Reactive species and DNA damage in chronic inflammation: reconciling chemical mechanisms and biological fates

Abstract

Chronic inflammation has long been recognized as a risk factor for many human cancers. One mechanistic link between inflammation and cancer involves the generation of nitric oxide, superoxide and other reactive oxygen and nitrogen species by macrophages and neutrophils that infiltrate sites of inflammation. Although pathologically high levels of these reactive species cause damage to biological molecules, including DNA, nitric oxide at lower levels plays important physiological roles in cell signaling and apoptosis. This raises the question of inflammation-induced imbalances in physiological and pathological pathways mediated by chemical mediators of inflammation. At pathological levels, the damage sustained by nucleic acids represents the full spectrum of chemistries and likely plays an important role in carcinogenesis. This suggests that DNA damage products could serve as biomarkers of inflammation and oxidative stress in clinically accessible compartments such as blood and urine. However, recent studies of the biotransformation of DNA damage products before excretion point to a weakness in our understanding of the biological fates of the DNA lesions and thus to a limitation in the use of DNA lesions as biomarkers. This review will address these and other issues surrounding inflammation-mediated DNA damage on the road to cancer. More Than an Association Between Chronic Inflammation and CancerStemming from the original observations by Virchow, 1 the link between chronic inflammation and cancer is now recognized as essentially a cause-and-effect relationship. 2-7 Epidemiological evidence suggests that more than 20% of all cancers are caused by chronic infection or other types of chronic inflammation, 8 with multiple lines of evidence from laboratory-and population-based studies pointing to a persistent local inflammatory state in organspecific carcinogenesis 9-15 even for tumors not epidemiologically linked to infection or inflammation. There are extremely strong correlations between chronic exposure to asbestos and mesotheloima, 16,17 and chronic infections and cancer for liver flukes (O. viverrini) and cholangiocarcinoma, 18,19 Helicobacter pylori and gastric cancer, 20-22 viral hepatitis and liver cancer 23 and Schistosoma haematobium and bladder cancer. 24,25 Although the epidemiological evidence is well established, the mechanisms underlying the link between chronic inflammation and cancer are not. These mechanisms can be arbitrarily divided into biological and chemical as illustrated in Figure 1 for infection-induced inflammation. The initial infection leads to cell death and changes in cell phenotype, with the release of cytokines and chemotactic factors that cause infiltration of macrophages, neutrophils, lymphocytes and other immune cells. The biological side of chronic inflammation entails the effects of cytokines and chemokines on host cell cycle and apoptosis, whereas the chemical side involves generation of a variety of reactive oxygen and nitrogen species by activated phagocytes with the goal of er...

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