Environmental carcinogenesis: when Nrf2 and the anti-oxidant response would drive the clonal evolution in colorectal cancer

• Published in: Toxicology letters Vol. 295; p. S33
• Main Authors: Huc, L., Surya, R., Dalleau, S., Baradat, M., Gueraud, F., Pierre, F.
• Format: Journal Article Conference Proceeding
• Language: English
• Published: Elsevier B.V 10-10-2018; Elsevier
• Subjects: Life Sciences
• ISSN: 0378-4274; 1879-3169
• DOI: 10.1016/j.toxlet.2018.06.1140

During environmental carcinogenesis, the anti-oxidant response exerts a primordial role in the protection of normal cells against chemicals, toxins or secondary diet by-products. In the case of colorectal cancer CRC, according to epidemiological studies, a large part could be prevented by modifying dietary habits, notably reducing red meat consumption. The deleterious effects of red-meat rich diet would involve the release of a high rate of heme iron in the colon, whose oxidative properties can disturb normal epithelium. In this context, we analysed the role of the anti-oxidant response dependent on Nrf2 in the progression of CRC. We adopted integrated strategies, involving in vivo, ex vivo and in vitro experiments. In the colon, heme iron induced the peroxidation of lipids and so, the neoformation of secondary aldehydes like 4-hydroxy-2-nonenal (HNE) increased in the lumen. Then we compared the effects of HNE with the fecal waters of hemoglobinand beef-fed rats in mouse normal colon epithelial cells and preneoplastic cells mutated on Apc (Adenomatous polyposis coli) gene. We demonstrated that preneoplastic cells exhibited a higher Nrf2-dependent response than normal cells, conferring a positive advantage for resistance to cell death regarding HNE and fecal waters. The early stimulation of Nrf2 signalling pathway by curcumin in vitro or added in the diet in vivo, respectively protected normal cells and prevented preneoplastic lesions in heme iron fed rats. Our results support the hypothesis that heme iron provided by redmeat–rich diet, promoted lipid peroxidation. Apc-mutated cells detoxified efficiently the secondary deleterious aldehydes and then resist to apoptosis. These different processes occurring in normal and preneoplastic cells constitutes a field cancerization that would drive the promotion of CRC by red meat consumption according to an evolutionary carcinogenesis.