机构：[1]Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China[2]Department of General Surgery, Gastrointestinal Surgical Institute, the First Affiliated Hospital of Nanchang University, Nanchang, China[3]Department of Colorectal Surgery, the First Affiliated Hospital of Nanjing Medical University, Nanjing, China江苏省人民医院[4]Department of Endocrinology, the Third People’s Hospital of Yunnan, Dali University School of Medicine, Kunming, China[5]Department of General Surgery, Tan Tock Seng Hospital, Singapore, Singapore[6]Division for Therapies Against Intractable Diseases, Institute for Comprehensive Medical Science (ICMS), Fujita Health University, Toyoake, Aichi, Japan[7]Department of Surgical Pathology, Instituto Nacional de Cancerología, Tlalpan, Mexico City, Mexico
Pancreatic ductal adenocarcinoma (PDAC) is the most common type of pancreatic cancer and is highly malignant due to its late diagnosis and early metastasis. Lung metastasis of PDAC occurs in a significant number of diagnosed patients and represents high severity of disease and poor clinical outcome. However, the molecular regulation of lung metastasis of PDAC is still not fully understood. Tumor-associated macrophages (TAMs) have recently been found to play an important role in cancer initiation, proliferation, progression, and metastasis. The proliferation, differentiation, and polarization of macrophages has been shown to be regulated by interleukin 1β (IL-1β), which is generated by NLR family pyrin domain containing 3 (NLRP3)-induced formation of inflammasome. Herein we investigated whether NLRP3 plays a role in lung metastasis of PDAC through regulation of macrophage polarization.Gene profiles for NLRP3 (+/+) and NLRP3 (-/-) macrophages obtained from the Gene Expression Omnibus (GEO) public database were compared and analyzed for altered genes related to macrophage polarization. The regulation of macrophage polarization by NLRP3 was examined in a coculture system with naïve NLRP3 (+/+) or NLRP3 (-/-) macrophages and PDAC cells. Cell growth was analyzed by a Cell Counting Kit-8 (CCK-8) assay. Cell invasiveness and migratory potential were analyzed by transwell cell invasion assay and cell migration assay, respectively. PDAC formation and lung metastasis were analyzed in a mouse model of PDAC with and without NLRP3 knockout.GEO database analysis revealed significant alteration in genes that regulate macrophage polarization in NLRP3-depleted macrophages. NLRP3-depletion in macrophages seemed to favor an M1/M2b polarization. In vitro, the presence of NLRP3 in macrophages led to M2a/c/d TAM-like polarization when they were cocultured with PDAC cells. Conversely, NLRP3 depletion in macrophages led to M1/M2b polarization when they were cocultured with PDAC cells. NLRP3-depletion significantly inhibited tumor growth and stage progression in a mouse model of PDAC and significantly reduced the occurrence of lung metastasis.Our results suggested that NLRP3 activation in TAM enhanced lung metastasis of PDAC through regulation of TAM polarization.2022 Translational Lung Cancer Research. All rights reserved.
基金：
This work was financially supported by the National Natural Science Foundation of China (No. 81400661).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2022]版：
大类|3 区医学
小类|3 区呼吸系统4 区肿瘤学
最新[2023]版：
大类|2 区医学
小类|3 区肿瘤学3 区呼吸系统
第一作者：
第一作者机构：[1]Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China
共同第一作者：
通讯作者：
通讯机构：[1]Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, Shanghai, China[*1]Department of General Surgery, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 100 Haining Road, Hongkou District, Shanghai 200080, China
推荐引用方式(GB/T 7714)：
Gu Haitao,Deng Wensheng,Zhang Yi,et al.NLRP3 activation in tumor-associated macrophages enhances lung metastasis of pancreatic ductal adenocarcinoma[J].Translational lung cancer research.2022,11(5):858-868.doi:10.21037/tlcr-22-311.
APA：
Gu Haitao,Deng Wensheng,Zhang Yi,Chang Yu,Shelat Vishal G...&Wang Zhaowen.(2022).NLRP3 activation in tumor-associated macrophages enhances lung metastasis of pancreatic ductal adenocarcinoma.Translational lung cancer research,11,(5)
MLA：
Gu Haitao,et al."NLRP3 activation in tumor-associated macrophages enhances lung metastasis of pancreatic ductal adenocarcinoma".Translational lung cancer research 11..5(2022):858-868
