Identification of a genetic locus controlling bacteria-driven colitis and associated cancer through effects on innate inflammation

Translational Gastroenterology Unit, Nuffield Department of Clinical Medicine, University of Oxford, John Radcliffe Hospital, Oxford OX3 9DU, England, UK.
Journal of Experimental Medicine (Impact Factor: 13.91). 06/2012; 209(7):1309-24. DOI: 10.1084/jem.20120239
Source: PubMed

ABSTRACT Chronic inflammation of the intestine has been associated with an elevated risk of developing colorectal cancer. Recent association studies have highlighted the role of genetic predisposition in the etiology of colitis and started to unravel its complexity. However, the genetic factors influencing the progression from colon inflammation to tumorigenesis are not known. We report the identification of a genetic interval Hiccs that regulates Helicobacter hepaticus-induced colitis and associated cancer susceptibility in a 129.RAG(-/-) mouse model. The 1.7-Mb congenic interval on chromosome 3, containing eight genes and five microRNAs, renders susceptible mice resistant to colitis and reduces tumor incidence and multiplicity. Bone marrow chimera experiments showed that resistance is conferred by the hematopoietic compartment. Moreover, the Hiccs locus controls the induction of the innate inflammatory response by regulating cytokine expression and granulocyte recruitment by Thy1(+) innate lymphoid cells. Using a tumor-promoting model combining chronic Helicobacter hepaticus infection and the carcinogen azoxymethane, we found that Hiccs also regulates the frequency of colitis-associated neoplasia. Our study highlights the importance of innate immune cells and their genetic configuration in driving progression from inflammation toward cancer and opens the door for analysis of these pathways in human inflammatory disorders and associated cancers.

