Infection-induced colitis in mice causes dynamic and tissue-specific changes in stress response and DNA damage leading to colon cancer

Abstract

Helicobacter hepaticus -infected Rag 2 -/- mice emulate many aspects of human inflammatory bowel disease, including the development of colitis and colon cancer. To elucidate mechanisms of inflammation-induced carcinogenesis, we undertook a comprehensive analysis of histopathology, molecular damage, and gene expression changes during disease progression in these mice. Infected mice developed severe colitis and hepatitis by 10 wk post-infection, progressing into colon carcinoma by 20 wk post-infection, with pronounced pathology in the cecum and proximal colon marked by infiltration of neutrophils and macrophages. Transcriptional profiling revealed decreased expression of DNA repair and oxidative stress response genes in colon, but not in liver. Mass spectrometric analysis revealed higher levels of DNA and RNA damage products in liver compared to colon and infection-induced increases in 5-chlorocytosine in DNA and RNA and hypoxanthine in DNA. Paradoxically, infection was associated with decreased levels of DNA etheno adducts. Levels of nucleic acid damage from the same chemical class were strongly correlated in both liver and colon. The results support a model of inflammation-mediated carcinogenesis involving infiltration of phagocytes and generation of reactive species that cause local molecular damage leading to cell dysfunction, mutation, and cell death. There are strong correlations among histopathology, phagocyte infiltration, and damage chemistry that suggest a major role for neutrophils in inflammation-associated cancer progression. Further, paradoxical changes in nucleic acid damage were observed in tissue- and chemistry-specific patterns. The results also reveal features of cell stress response that point to microbial pathophysiology and mechanisms of cell senescence as important mechanistic links to cancer.

Isolation and characterization of a novel Helicobacter species, Helicobacter jaachi sp. nov., from common marmosets (Callithrix jaachus)

“…Further, numerous experimental Helicobacter sp. infections in mice have reproduced salient features of IBD and hepatobiliary disease observed in marmosets (Erdman et al, 2009;Fox, 2002;Fox et al, 1996Fox et al, , 2011Hailey et al, 1998;Knutson et al, 2013;Maggio-Price et al, 2005;Mangerich et al, 2012;Meeker et al, 2014).…”

NovelHelicobacterspeciesH.japonicumisolated from laboratory mice from Japan induces typhlocolitis and lower bowel carcinoma in C57BL/129 IL10−/−mice

“…CDT has nuclease activity, causes DNA DSBs, inhibits ATM-dependent response pathways and suppresses repair of DNA adducts. Importantly, H.hepaticus infection in 129 rag deficient mice cause inflammatory immune responses associated with highly reactive oxygen and nitrogen species capable of causing tissue injury, death or mutation of cells (49)(50)(51). Further, DSBs have been involved with H.pylori-induced gastric cancer (52).…”

Chemical and cytokine features of innate immunity characterize serum and tissue profiles in inflammatory bowel disease

“…Neutrophil recruitment and activation are key steps in the intestinal innate immune response observed in IBD (6)(7)(8), and studies with animal models of colitis highlight the relationship between neutrophil infiltration and disease severity (9)(10)(11). We recently reported results of a comprehensive analysis of histopathology, changes in gene expression, and nucleic acid damage occurring during progression of lower bowel disease in Rag2 −/− mice infected with Helicobacter hepaticus (Hh) (10).…”

“…A prominent target of HOCl is tyrosine, which leads to the formation of the stable aromatic residue, 3-chlorotyrosine (Cl-Tyr) (21,22). MPO also produces chlorinating species that react with DNA to form chlorinated adducts such as 5-chloro-2′-deoxycytidine (5-Cl-dC) (23), the presence of which was identified in colon tissue of H. hepaticus-infected Rag2 −/− mice (10). This modification of DNA may provide a mechanistic link between neutrophil activity and colitis-associated carcinoma (10,24,25).…”

“…We recently reported results of a comprehensive analysis of histopathology, changes in gene expression, and nucleic acid damage occurring during progression of lower bowel disease in Rag2 −/− mice infected with Helicobacter hepaticus (Hh) (10). This mouse model emulates many aspects of human IBD, and infected mice develop severe colitis that progress into colon carcinoma, with pronounced pathology in the cecum and proximal colon marked by infiltration of neutrophils and macrophages (12,13).…”