由β2肾上腺素能-神经生长因子前馈环路介导的神经-间充质相互作用促进了结直肠癌的进展。

IF 29.7 1区医学 Q1 ONCOLOGY Cancer discovery Pub Date : 2025-01-13 DOI:10.1158/2159-8290.CD-24-0287

Hiroki Kobayashi, Tadashi Iida, Yosuke Ochiai, Ermanno Malagola, Xiaofei Zhi, Ruth A White, Jin Qian, Feijing Wu, Quin T Waterbury, Ruhong Tu, Biyun Zheng, Jonathan S LaBella, Leah B Zamechek, Atsushi Ogura, Susan L Woods, Daniel L Worthley, Atsushi Enomoto, Timothy C Wang

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引用次数: 0

摘要

癌症相关成纤维细胞（CAFs）和神经作为肿瘤微环境的组成部分，已分别被证明可直接促进胃肠道癌症的发生。然而，这些细胞是否相互影响以调控癌症进展仍是未知数。我们发现，在结直肠癌（CRC）中，去甲肾上腺素诱导 CAFs 分泌依赖 ADRB2 的神经生长因子（NGF），这反过来又增加了肿瘤内交感神经的支配和去甲肾上腺素的积累。肾上腺素能刺激通过 ADRA2A/Gi- 介导的是相关蛋白（YAP）激活加速了 CRC 的生长。来自 CAFs 的 NGF 可通过 PI3K/AKT 通路直接促进 CRC 细胞生长。用肌球蛋白受体激酶（Trk）抑制剂治疗小鼠，可减少YAP和AKT的活化以及CRC的进展。在人类 CRC 中，NGF 的高表达与间质样肿瘤亚型和患者生存率低有关。这些发现表明，CAF-神经串联在促进 CRC 进展方面发挥着核心作用。用Trk抑制剂阻断这种前馈循环可能是治疗CRC的一种潜在方法。

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Neuro-Mesenchymal Interaction Mediated by a β2-Adrenergic Nerve Growth Factor Feedforward Loop Promotes Colorectal Cancer Progression.

Significance: Our work demonstrates that the bidirectional interplay between sympathetic nerves and NGF-expressing CAFs drives colorectal tumorigenesis. This study also offers novel mechanistic insights into catecholamine action in colorectal cancer. Inhibiting the neuro-mesenchymal interaction by TRK blockade could be a potential strategy for treating colorectal cancer.

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来源期刊

Cancer discovery ONCOLOGY-

CiteScore

22.90

自引率

1.40%

发文量

838

审稿时长

6-12 weeks

期刊介绍： Cancer Discovery publishes high-impact, peer-reviewed articles detailing significant advances in both research and clinical trials. Serving as a premier cancer information resource, the journal also features Review Articles, Perspectives, Commentaries, News stories, and Research Watch summaries to keep readers abreast of the latest findings in the field. Covering a wide range of topics, from laboratory research to clinical trials and epidemiologic studies, Cancer Discovery spans the entire spectrum of cancer research and medicine.