DNA damage induced by chronic inflammation contributes to colon carcinogenesis in mice

Abstract

Chronic inflammation increases cancer risk. While it is clear that cell signaling elicited by inflammatory cytokines promotes tumor development, the impact of DNA damage production resulting from inflammation-associated reactive oxygen and nitrogen species (RONS) on tumor development has not been directly tested. RONS induce DNA damage that can be recognized by alkyladenine DNA glycosylase (Aag) to initiate base excision repair. Using a mouse model of episodic inflammatory bowel disease by repeated administration of dextran sulfate sodium in the drinking water, we show that Aag-mediated DNA repair prevents colonic epithelial damage and reduces the severity of dextran sulfate sodium-induced colon tumorigenesis. Importantly, DNA base lesions expected to be induced by RONS and recognized by Aag accumulated to higher levels in Aag-deficient animals following stimulation of colonic inflammation. Finally, as a test of the generality of this effect we show that Aag-deficient animals display more severe gastric lesions that are precursors of gastric cancer after chronic infection with Helicobacter pylori. These data demonstrate that the repair of DNA lesions formed by RONS during chronic inflammation is important for protection against colon carcinogenesis.

Aag-initiated base excision repair promotes ischemia reperfusion injury in liver, brain, and kidney

“…Therefore, repair by Aag, a monofunctional glycosylase with an unusually broad range of substrates, may generate excessive amounts of BER intermediates and, in particular, highly toxic dRP intermediates, possibly explaining why Aag-initiated BER is toxic and Ung/Ogg1/Neil1 initiated repair is not (34)(35)(36). We previously observed that Aag −/− mice are more susceptible than WT mice to inflammation-associated colon cancer (12); this may at first appear to contradict the findings reported here. However, Aag-mediated cell death in the inflamed colon may serve to protect the colon against the accumulation of mutant cells, thus reducing carcinogenesis in the long term.…”

“…Aag therefore seemed likely to provide resistance to I/R-induced toxicity. In support of this hypothesis, we previously found that Aag −/− mice suffer more inflammation-associated intestinal tissue damage and colon carcinogenesis than WT mice (5,12); with this in mind, we set out to examine whether the Aag DNA glycosylase modulates I/R-induced tissue injury in three distinct tissue environmentsnamely liver, brain, and kidney. To our surprise, we find that Aaginitiated BER actually exacerbates, rather than attenuates, I/R tissue injury in all three organs.…”

NF-κB Signaling Pathway, Inflammation and Colorectal Cancer

“…The inflammatory site is characterized by the release of cytokines, growth factors, proteases and ROS, which regulate the sequential recruitment of leukocytes and stimulate endothelial cells and fibroblast to divide and produce components for tissue remodeling. It has been proposed that noxious compounds released during chronic inflammation damage DNA and/or alter cell survival, results in carcinogenesis of CRC (56). NSAIDs have been shown to reduce adenoma and colon cancer development in patients with IBD and hereditary colon cancer (57,58).…”

Monocytes and Macrophages in Cancer: Development and Functions

“…In sites of chronic unresolved inflammation, macrophages initially triggered by a pathogen or tissue stress, recruit monocytes that develop into additional inflammatory macrophages, producing cytokines and chemokines propagating and amplifying the inflammatory cascade [66]. Activated macrophages, located in the sub-epithelial spaces, can contribute to genetic mutations in the adjacent epithelial cells through the production of DNA-damaging reactive nitrogen and oxygen species [69][70][71]. Yet, if DNA repair fails and these mutations accumulate and stabilize, neoplasia can develop and lead to the production of a new wave of TDFs, including M-CSF and CCL2, which will influence the recruitment of more monocytes/macrophages.…”