Article abstract
Nature Medicine 15, 1016 - 1022 (2009)
Published online: 23 August 2009 | doi:10.1038/nm.2015
A human colonic commensal promotes colon tumorigenesis via activation of T helper type 17 T cell responses
Shaoguang Wu1,8, Ki-Jong Rhee1,7,8, Emilia Albesiano2, Shervin Rabizadeh3,8, Xinqun Wu1,2, Hung-Rong Yen2,4, David L Huso5, Frederick L Brancati1, Elizabeth Wick6, Florencia McAllister1,2, Franck Housseau2, Drew M Pardoll1,2 & Cynthia L Sears1,2
Abstract
The intestinal flora may promote colon tumor formation. Here we explore immunologic mechanisms of colonic carcinogenesis by a human colonic bacterium, enterotoxigenic Bacteroides fragilis (ETBF). ETBF that secretes B. fragilis toxin (BFT) causes human inflammatory diarrhea but also asymptomatically colonizes a proportion of the human population. Our results indicate that whereas both ETBF and nontoxigenic B. fragilis (NTBF) chronically colonize mice, only ETBF triggers colitis and strongly induces colonic tumors in multiple intestinal neoplasia (Min) mice. ETBF induces robust, selective colonic signal transducer and activator of transcription-3 (Stat3) activation with colitis characterized by a selective T helper type 17 (TH17) response distributed between CD4+ T cell receptor-
(TCR)+ and CD4–8–TCR
+ T cells. Antibody-mediated blockade of interleukin-17 (IL-17) as well as the receptor for IL-23, a key cytokine amplifying TH17 responses, inhibits ETBF-induced colitis, colonic hyperplasia and tumor formation. These results show a Stat3- and TH17-dependent pathway for inflammation-induced cancer by a common human commensal bacterium, providing new mechanistic insight into human colon carcinogenesis.
- Department of Medicine, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Department of Oncology and the Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Department of Pediatrics, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Graduate Institute of Clinical Medical Sciences, College of Medicine, Chang Gung University and Center for Traditional Chinese Medicine, Chang Gung Memorial Hospital, Taoyuan, Taiwan.
- Department of Molecular and Comparative Pathobiology, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Department of Surgery, Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
- Present addresses: Department of Medicine, University of Illinois, Chicago, Illinois, USA (K.-J.R.) and Cedars Sinai Medical Center, Los Angeles, California, USA (S.R.).
- These authors contributed equally to this work.
Correspondence to: Cynthia L Sears1,2 e-mail: csears@jhmi.edu
Correspondence to: Franck Housseau2 e-mail: fhousse1@jhmi.edu
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