Inflammatory Mediators and Gut Microbial Toxins Drive Colon Tumorigenesis by IL-23 Dependent Mechanism.
Inflammatory Mediators and Gut Microbial Toxins Drive Colon Tumorigenesis by IL-23 Dependent Mechanism.
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DOI：
10.3390/cancers13205159
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发表时间：
2021-10-14
期刊：
影响因子：
5.2
通讯作者：
Rao CV
中科院分区：
文献类型：
--
作者：
Panneerselvam J;Madka V;Rai R;Morris KT;Houchen CW;Chandrakesan P;Rao CV
在美国和世界范围内，富含高脂肪的西式饮食是导致肥胖和结肠癌风险增加的主要原因。炎症分子是肥胖和结肠肿瘤发生调节之间的一个公认的联系。特别是，IL-23在西式饮食对肥胖、肠道微生物群和结肠肿瘤发生的影响中起着重要作用。然而，IL-23在结肠肿瘤进展中产生的潜在机制以及IL-23是否可能是一个潜在的靶点尚不清楚。我们的研究结果表明，致瘤性先天免疫细胞，包括树突状细胞和巨噬细胞在细菌毒素和类二十烷细胞产生IL-23中的作用。IL-23在致瘤性树突状细胞和巨噬细胞中的下调抑制了结肠肿瘤细胞和类器官的生长。综上所述，在临床试验中，靶向IL-23可能是预防和治疗高脂肪/肥胖相关结肠癌的一个有希望的选择。肥胖相关的慢性炎症会增加结肠癌的风险。白细胞介素-23 （IL-23）是一种潜在的炎症介质，将肥胖与慢性结肠炎症、肠道微生物群改变和结肠癌发生联系起来。我们旨在阐明促炎类二十烷和肠道细菌毒素在启动树突状细胞和巨噬细胞分泌IL-23以促进结肠肿瘤进展中的作用。为了研究IL-23与肥胖和结肠肿瘤发生的关系，我们利用TCGA数据集和来自人类和临床前模型的结肠肿瘤。为了了解炎症介质和肠道微生物毒素产生IL-23，我们进行了几项体外机制研究来模拟肿瘤微环境。结肠肿瘤进行离体实验。我们的研究结果表明，IL-23在肥胖个体和结肠肿瘤中升高，并与无病生存率降低相关。体外研究表明，IL-23处理增加了结肠肿瘤细胞的自我更新、迁移和侵袭，同时破坏了上皮屏障的通透性。培养后的树突状细胞/巨噬细胞与结肠癌细胞共培养实验通过增加IL-23的分泌水平，显著增加肿瘤的侵袭性，离体大鼠结肠肿瘤器官分型实验进一步支持了这些观察结果。我们的研究结果表明，肠道微生物毒素和类二十烷酸促进IL-23的产生，IL-23在肥胖相关的结肠肿瘤进展中起重要作用。这种新发现的联系代表了预防和治疗肥胖相关结肠癌的潜在目标。
Western-style diet, rich in high fat, is the major cause of obesity and enhanced risk of colon cancer in the USA and worldwide. The inflammatory molecules are a well-established link between obesity and the modulation of colon tumorigenesis. In particular, IL-23 plays an important role in the impact of a western-style diet on obesity, the gut microbiome, and colon tumorigenesis. However, the underlying mechanism of IL-23 production for colon tumor progression and whether IL-23 can be a potential target is not clear. Our findings signify the role of pro-tumorigenic innate immune cells, including dendritic cells and macrophages in IL-23 production by bacterial toxins and eicosanoids. IL-23 knockdown in the tumorigenic dendritic cells and macrophages inhibited the colon tumor cell and organoids growth. Taken together, targeting IL-23 may be a promising option for the prevention and treatment of high-fat/obesity-associated colon cancer in clinical trials. Obesity-associated chronic inflammation predisposes colon cancer risk development. Interleukin-23 (IL-23) is a potential inflammatory mediator linking obesity to chronic colonic inflammation, altered gut microbiome, and colon carcinogenesis. We aimed to elucidate the role of pro-inflammatory eicosanoids and gut bacterial toxins in priming dendritic cells and macrophages for IL-23 secretion to promote colon tumor progression. To investigate the association of IL-23 with obesity and colon tumorigenesis, we utilized TCGA data set and colonic tumors from humans and preclinical models. To understand IL-23 production by inflammatory mediators and gut microbial toxins, we performed several in vitro mechanistic studies to mimic the tumor microenvironment. Colonic tumors were utilized to perform the ex vivo experiments. Our findings showed that IL-23 is elevated in obese individuals, colonic tumors and correlated with reduced disease-free survival. In vitro studies showed that IL-23 treatment increased the colon tumor cell self-renewal, migration, and invasion while disrupting epithelial barrier permeability. Co-culture experiments of educated dendritic cells/macrophages with colon cancer cells significantly increased the tumor aggression by increasing the secretory levels of IL-23, and these observations are further supported by ex vivo rat colonic tumor organotypic experiments. Our results demonstrate gut microbe toxins and eicosanoids facilitate IL-23 production, which plays an important role in obesity-associated colonic tumor progression. This newly identified nexus represents a potential target for the prevention and treatment of obesity-associated colon cancer.
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DOI：
10.1097/shk.0b013e31828f9c92
发表时间：
2013-05
期刊：
Shock (Augusta, Ga.)
影响因子：
--
作者：
Bosmann M;Grailer JJ;Russkamp NF;Ruemmler R;Zetoune FS;Sarma JV;Ward PA
通讯作者：
Ward PA
DOI：
10.1038/nrclinonc.2016.217
发表时间：
2017-07
期刊：
Nature reviews. Clinical oncology
影响因子：
--
作者：
Mantovani A;Marchesi F;Malesci A;Laghi L;Allavena P
通讯作者：
Allavena P
影响因子：
5.8
作者：
Majchrzak, Kinga;Nelson, Michelle H.;Bailey, Stefanie R.;Bowers, Jacob S.;Yu, Xue-Zhong;Rubinstein, Mark P.;Himes, Richard A.;Paulos, Chrystal M.
通讯作者：
Paulos, Chrystal M.
影响因子：
8.3
作者：
Gelderblom, Mathias;Gallizioli, Mattia;Magnus, Tim
通讯作者：
Magnus, Tim
影响因子：
4.6
作者：
Chen D;Li W;Liu S;Su Y;Han G;Xu C;Liu H;Zheng T;Zhou Y;Mao C
通讯作者：
Mao C