding a cytochrome IV oxidase assembly factor, prevented the metabolic shift induced by Adrb2 deletion and rescued prostate cancer progression. This cross-talk between nerves and endothelial metabolism could potentially be targeted as an anticancer therapy.”
"Oxidative phosphorylation generates more energy than glycolysis," Frenette explained. "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."
Given the results of the previous research, Montefiore-Einstein is conducting a pilot study to investigate whether or not beta blockers—also known as beta-adrenergic blocking agents, drugs that reduce blood pressure by blocking epinephrine and norepinephrine from binding to receptors—could be used to kill cancer cells in men with prostate cancer.
"While we need to learn more about the role that norepinephrine-releasing nerves play in prostate cancer, it's certainly worth exploring whether beta-blockers can improve disease outcomes," according to Frenette, who added that retrospective epidemiological studies have shown that beta blockers were associated with reduced metastasis and increased survival in prostate cancer patients.
The other Einstein authors for the 2017 paper are: first author Ali H. Zahalka, an M.D.-Ph,D, student at Einstein; Fumio Nakahara; and Cristian D. Cruz. Additional contributors are Anna Arnal-Estapé, Ph.D., formerly a post-doctoral fellow with Dr. Frenette and now at Yale School of Medicine, New Haven, CT; and Maria Maryanovich, Ph.D., and Lydia W. S. Finley, Ph.D., at Memorial Sloan Kettering Cancer Center, New York, NY.
SOURCE: Albert Einstein School of Medicine press release