8-hydroxyguanosine and Carcinogenesis

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.

Topics: Adenomatous Polyposis Coli; Adult; Aged; Aged, 80 and over; Animals; Antioxidants; Carcinogenesis; Colitis; Colon; Colorectal Neoplasms; Colorectal Neoplasms, Hereditary Nonpolyposis; Dextran Sulfate; Disease Models, Animal; DNA Damage; DNA Repair; Dysbiosis; Escherichia coli; Female; Guanosine; Helicobacter Infections; Helicobacter pylori; Humans; Inflammation; Interleukin-10; Male; Mice, Inbred C57BL; Middle Aged; Mutation; Oxidative Stress

Androgens are thought to cause prostate cancer, but the underlying mechanisms are unclear. Data from animal studies suggest that for androgens to cause prostate cancer, they must be aromatized to estrogen and act in concert with estrogen metabolites. We tested the hypothesis that androgen-receptor and estrogen receptor-mediated effects of androgen and estrogen are necessary, as well as genotoxicity of estrogen metabolites. NBL rats were treated with androgenic and estrogenic compounds for 16-75 weeks through slow-release silastic implants or pellets. Testosterone alone induced cancer in the prostate of 37% of rats. 5α-Dihydrotestosterone, which cannot be converted to estradiol or testosterone, did not cause a significant prostate cancer incidence (4%). Addition of estradiol to 5α-dihydrotestosterone treatment did not markedly enhance prostate cancer incidence (14%), unlike adding estradiol to testosterone treatment which induced a 100% tumor incidence. Testosterone plus estradiol treatment induced a DNA adduct detectable by

Topics: Androgens; Animals; Carcinogenesis; Carcinoma; Dihydrotestosterone; DNA Adducts; DNA Damage; Estradiol; Estrogens; Estrogens, Catechol; Guanosine; Humans; Incidence; Male; Prostate; Prostatic Neoplasms; Rats; Receptors, Estrogen; Testosterone