Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
Bacteroides fragilis Toxin Coordinates a Pro-carcinogenic Inflammatory Cascade via Targeting of Colonic Epithelial Cells.
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DOI：
10.1016/j.chom.2018.01.007
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发表时间：
2018-02-14
影响因子：
30.3
通讯作者：
Housseau F
中科院分区：
文献类型：
--
作者：
Chung L;Thiele Orberg E;Geis AL;Chan JL;Fu K;DeStefano Shields CE;Dejea CM;Fathi P;Chen J;Finard BB;Tam AJ;McAllister F;Fan H;Wu X;Ganguly S;Lebid A;Metz P;Van Meerbeke SW;Huso DL;Wick EC;Pardoll DM;Wan F;Wu S;Sears CL;Housseau F
促癌细菌有可能引发和/或促进结肠癌，部分原因是免疫机制尚未完全了解。使用人类致病性肠道致病性脆弱拟杆菌（ETBF）定植的ApcMin小鼠作为微生物诱导的结肠肿瘤发生的模型，我们表明脆弱拟杆菌毒素（BFT）触发结肠上皮细胞（CEC）中需要IL-17 R、NF-κB和Stat 3信号传导的促癌多步炎症级联反应。尽管有必要，但CEC中的Stat 3激活不足以触发ETBF结肠肿瘤发生。值得注意的是，CEC中的IL-17依赖性NF-κB活化诱导了C-X-C趋化因子的近端至远端粘膜梯度，包括CXCL 1，其介导了表达CXCR 2的多形核不成熟髓样细胞的募集，并与ETBF介导的远端结肠肿瘤发生平行发生。因此，BFT诱导从CEC到粘膜Th 17应答的致癌信号传递，导致远端结肠CEC中选择性地激活NFκB，共同触发髓样细胞依赖性远端结肠肿瘤发生。
Pro-carcinogenic bacteria have the potential to initiate and/or promote colon cancer, in part via immune mechanisms that are incompletely understood. Using ApcMin mice colonized with the human pathobiont enterotoxigenic Bacteroides fragilis (ETBF) as a model of microbial-induced colon tumorigenesis, we show that the Bacteroides fragilis toxin (BFT) triggers a pro-carcinogenic multi-step inflammatory cascade requiring IL-17R, NF-κB, and Stat3 signaling in colonic epithelial cells (CECs). Although necessary, Stat3 activation in CECs is not sufficient to trigger ETBF colon tumorigenesis. Notably, IL-17-dependent NF-κB activation in CECs induces a proximal to distal mucosal gradient of C-X-C chemokines, including CXCL1 that mediates the recruitment of CXCR2-expressing polymorphonuclear immature myeloid cells with parallel onset of ETBF-mediated distal colon tumorigenesis. Thus, BFT induces a procarcinogenic signaling relay from the CEC to a mucosal Th17 response that results in NFκB activation selectively in distal colon CECs, that collectively triggers myeloid cell-dependent distal colon tumorigenesis.
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影响因子：
64.5
作者：
Acharyya S;Oskarsson T;Vanharanta S;Malladi S;Kim J;Morris PG;Manova-Todorova K;Leversha M;Hogg N;Seshan VE;Norton L;Brogi E;Massagué J
通讯作者：
Massagué J
影响因子：
6.4
作者：
Shields, Christina E. DeStefano;Van Meerbeke, Sara W.;Sears, Cynthia L.
通讯作者：
Sears, Cynthia L.
CXCR2 的抑制可显着抑制炎症驱动和自发性肿瘤发生
影响因子：
15.9
作者：
Jamieson, Thomas;Clarke, Mairi;Sansom, Owen J.
通讯作者：
Sansom, Owen J.
影响因子：
64.8
作者：
Grivennikov, Sergei I.;Wang, Kepeng;Mucida, Daniel;Stewart, C. Andrew;Schnabl, Bernd;Jauch, Dominik;Taniguchi, Koji;Yu, Guann-Yi;Oesterreicher, Christoph H.;Hung, Kenneth E.;Datz, Christian;Feng, Ying;Fearon, Eric R.;Oukka, Mohamed;Tessarollo, Lino;Coppola, Vincenzo;Yarovinsky, Felix;Cheroutre, Hilde;Eckmann, Lars;Trinchieri, Giorgio;Karin, Michael
通讯作者：
Karin, Michael
影响因子：
11.2
作者：
Housseau F;Wu S;Wick EC;Fan H;Wu X;Llosa NJ;Smith KN;Tam A;Ganguly S;Wanyiri JW;Iyadorai T;Malik AA;Roslani AC;Vadivelu JS;Van Meerbeke S;Huso DL;Pardoll DM;Sears CL
通讯作者：
Sears CL