Download full-text


Available from: Stefanie Kirchberger, May 28, 2014
1 Follower
  • Source
    • "Loci on chromosome 3 have also been shown as strain-dependent contributors to lesions in a Trichuris muris-induced model of colitis (Levison et al. 2013), a G-protein alpha inhibitory 2 chain (Gnai2 -/-) mutant (Borm et al. 2005), T-bet(-/-). Rag2(-/-) double-deficient mice (Ermann et al. 2011), Gpx1(-/-).Gpx2(-/-) double-deficient mice (Esworthy et al. 2011a, b) and a H. hepaticus-induced colitis and colonic tumor model (Boulard et al. 2012). However, these studies focused on a relatively small number of common strains. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Inflammatory bowel disease (IBD) is an immune-mediated condition driven by improper responses to intestinal microflora in the context of environmental and genetic background. GWAS in humans have identified many loci associated with IBD, but animal models are valuable for dissecting the underlying molecular mechanisms, characterizing environmental and genetic contributions and developing treatments. Mouse models rely on interventions such as chemical treatment or introduction of an infectious agent to induce disease. Here, we describe a new model for IBD in which the disease develops spontaneously in 20-week-old mice in the absence of known murine pathogens. The model is part of the Collaborative Cross and came to our attention due to a high incidence of rectal prolapse in an incompletely inbred line. Necropsies revealed a profound proliferative colitis with variable degrees of ulceration and vasculitis, splenomegaly and enlarged mesenteric lymph nodes with no discernible anomalies of other organ systems. Phenotypic characterization of the CC011/Unc mice with homozygosity ranging from 94.1 to 99.8 % suggested that the trait was fixed and acted recessively in crosses to the colitis-resistant C57BL/6J inbred strain. Using a QTL approach, we identified four loci, Ccc1, Ccc2,Ccc3 and Ccc4 on chromosomes 12, 14, 1 and 8 that collectively explain 27.7 % of the phenotypic variation. Surprisingly, we also found that minute levels of residual heterozygosity in CC011/Unc have significant impact on the phenotype. This work demonstrates the utility of the CC as a source of models of human disease that arises through new combinations of alleles at susceptibility loci. Electronic supplementary material The online version of this article (doi:10.1007/s00335-013-9499-2) contains supplementary material, which is available to authorized users.
    Mammalian Genome 02/2014; 25(3-4). DOI:10.1007/s00335-013-9499-2 · 2.88 Impact Factor
  • Source
    • "Exp. cells (Cammarota et al. 2010; Rakhesh et al. 2012). Mice experimental studies help us understand the relationship between genetic predisposition, infection-induced inflammation , neutrophils influx and the development of cancer (Boulard et al. 2012). Understanding the excitation of signaling pathways and the factors regulating cell functioning in the intestinal wall and the environment responsible for these receptor reactions is crucial. "
    [Show abstract] [Hide abstract]
    ABSTRACT: The innate immune system uses Toll-like receptors (TLR) to detect the presence of pathogen patterns thus allowing for rapid host defense responses. Stimulation of TLR results in inflammatory response and regulatory cytokine production affecting acquired immunity. The aim of the study was an evaluation of TLR2 and TLR4 expression on the surface of human colon cancer cells in primary culture with or without autologous peripheral blood mononuclear cells. Surgical specimens of colon cancer were processed to obtain cancer cells. Cancer cells separation was conducted first by mechanical tissue disintegration and than by gradient centrifugation to obtain 95 % cell confluence. By staining the isolated cells the pathologist determined them as adenocarcinoma. Colon cancer cells were then co-cultured in 24 h culture alone or together with autologous lymphocytes. Reverse-transcription polymerase chain reaction was performed for detection of TLR2 and TLR4 mRNA in colon cancer and normal colon epithelial cells using commercially available primers. Resting as well as phytohemagglutinin or lipopolysaccharide (LPS) stimulated cells were tested. Receptor proteins on cancer cells were examined by immunohistochemistry. TLR4 mRNA was detected in cancer cells. Autologous lymphocytes do not exert any effect on these receptors expression. TLR4 mRNA expression was not observed in normal colon epithelial cells. TLR2 mRNA was present on LPS stimulated cancer cells as well as on resting and stimulated lymphocytes. Expression of TLR2 and TLR4 receptor proteins on colon cancer cells were confirmed by immunohistochemistry. TLR4 may be responsible for uncontrolled tumor growth under LPS stimulation in human colon environment.
    Archivum Immunologiae et Therapiae Experimentalis 01/2014; 62(3). DOI:10.1007/s00005-013-0260-z · 2.82 Impact Factor
  • Source
    • "For analysis of precarcinogenic aberrant crypts, colons were fixed in 10% formalin, stained in 2% methylene blue, and analyzed using a dissection microscope and sliding caliper. For histological analysis, 200–300 sections of paraffinembedded Swiss-rolled colons and cecums were prepared, and every 10th section was H&E-stained and blindly graded by a pathologist using criteria for grading dysplasia in human IBD as previously described (Boulard et al., 2012). Tumors were staged as per TNM classification of human CRC. "
    [Show abstract] [Hide abstract]
    ABSTRACT: Patients with inflammatory bowel disease (IBD) have an increased risk of colon cancer. However, the immune cells and cytokines that mediate the transition from intestinal inflammation to cancer are poorly understood. We show that bacteria-induced colon cancer is accompanied by differential accumulation of IL-17(+)IL-22(+) colonic innate lymphoid cells (cILCs), which are phenotypically distinct from LTi and NK-22 cells, and that their depletion in mice with dysplastic inflammation blocks the development of invasive colon cancer. Analysis of the functional role of distinct Type 17 cytokines shows that although blockade of IL-17 inhibits some parameters of intestinal inflammation, reduction in dysplasia and colorectal cancer (CRC) requires neutralization of IL-22 indicating a unique role for IL-22 in the maintenance of cancer in this model. Mechanistic analyses showed that IL-22 selectively acts on epithelial cells to induce Stat3 phosphorylation and proliferation. Importantly, we could detect IL-22(+)CD3(+) and IL-22(+)CD3(-) cells in human CRC. Our results describe a new activity of IL-22 in the colon as a nonredundant mediator of the inflammatory cascade required for perpetuation of CRC, highlighting the IL-22 axis as a novel therapeutic target in colon cancer.
    Journal of Experimental Medicine 04/2013; 210(5). DOI:10.1084/jem.20122308 · 13.91 Impact Factor
Show more