Abstract
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 microbe-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 pro-carcinogenic signaling relay from the CEC to a mucosal Th17 response that results in selective NF-κB activation in distal colon CECs, which collectively triggers myeloid-cell-dependent distal colon tumorigenesis. Chung et al. uncover a complex, microbe-driven carcinogenic mechanism whereby the Bacteroides fragilis toxin targets the colonic epithelium to trigger an IL-17 mucosal immune response that relays back to epithelial cells, inciting pro-tumoral myeloid cell infiltration, principally to the distal colon, corresponding to the region of tumorigenesis in ApcMin/− mice.
Original language | English (US) |
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Pages (from-to) | 203-214.e5 |
Journal | Cell Host and Microbe |
Volume | 23 |
Issue number | 2 |
DOIs | |
State | Published - Feb 14 2018 |
Keywords
- Nf-κB
- STAT-3
- colorectal cancer
- inflammation
- mucosal immunology
- myeloid cells
ASJC Scopus subject areas
- Parasitology
- Microbiology
- Virology