Nuclear oxidative damage correlates with poor survival in colorectal cancer

Abstract

Oxidative DNA damage results from DNA adducts such as 8-oxo-7, 8 dihydro-2 0 -deoxyguanosine (8-oxo-dG), which is a pro-mutagenic lesion. No known association between 8-oxo-dG, disease progression and survival exists in colorectal cancer (CRC). We examined levels of 8-oxo-dG in sporadic CRC to determine its relationship with pathological stage and outcome. A total of 143 CRC patients and 105 non-cancer patients were studied. Nuclear and cytoplasmic 8-oxo-dG was assessed using immunohistochemistry. Double immunofluorescence using 8-oxo-dG and manganese superoxide dismutase (MnSOD) antibodies localised cytoplasmic 8-oxo-dG. Apoptosis was detected using TUNEL. Nuclear staining levels were similar in tumour tissue and matched normal mucosa in both epithelial (P ¼ 0.22) and stromal (P ¼ 0.85) cells. Epithelial cytoplasmic staining was greater in tumour tissue (Po0.001). Double immunofluorescence localised cytoplasmic 8-oxo-dG to mitochondria. Epithelial and stromal nuclear 8-oxo-dG decreased with local disease spread, but highest levels were found in distant disease (Po0.01). Survival was related to epithelial nuclear and stromal staining in normal mucosa (Po0.001) and tumour (Po0.01) but was unrelated to cytoplasmic staining. Normal control cells in tissue from cancer patients with high levels of 8-oxo-dG failed to undergo cell death. 8-oxo-dG may be an important biomarker of disease risk, progression and survival for CRC patients. British Journal of Cancer (2009) Colorectal cancer is one of the commonest cancers in the Western World (Ferlay et al, 2007) and genetic events associated with tumour initiation and progression have been extensively studied (Fearon and Vogelstein, 1990). The majority of mutations found in sporadic colorectal cancer are due to single-base substitutions (Sjoblom et al, 2006) such as GC to TA transversions.Oxidative stress is defined as a disturbance in the balance between the production of reactive oxygen species and antioxidant defences. It is associated with aging and implicated in a variety of disease processes including atherosclerosis, diabetes mellitus and cancer (Pacifici and Davies, 1991;Maritim et al, 2003;Valko et al, 2004;Minuz et al, 2006). Endogenous sources of reactive oxygen species production include oxidative phosphorylation and inflammatory cell activation, and despite multiple conserved redox modulating systems, a proportion of reactive oxygen species continuously escape the mitochondrial respiratory chain. The significance of reactive oxygen species within antioxidant systems and its role in carcinogenesis is not fully understood. Enhanced antioxidant mechanisms in gastrointestinal tumour cells in vivo are associated with chemo-resistance, metastasis and poor prognosis, whereas many in vitro studies suggest that antioxidant enzymes have tumour-suppressing properties (Janssen et al, 1998;Toh et al, 2000), although the majority of conflicting results may be explained by reference to the net redox status of malignant cells (Kinnula and Crapo, 2004).The DNA adduct, 8-oxo-7,...

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