Cancer-associated fibroblasts (CAFs) and nerves, components of the tumor microenvironment, have each been shown to directly promote gastrointestinal cancers. However, it remains unknown whether these cells interact with each other to regulate cancer progression. We found that in colorectal cancer (CRC) norepinephrine induces ADRB2-dependent nerve growth factor (NGF) secretion from CAFs, which in turn increases intra-tumor sympathetic innervation and norepinephrine accumulation. Adrenergic stimulation accelerates CRC growth through ADRA2A/Gi-mediated activation of Yes-Associated Protein (YAP). NGF from CAFs directly enhances CRC cell growth via the PI3K/AKT pathway. Treatment with a tropomyosin receptor kinase (Trk) inhibitor decreased YAP and AKT activation and CRC progression in mice. In human CRC, high NGF expression is associated with the mesenchymal-like tumor subtype and poor patient survival. These findings suggest a central role for reciprocal CAF-nerve crosstalk in promoting CRC progression. Blocking this feedforward loop with a Trk inhibitor may represent a potential therapeutic approach for CRC.

中文翻译：

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由 β2 肾上腺素能神经生长因子前馈环介导的神经间质相互作用促进结直肠癌进展。


癌症相关成纤维细胞 (CAF) 和神经是肿瘤微环境的组成部分，均已被证明可直接促进胃肠道癌症。然而，这些细胞是否相互作用来调节癌症进展仍不清楚。我们发现，在结直肠癌 (CRC) 中，去甲肾上腺素会诱导 CAF 分泌 ADRB2 依赖性神经生长因子 (NGF)，从而增加肿瘤内交感神经支配和去甲肾上腺素积累。肾上腺素能刺激通过 ADRA2A/Gi 介导的 Yes 相关蛋白 (YAP) 激活加速 CRC 生长。 CAF 中的 NGF 通过 PI3K/AKT 途径直接促进 CRC 细胞生长。原肌球蛋白受体激酶 (Trk) 抑制剂治疗可减少小鼠 YAP 和 AKT 激活以及 CRC 进展。在人类结直肠癌中，NGF 高表达与间质样肿瘤亚型和患者生存率低相关。这些发现表明 CAF 神经相互串扰在促进 CRC 进展中发挥着核心作用。用 Trk 抑制剂阻断该前馈回路可能是 CRC 的一种潜在治疗方法。