Research Article

Adrenergic nerves activate an angio-metabolic switch in prostate cancer

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Science  20 Oct 2017:
Vol. 358, Issue 6361, pp. 321-326
DOI: 10.1126/science.aah5072

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Tumor angiogenesis gets nervous

The microenvironment of solid tumors hosts many intercellular conversations that can either enhance or inhibit tumor growth. Interestingly, the tumor cells need not be direct participants in these conversations. Zahalka et al. studied genetically manipulated mouse models and found that adrenergic signals from autonomic nerves in the prostate cancer microenvironment fueled tumor growth by altering the metabolism of blood vessel endothelial cells (see the Perspective by Hayakawa and Wang). These nerve-derived signals suppressed oxidative phosphorylation in the endothelial cells, activating an angiogenic switch that facilitated rapid tumor growth. This cross-talk between nerves and endothelial cells could potentially offer a target for cancer therapies.

Science, this issue p. 321; see also p. 305

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.

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