Original ResearchFull Report: Basic and Translational—Alimentary TractIDO1 Metabolites Activate β-catenin Signaling to Promote Cancer Cell Proliferation and Colon Tumorigenesis in Mice
Section snippets
Mice
Wild type (WT), IDO1 knock-out (IDO1-/-), and Rag1-/-, all on the C57BL/6J, originally were purchased from The Jackson Laboratory (Bar Harbor, ME) and then bred in-house to generate comparator groups. IDO1/Rag1 double knock-out (DbKO) mice were generated from these strains. At the start of experiments all mice were 6–12 weeks old and weighed 16–22 g. Age-matched female mice were used preferentially in experiments. Animals were maintained in a specific pathogen-free facility and all comparator
IDO1 Expression in Colitis-Associated Tumors
Expression levels of IDO1 and cytokines recognized as IDO1 inducers were measured in tumors and adjacent inflamed tissue and compared with noncolitis control mice. Levels of IFNγ, tumor necrosis factor α, and IDO1 mRNA and IDO1 protein were significantly higher in tumor tissue than in inflamed tissue adjacent to the tumors or control (noncolitis) specimens (Figure 1A and B). IFN-alfa, a cytokine known to induce IDO1 in plasmacytoid dendritic cells, was not increased significantly in either
Discussion
Inflammation and immune cell infiltration are present in both sporadic and colitis-associated colon cancers. To support continued growth and progression, it is advantageous for tumors to develop adaptive strategies to combat ongoing inflammation and immune assault. By using a murine model of colitis-associated tumorigenesis and human cell lines, we established a role for IDO1 as an adaptive mechanism promoting colon cancer epithelial proliferation.
The most striking finding of this study was
Acknowledgments
Matthew Ciorba extends his most sincere gratitude to Nicholas O. Davidson MD, Thaddeus Stappenbeck MD, PhD, and George Predergast who serve as advisors in career development and on award DK089016.
References (41)
- et al.
Overexpression of indoleamine 2,3-dioxygenase in human inflammatory bowel disease
Clin Immunol
(2004) - et al.
Inhibition of indoleamine 2,3-dioxygenase augments trinitrobenzene sulfonic acid colitis in mice
Gastroenterology
(2003) - et al.
GCN2 kinase in T cells mediates proliferative arrest and anergy induction in response to indoleamine 2,3-dioxygenase
Immunity
(2005) - et al.
Involvement of cyclin D3 in liver metastasis of colorectal cancer, revealed by genome-wide copy-number analysis
Lab Invest
(2005) - et al.
Nampt: linking NAD biology, metabolism and cancer
Trends Endocrinol Metab
(2009) - et al.
Inflammasomes in intestinal inflammation and cancer
Gastroenterology
(2011) - et al.
Indoleamine 2,3-dioxygenase and tumor-induced tolerance
J Clin Invest
(2007) - et al.
Prognostic value of indoleamine 2,3-dioxygenase expression in colorectal cancer: effect on tumor-infiltrating T cells
Clin Cancer Res
(2006) - et al.
The paradoxical patterns of expression of indoleamine 2,3-dioxygenase in colon cancer
J Transl Med
(2009) - et al.
Clinicopathological significance of indoleamine 2,3-dioxygenase 1 expression in colorectal cancer
Br J Cancer
(2012)
Indoleamine 2,3 dioxygenase in intestinal disease
Curr Opin Gastroenterol
Inflamed intestinal mucosa features a specific epithelial expression pattern of indoleamine 2,3-dioxygenase
Int J Immunopathol Pharmacol
Analysis of mucosal gene expression in inflammatory bowel disease by parallel oligonucleotide arrays
Physiol Genomics
Gene expression patterns in experimental colitis in IL-10-deficient mice
Inflamm Bowel Dis
Induction of IDO-1 by immunostimulatory DNA limits severity of experimental colitis
J Immunol
Serum analysis of tryptophan catabolism pathway: correlation with Crohn's disease activity
Inflamm Bowel Dis
Gut CD103+ dendritic cells express indoleamine 2,3-dioxygenase which influences T regulatory/T effector cell balance and oral tolerance induction
Gut
Intestinal inflammation and cancer
Gastroenterology
Inflammation and colon cancer
Gastroenterology
Modeling colitis-associated cancer with azoxymethane (AOM) and dextran sulfate sodium (DSS)
J Vis Exp
Cited by (0)
Authors names in bold designate shared first authorship.
Conflicts of interest The authors disclose no conflicts.
Funding Supported in part by National Institutes of Health grants DK089016 (M.A.C.), DK064798 (R.D.N.), DK075713 (W.F.S.), and P30-DK52574 (Washington University Digestive Diseases Research Cores Center). Ameet Thaker was a medical student research fellow of the Howard Hughes Medical Institute, and Matthew Ciorba received a Central Society for Clinical Research Early Career Development Award.