Adrenergic nerves activate an angio-metabolic switch in prostate cancer

• Published in: Science (American Association for the Advancement of Science) Vol. 358; no. 6361; pp. 321 - 326
• Main Authors: Zahalka, Ali H., Arnal-Estapé, Anna, Maryanovich, Maria, Nakahara, Fumio, Cruz, Cristian D., Finley, Lydia W. S., Frenette, Paul S.
• Format: Journal Article
• Language: English
• Published: United States American Association for the Advancement of Science 20.10.2017; The American Association for the Advancement of Science
• Subjects: Adrenergic nerves; Adrenergic receptors; Alkyl and Aryl Transferases - metabolism; Angiogenesis; Animal models; Animals; Blood vessels; Cancer; Carrier Proteins - metabolism; Clonal deletion; Cytochrome; Electron Transport Complex IV - metabolism; Endothelial cells; Endothelium, Vascular - metabolism; Fibers; Gene Deletion; Glycolysis; Humans; Male; Membrane Proteins - metabolism; Metabolism; Mice; Mitochondrial Proteins - metabolism; Neovascularization, Pathologic - genetics; Neovascularization, Pathologic - metabolism; Nerve Fibers - physiology; Nerves; Noradrenaline; Norepinephrine; Norepinephrine - metabolism; Oxidative Phosphorylation; Phosphorylation; Prostate - innervation; Prostate - metabolism; Prostate - physiopathology; Prostate cancer; Prostatic Neoplasms - blood supply; Prostatic Neoplasms - metabolism; Receptors, Adrenergic, beta-2 - genetics; Receptors, Adrenergic, beta-2 - metabolism; Rodents; Signal Transduction; Signaling; Solid tumors; Stroma; Tumor cells; Tumor Microenvironment; Tumors
• ISSN: 0036-8075; 1095-9203
• DOI: 10.1126/science.aah5072

Nerves closely associate with blood vessels and help to pattern the vasculature during development. Recent work suggests that newly formed nerve fibers may regulate the tumor microenvironment, but their exact functions are unclear. Studying mouse models of prostate cancer, we show that endothelial β-adrenergic receptor signaling via adrenergic nerve–derived noradrenaline in the prostate stroma is critical for activation of an angiogenic switch that fuels exponential tumor growth. Mechanistically, this occurs through alteration of endothelial cell metabolism. 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.