RESUMO
Inflammatory bowel disease (IBD) patients have an increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Several studies have shown that IBD patients have signs of increased oxidative damage, which could be a result of genetic and environmental factors such as an excess in oxidant molecules released during chronic inflammation, mitochondrial dysfunction, a failure in antioxidant capacity, or oxidant promoting diets. It has been suggested that chronic oxidative environment in the intestine leads to the DNA lesions that precipitate colon carcinogenesis in IBD patients. Indeed, several preclinical and clinical studies show that different endogenous and exogenous antioxidant molecules are effective at reducing oxidation in the intestine. However, most clinical studies have focused on the short-term effects of antioxidants in IBD patients but not in CAC. This review article examines the role of oxidative DNA damage as a possible precipitating event in CAC in the context of chronic intestinal inflammation and the potential role of exogenous antioxidants to prevent these cancers.
Assuntos
Antioxidantes/farmacologia , Neoplasias Associadas a Colite/prevenção & controle , Colite/complicações , Animais , Neoplasias Associadas a Colite/etiologia , Neoplasias Associadas a Colite/patologia , HumanosRESUMO
Inflammatory bowel disease patients have a greatly increased risk of developing colitis-associated colon cancer (CAC); however, the basis for inflammation-induced genetic damage requisite for neoplasia is unclear. Using three models of CAC, we find that sustained inflammation triggers 8-oxoguanine DNA lesions. Strikingly, antioxidants or iNOS inhibitors reduce 8-oxoguanine and polyps in CAC models. Because the mismatch repair (MMR) system repairs 8-oxoguanine and is frequently defective in colorectal cancer (CRC), we test whether 8-oxoguanine mediates oncogenesis in a Lynch syndrome (MMR-deficient) model. We show that microbiota generates an accumulation of 8-oxoguanine lesions in MMR-deficient colons. Accordingly, we find that 8-oxoguanine is elevated in neoplastic tissue of Lynch syndrome patients compared to matched untransformed tissue or non-Lynch syndrome neoplastic tissue. While antioxidants reduce 8-oxoguanine, they do not reduce CRC in Lynch syndrome models. Hence, microbe-induced oxidative/nitrosative DNA damage play causative roles in inflammatory CRC models, but not in Lynch syndrome models.
Assuntos
Colite/complicações , Colite/patologia , Neoplasias Colorretais/complicações , Neoplasias Colorretais/patologia , Dano ao DNA , Helicobacter pylori/fisiologia , Estresse Oxidativo , Polipose Adenomatosa do Colo/complicações , Polipose Adenomatosa do Colo/patologia , Adulto , Idoso , Idoso de 80 Anos ou mais , Animais , Antioxidantes/farmacologia , Carcinogênese/efeitos dos fármacos , Carcinogênese/patologia , Colite/induzido quimicamente , Colite/microbiologia , Colo/efeitos dos fármacos , Colo/patologia , Neoplasias Colorretais/microbiologia , Neoplasias Colorretais Hereditárias sem Polipose/genética , Reparo do DNA/efeitos dos fármacos , Sulfato de Dextrana , Modelos Animais de Doenças , Disbiose/complicações , Disbiose/patologia , Escherichia coli/metabolismo , Feminino , Guanosina/análogos & derivados , Guanosina/metabolismo , Infecções por Helicobacter/complicações , Helicobacter pylori/efeitos dos fármacos , Humanos , Inflamação/complicações , Inflamação/patologia , Interleucina-10/deficiência , Interleucina-10/metabolismo , Masculino , Camundongos Endogâmicos C57BL , Pessoa de Meia-Idade , Mutação/genética , Estresse Oxidativo/efeitos dos fármacosRESUMO
In a recent issue of Science, Wilson et al. (2019) provide direct evidence that the bacterial-produced colibactin alkylates DNA in vivo, resulting in DNA adducts, which mediates its genotoxic effect. This work reinforces the role of colibactin-producing bacteria in colon cancer pathogenesis.