Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice.
Stimulation of hypothalamic oxytocin neurons suppresses colorectal cancer progression in mice.
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刺激下丘脑催产素神经元可抑制小鼠结直肠癌的进展
DOI：
10.7554/elife.67535
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发表时间：
2021-09-16
期刊：
影响因子：
7.7
通讯作者：
Zhang G
中科院分区：
文献类型：
--
作者：
Pan S;Yin K;Tang Z;Wang S;Chen Z;Wang Y;Zhu H;Han Y;Liu M;Jiang M;Xu N;Zhang G
新出现的证据表明，神经系统参与了外周肿瘤的发展，然而，中枢神经系统的作用在很大程度上仍然未知。在这里，通过结合遗传学，化学发生学，药理学和电生理学的方法，我们表明，下丘脑催产素（Oxt）产生的神经元调节结肠炎相关的癌症（CAC）在小鼠中的进展。Oxt神经元的缺失或激活可增强或抑制CAC的进展。重要的是，用雷公藤红素（一种五环三萜类化合物）进行脑治疗可兴奋Oxt神经元并抑制CAC进展，并且这种抗肿瘤作用在Oxt神经元损伤小鼠中显著减弱。此外，用雷公藤红素进行脑处理抑制了腹腔-肠系膜上神经节（CG-SMG）中的交感神经元活动，并且β2肾上腺素能受体的活化消除了Oxt神经元活化或集中施用雷公藤红素的抗肿瘤作用。总之，这些发现表明，下丘脑Oxt神经元通过调节CG-SMG中的神经元活性来调节CAC进展。使用化学物质刺激Oxt神经元，例如雷公藤红素，可能是治疗结直肠癌的新策略。
Emerging evidence suggests that the nervous system is involved in tumor development in the periphery, however, the role of the central nervous system remains largely unknown. Here, by combining genetic, chemogenetic, pharmacological, and electrophysiological approaches, we show that hypothalamic oxytocin (Oxt)-producing neurons modulate colitis-associated cancer (CAC) progression in mice. Depletion or activation of Oxt neurons could augment or suppress CAC progression. Importantly, brain treatment with celastrol, a pentacyclic triterpenoid, excites Oxt neurons and inhibits CAC progression, and this anti-tumor effect was significantly attenuated in Oxt neuron-lesioned mice. Furthermore, brain treatment with celastrol suppresses sympathetic neuronal activity in the celiac-superior mesenteric ganglion (CG-SMG), and activation of β2 adrenergic receptor abolishes the anti-tumor effect of Oxt neuron activation or centrally administered celastrol. Taken together, these findings demonstrate that hypothalamic Oxt neurons regulate CAC progression by modulating the neuronal activity in the CG-SMG. Stimulation of Oxt neurons using chemicals, for example, celastrol, might be a novel strategy for colorectal cancer treatment.