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伤害感受神经元通过降钙素基因相关肽-受体活性修饰蛋白1轴促进胃肿瘤进展。

Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis.

作者信息

Zhi Xiaofei, Wu Feijing, Qian Jin, Ochiai Yosuke, Lian Guodong, Malagola Ermanno, Zheng Biyun, Tu Ruhong, Zeng Yi, Kobayashi Hiroki, Xia Zhangchuan, Wang Ruizhi, Peng Yueqing, Shi Qiongyu, Chen Duan, Ryeom Sandra W, Wang Timothy C

机构信息

Division of Digestive and Liver Diseases, Irving Cancer Research Center, Columbia University Medical Center, New York, NY, USA.

Department of General Surgery, Affiliated Hospital of Nantong University, Nantong, China.

出版信息

Nature. 2025 Apr;640(8059):802-810. doi: 10.1038/s41586-025-08591-1. Epub 2025 Feb 19.


DOI:10.1038/s41586-025-08591-1
PMID:39972142
Abstract

Cancer cells have been shown to exploit neurons to modulate their survival and growth, including through the establishment of neural circuits within the central nervous system. Here we report a distinct pattern of cancer-nerve interactions between the peripheral nervous system and gastric cancer. In multiple mouse models of gastric cancer, nociceptive nerves demonstrated the greatest degree of nerve expansion in an NGF-dependent manner. Neural tracing identified CGRP peptidergic neurons as the primary gastric sensory neurons. Three-dimensional co-culture models showed that sensory neurons directly connect with gastric cancer spheroids. Chemogenetic activation of sensory neurons induced the release of calcium into the cytoplasm of cancer cells, promoting tumour growth and metastasis. Pharmacological ablation of sensory neurons or treatment with CGRP inhibitors suppressed tumour growth and extended survival. Depolarization of gastric tumour membranes through in vivo optogenetic activation led to enhanced calcium flux in jugular nucleus complex and CGRP release, defining a cancer cell-peptidergic neuronal circuit. Together, these findings establish the functional connectivity between cancer and sensory neurons, identifying this pathway as a potential therapeutic target.

摘要

癌细胞已被证明会利用神经元来调节其存活和生长,包括通过在中枢神经系统内建立神经回路来实现。在此,我们报告了外周神经系统与胃癌之间一种独特的癌 - 神经相互作用模式。在多种胃癌小鼠模型中,伤害性神经以依赖神经生长因子(NGF)的方式表现出最大程度的神经扩张。神经追踪确定降钙素基因相关肽(CGRP)肽能神经元为主要的胃感觉神经元。三维共培养模型显示感觉神经元直接与胃癌球体相连。感觉神经元的化学遗传激活诱导癌细胞胞质内钙的释放,促进肿瘤生长和转移。感觉神经元的药理学消融或用CGRP抑制剂治疗可抑制肿瘤生长并延长生存期。通过体内光遗传学激活使胃肿瘤膜去极化导致颈核复合体中钙通量增加和CGRP释放,确定了一种癌细胞 - 肽能神经元回路。总之,这些发现确立了癌症与感觉神经元之间的功能连接,将该途径确定为一个潜在的治疗靶点。

相似文献

[1]
Nociceptive neurons promote gastric tumour progression via a CGRP-RAMP1 axis.

Nature. 2025-4

[2]
Nociceptive neurons interact directly with gastric cancer cells via a CGRP/Ramp1 axis to promote tumor progression.

bioRxiv. 2024-3-8

[3]
Sensory nerves drive migration of dental pulp stem cells via the CGRP-Ramp1 axis in pulp repair.

Cell Mol Life Sci. 2024-8-28

[4]
Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Cell. 2022-10-27

[5]
Innervation of nociceptor neurons in the spleen promotes germinal center responses and humoral immunity.

Cell. 2024-6-6

[6]
Signaling pathways that mediate nerve growth factor-induced increase in expression and release of calcitonin gene-related peptide from sensory neurons.

Neuroscience. 2010-9-24

[7]
Cerebellar distribution of calcitonin gene-related peptide (CGRP) and its receptor components calcitonin receptor-like receptor (CLR) and receptor activity modifying protein 1 (RAMP1) in rat.

Mol Cell Neurosci. 2010-10-30

[8]
Differentiation of nerve fibers storing CGRP and CGRP receptors in the peripheral trigeminovascular system.

J Pain. 2013-8-17

[9]
Calcitonin receptor-like receptor (CLR), receptor activity-modifying protein 1 (RAMP1), and calcitonin gene-related peptide (CGRP) immunoreactivity in the rat trigeminovascular system: differences between peripheral and central CGRP receptor distribution.

J Comp Neurol. 2008-3-20

[10]
Elevated levels of calcitonin gene-related peptide in upper spinal cord promotes sensitization of primary trigeminal nociceptive neurons.

Neuroscience. 2016-12-17

引用本文的文献

[1]
Neurotransmitters: an emerging target for therapeutic resistance to tumor immune checkpoint inhibitors.

Mol Cancer. 2025-8-11

[2]
Integrating neuroscience and oncology: neuroimmune crosstalk in the initiation and progression of digestive system tumors.

Mol Cancer. 2025-8-10

[3]
Trigeminal nerve-driven neurogenic inflammation linking migraine to glioblastoma invasion: a literature review.

Front Immunol. 2025-7-16

[4]
Neuro-immune cross-talk in cancer.

Nat Rev Cancer. 2025-6-16

[5]
Study on gene expression in stomach at different developmental stages of human embryos.

Front Cell Dev Biol. 2025-5-30

[6]
Functional cancer-cell-nociceptive neuronal circuits drive gastric tumor progression.

Sci China Life Sci. 2025-6-5

[7]
From sensation to regulation: the diverse functions of peripheral sensory nervous system.

Front Immunol. 2025-5-16

[8]
Cancer-nervous system crosstalk: from biological mechanism to therapeutic opportunities.

Mol Cancer. 2025-5-5

[9]
A sensory neuron-gastric cancer circuit.

Nat Rev Gastroenterol Hepatol. 2025-5

[10]
Cancer neuroscience in head and neck: interactions, modulation, and therapeutic strategies.

Mol Cancer. 2025-3-31

本文引用的文献

[1]
Functional neuronal circuits promote disease progression in cancer.

Sci Adv. 2023-5-10

[2]
Cancer hallmarks intersect with neuroscience in the tumor microenvironment.

Cancer Cell. 2023-3-13

[3]
Sensory nerves enhance triple-negative breast cancer invasion and metastasis via the axon guidance molecule PlexinB3.

NPJ Breast Cancer. 2022-11-4

[4]
Nociceptor neurons affect cancer immunosurveillance.

Nature. 2022-11

[5]
Nociceptor neurons direct goblet cells via a CGRP-RAMP1 axis to drive mucus production and gut barrier protection.

Cell. 2022-10-27

[6]
Gut-innervating nociceptors regulate the intestinal microbiota to promote tissue protection.

Cell. 2022-10-27

[7]
Opposing roles of hepatic stellate cell subpopulations in hepatocarcinogenesis.

Nature. 2022-10

[8]
Glioblastoma hijacks neuronal mechanisms for brain invasion.

Cell. 2022-8-4

[9]
Cancer risk in patients with migraine: A population-based cohort study in Denmark.

Headache. 2022-1

[10]
Direct neuronal reprogramming: Fast forward from new concepts toward therapeutic approaches.

Neuron. 2022-2-2

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