Chronic stress induces pulmonary epithelial cells to produce acetylcholine that remodels lung pre-metastatic niche of breast cancer by enhancing NETosis

Journal of Experimental & Clinical Cancer Research

Research

Leyi Zhang¹  Jian Huang¹  Zhen Wang¹  Jun Pan¹  Xiaoxiao Hu²  Yi Zhang²  Jiahuan Jiang²  Ke Su²  Guohong Ren²  Peng Li²  Chenghui Yang³  Lili Li⁴  Xiaomei Wang⁵ 

[1] Department of Breast Surgery, Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 88 Jiefang Road, 310009, Hangzhou, P.R. China;Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Department of Breast Surgery, First Affiliated Hospital of Wenzhou Medical University, 325000, Wenzhou, P.R. China;Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Cancer Institute, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Department of Oncology, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, Zhejiang, China;Key Laboratory of Tumor Microenvironment and Immune Therapy of Zhejiang Province, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;Department of Pathology, Second Affiliated Hospital, Zhejiang University School of Medicine, 310009, Hangzhou, P.R. China;

关键词: Breast cancer;    Lung metastasis;    Chronic stress;    Acetycholine;    Neutrophils;    NETosis;   

DOI  :  10.1186/s13046-023-02836-5

 received in 2023-08-08, accepted in 2023-09-19,  发布年份 2023

来源: Springer

【 摘 要 】

BackgroundChronic stress promotes most hallmarks of cancer through impacting the malignant tissues, their microenvironment, immunity, lymphatic flow, etc. Existing studies mainly focused on the roles of stress-induced activation of systemic sympathetic nervous system and other stress-induced hormones, the organ specificity of chronic stress in shaping the pre-metastatic niche remains largely unknown. This study investigated the role of chronic stress in remodeling lung pre-metastatic niche of breast cancer.MethodsBreast cancer mouse models with chronic stress were constructed by restraint or unpredictable stress. Expressions of tyrosine hydroxylase, vesicular acetylcholine transporter (VAChT), EpCAM and NETosis were examined by immunofluorescence and confocal microscopy. mRNA and protein levels of choline acetyltransferase (ChAT), VAChT, and peptidylarginine deiminase 4 were detected by qRT-PCR and Western blotting, respectively. Immune cell subsets were analyzed by flow cytometry. Acetylcholine (ACh) and chemokines were detected by ELISA and multi chemokine array, respectively. ChAT in lung tissues from patients was examined by immunohistochemistry.ResultsBreast cancer-bearing mice suffered chronic stress metastasized earlier and showed more severe lung metastasis than did mice in control group. VAChT, ChAT and ChAT+ epithelial cells were increased significantly in lung of model mice undergone chronic stress. ACh and chemokines especially CXCL2 in lung culture supernatants from model mice with chronic stress were profoundly increased. Chronic stress remodeled lung immune cell subsets with striking increase of neutrophils, enhanced NETosis in lung and promoted NETotic neutrophils to capture cancer cells. ACh treatment resulted in enhanced NETosis of neutrophils. The expression of ChAT in lung tissues from breast cancer patients with lung metastasis was significantly higher than that in patients with non-tumor pulmonary diseases.ConclusionsChronic stress promotes production of CXCL2 that recruits neutrophils into lung, and induces pulmonary epithelial cells to produce ACh that enhances NETosis of neutrophils. Our findings demonstrate for the first time that chronic stress induced epithelial cell derived ACh plays a key role in remodeling lung pre-metastatic niche of breast cancer.

【 授权许可】

CC BY   
© Italian National Cancer Institute ‘Regina Elena’ 2023

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