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A16 ROLE OF MYELOID CELLS IN THE INITIATION OF COLITIS-ASSOCIATED COLON CANCER
- Publication Year :
- 2020
- Publisher :
- Oxford University Press, 2020.
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Abstract
- Background Colorectal cancer (CRC) is the second leading cause of cancer death, with a major risk factor being chronic inflammation. Despite the clear association between inflammation and cancer, the mechanism by which colitis leads to CRC is not well understood. We recently showed that the presence of inflammation does not always correlate with colonic tumorigenesis, as the type of colitis (i.e. colitis-inducing agent) appears to be important for tumor initiation. Aims In this study, we aim to explore the mechanism by which inflammation contributes to the initiation of colitis-associated cancer. We hypothesized that dextran sodium sulfate (DSS)-induced colitis leads to the infiltration of a specific immune cell type that is associated with colonic tumorigenesis. Methods To generate tamoxifen-inducible Cre transgenic mice that allow for Dclk1+ cell lineage tracing and cell-specific knock-out of the tumor suppressor adenomatous polyposis coli (APC), we first crossed our transgenic Dclk1CreERT2 mice to both ROSA26tdTomato and APCfl/fl mice (Dclk1/APCfl/fl). Following Tamoxifen induction, mice were treated with the colitis-inducing agents DSS, trinitrobenzene sulfonic acid (TNBS), oxazolone, or Citrobacter rodentium. The tumor studies were repeated using azoxymethane (AOM)-DSS induced colitis-associated cancer model. Results Treatment with any of the four colitis-inducing agents (DSS, TNBS, oxazolone, or C. rodentium) induced colonic inflammation as detected by increased myeloperoxidase (MPO) activity and histologic analysis. Interestingly, DSS administration led to colonic tumors, whereas TNBS, oxazolone, or C. rodentium did not, even up to 52 weeks following colitis induction. FACS analysis of immune cells in the colon revealed no difference in the number of T or B cells in mice treated with any of the colitis-inducing agents. We did, however, detect significantly increased levels of Ly6G+ neutrophils and F4/80+ macrophages in DSS-treated mice compared to mice in any of the other three models of colitis. Consistent with this myeloid cell infiltration, significantly upregulated protein levels of G-CSF, IL-6, TNF-α, and CXCL1 were detected in DSS-treated mice compared to the other three models of colitis. IL-1α, IL-1β, IL-4, IL-10, and TGF-β levels were unchanged. Conclusions Our data suggest that infiltration of Ly6G+ neutrophils and pro-inflammatory F4/80+ macrophages, unique to DSS-induced colitis, contributes to colonic tumor formation. These data demonstrate that specific immune cell types, rather than the presence of colonic inflammation, play a critical role in the initiation of colitis-associated CRC. Funding Agencies CAG, CIHR
Details
- Language :
- English
- Database :
- OpenAIRE
- Accession number :
- edsair.doi.dedup.....c8b980c01bcec37d87600026d0b89a5c