Tumor burden, considered a common chronic stressor, can cause widespread anxiety. Evidence suggests that cancer-induced anxiety can promote tumor progression, but the underlying neural mechanism remains unclear. Here, we used neuroscience and cancer tools to investigate how the brain contributes to tumor progression via nerve-tumor crosstalk in a mouse model of breast cancer. We show that tumor-bearing mice exhibited significant anxiety-like behaviors and that corticotropin-releasing hormone (CRH) neurons in the central medial amygdala (CeM) were activated. Moreover, we detected newly formed sympathetic nerves in tumors, which established a polysynaptic connection to the brain. Pharmacogenetic or optogenetic inhibition of CeM^CRH neurons and the CeM^CRH→lateral paragigantocellular nucleus (LPGi) circuit significantly alleviated anxiety-like behaviors and slowed tumor growth. Conversely, artificial activation of CeM^CRH neurons and the CeM^CRH→LPGi circuit increased anxiety and tumor growth. Importantly, we found alprazolam, an antianxiety drug, to be a promising agent for slowing tumor progression. Furthermore, we show that manipulation of the CeM^CRH→LPGi circuit directly regulated the activity of the intratumoral sympathetic nerves and peripheral nerve–derived norepinephrine, which affected tumor progression by modulating antitumor immunity. Together, these findings reveal a brain-tumor neural circuit that contributes to breast cancer progression and provide therapeutic insights for breast cancer.

中文翻译：

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脑肿瘤神经回路控制小鼠乳腺癌的进展


肿瘤负担被认为是一种常见的慢性压力源，可引起广泛的焦虑。有证据表明癌症引起的焦虑可以促进肿瘤进展，但潜在的神经机制仍不清楚。在这里，我们使用神经科学和癌症工具来研究大脑如何通过乳腺癌小鼠模型中的神经-肿瘤串扰促进肿瘤进展。我们发现，荷瘤小鼠表现出明显的焦虑样行为，并且中央内侧杏仁核（CeM）中的促肾上腺皮质激素释放激素（CRH）神经元被激活。此外，我们在肿瘤中检测到新形成的交感神经，它与大脑建立了多突触连接。 CeM ^CRH 神经元和 CeM ^CRH →外侧副巨细胞核 (LPGi) 回路的药物遗传学或光遗传学抑制可显着减轻焦虑样行为并减缓肿瘤生长。相反，人工激活 CeM ^CRH 神经元和 CeM ^CRH →LPGi 回路会增加焦虑和肿瘤生长。重要的是，我们发现阿普唑仑（一种抗焦虑药）是一种有前途的减缓肿瘤进展的药物。此外，我们还发现，操纵 CeM ^CRH →LPGi 回路可直接调节肿瘤内交感神经和周围神经衍生的去甲肾上腺素的活性，从而通过调节抗肿瘤免疫来影响肿瘤进展。总之，这些发现揭示了促进乳腺癌进展的脑肿瘤神经回路，并为乳腺癌的治疗提供了见解。