Zahalka Ali H, Arnal-Estapé Anna, Maryanovich Maria, Nakahara Fumio, Cruz Cristian D, Finley Lydia W S, Frenette Paul S
Ruth L. and David S. Gottesman Institute for Stem Cell and Regenerative Medicine Research, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Department of Cell Biology, Albert Einstein College of Medicine, Bronx, NY 10461, USA.
Science. 2017 Oct 20;358(6361):321-326. 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 , the gene encoding the β-adrenergic receptor, leads to inhibition of angiogenesis through enhancement of endothelial oxidative phosphorylation. Codeletion of and , a gene encoding a cytochrome IV oxidase assembly factor, prevented the metabolic shift induced by deletion and rescued prostate cancer progression. This cross-talk between nerves and endothelial metabolism could potentially be targeted as an anticancer therapy.
神经与血管紧密相连，并在发育过程中协助构建脉管系统。近期研究表明，新形成的神经纤维可能调节肿瘤微环境，但其确切功能尚不清楚。通过对前列腺癌小鼠模型的研究，我们发现，前列腺基质中由肾上腺素能神经衍生的去甲肾上腺素介导的内皮β-肾上腺素能受体信号传导，对于激活促进肿瘤指数级生长的血管生成开关至关重要。从机制上讲，这是通过改变内皮细胞代谢实现的。内皮细胞通常依靠有氧糖酵解来进行血管生成。我们发现，编码β-肾上腺素能受体的基因Endothelial的缺失，会通过增强内皮细胞氧化磷酸化来抑制血管生成。Endothelial与编码细胞色素IV氧化酶组装因子的基因Coassembly的共同缺失，可防止由Endothelial缺失诱导的代谢转变，并挽救前列腺癌进展。神经与内皮细胞代谢之间的这种相互作用可能成为一种潜在的抗癌治疗靶点。
