Adrenergic nerves activate an angio-metabolic switch in prostate cancer

Science. 2017 Oct 20;358(6361):321-326. doi: 10.1126/science.aah5072.

Abstract

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.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Alkyl and Aryl Transferases / metabolism
  • Animals
  • Carrier Proteins / metabolism
  • Electron Transport Complex IV / metabolism
  • Endothelium, Vascular / metabolism
  • Gene Deletion
  • Humans
  • Male
  • Membrane Proteins / metabolism
  • Mice
  • Mitochondrial Proteins / metabolism
  • Neovascularization, Pathologic / genetics
  • Neovascularization, Pathologic / metabolism*
  • Nerve Fibers / physiology*
  • Norepinephrine / metabolism*
  • Oxidative Phosphorylation
  • Prostate / innervation
  • Prostate / metabolism
  • Prostate / physiopathology
  • Prostatic Neoplasms / blood supply*
  • Prostatic Neoplasms / metabolism*
  • Receptors, Adrenergic, beta-2 / genetics
  • Receptors, Adrenergic, beta-2 / metabolism*
  • Signal Transduction
  • Tumor Microenvironment

Substances

  • COA6 protein, human
  • Carrier Proteins
  • Membrane Proteins
  • Mitochondrial Proteins
  • Receptors, Adrenergic, beta-2
  • COX10 protein, human
  • Electron Transport Complex IV
  • Alkyl and Aryl Transferases
  • Norepinephrine