Iron: An emerging factor in colorectal carcinogenesis

Figure 1 Potential roles of iron in the development of colorectal cancer. Luminal iron may cause DNA damage through the generation of reactive oxygen species (ROS) via the Fenton reaction. Haem may also stimulate the production of N-nitroso compounds (NOC) in the colon which are mutagenic. (I) In the initiation phase of tumorigenesis, DNA damage leads to mutations in key genes regulating cell proliferation and survival such as APC or β-catenin of the Wnt pathway; (II) In the promotion phase, the increase in cell proliferation and survival due to the deleterious effects of NOC and ROS leads to further genetic instability and an accumulation of more mutations. Iron is an important nutrient required for proliferation during this phase. Iron also increases intestinal inflammation and the pro-inflammatory cytokines, TNFα and IL-6 released from inflammatory cells increase cell survival through inhibition of apoptosis via the activation of NFκB; (III) In the progression phase, tumour cells gain independence from survival signals and progress towards a malignant phenotype. Iron has been shown to activate NFκB increasing inducible nitric oxide synthase (iNOS) and cyclo-oxygenase (COX)-2 expression in macrophages. Activated macrophages produce more ROS, increase infiltration through degradation of the extracellular matrix (ECM) and promote angiogenesis by release of nitric oxide (NO), prostaglandin E2 (PGE2), IL-1, -6 and -8 as well as TNFα, ultimately leading to tissue invasion and metastasis.