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Epidemiological data strongly support a role for dietary and haem iron in colorectal carcinogenesis through multiple pathways
The aetiopathogenesis of colorectal carcinoma (CRC) remains the holy grail for researchers in the field. CRC arises from benign neoplasms and evolves into adenocarcinoma through a stepwise histological progression sequence, proceeding from either adenomas or hyperplastic polyps/serrated adenomas. Genetic alterations are associated with specific steps in this polyp-adenocarcinoma sequence and are believed to drive the histological progression towards colon cancer. Approximately 50% of CRCs are attributed to dietary factors and about 15–20% to genetic factors, including the high risk familial syndromes.1 Large prospectively collected epidemiological data have suggested that iron may confer an increased risk for CRC.2
WHAT ARE THE MECHANISMS BY WHICH IRON CONFERS AN INCREASED RISK OF CRC?
An apparent dose-response for serum ferritin level and adenoma risk suggests that exposure to dietary iron may be involved in the development of colorectal adenomas (and particularly proximal adenomas).3 Dietary haem iron (through its effect on epithelial proliferation) is associated with an increased risk of proximal colon cancer, especially in women who drink alcohol.4 In the dextran sodium sulphate model of mouse colitis, a twofold increase in dietary iron increased iron accumulation in colonic luminal contents at the colonic mucosal surface and in superficial epithelial cells with a concomitant increase in colitis associated CRC incidence.5 High dietary iron decreases tocopherol levels in rat colonocytes, promotes oxidative stress (through generation of lipid peroxides and reactive oxygen species (ROS)) in faeces and colonocytes,6–8 and decreases the activity of the colonic antioxidant enzyme manganese superoxide dismutase.9 ROS activation of activator protein 1 and nuclear factor κB signal transduction pathways leads to transcription of genes involved in cell growth regulatory pathways.10
In addition, some studies suggest that possession of HFE gene mutations are statistically associated with increased rates of CRC,11 …
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