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P029. Oral iron supplementation promotes inflammation and colorectal carcinogenesis in a mouse model of colitis-associated cancer

B. Klopcic1, A. Chua2, D. Ho3, J. Olynyk4, D. Trinder2, I. Lawrance1

1Centre for Inflammatory Bowel Diseases, School of Medicine and Pharmacology, UWA, Fremantle Hospital, Fremantle, Australia; 2School of Medicine and Pharmacology, University of Western Australia, Western Australian Institute for Medical Research, Perth, Australia; 3University of Western Australia, School of Medicine and Pharmacology, Fremantle Hospital, Fremantle, Australia; 4Department of Gastroenterology, Fremantle Hospital + Curtin Health Innovation Research Institute, Western Australian Institute for Medical Research, Perth, Australia

Background: Chronic intestinal inflammation increases the risk of colorectal cancer. Anaemia of inflammation is a common complication in IBD and is frequently treated by oral iron supplementation. Whilst oral iron has been shown to increase inflammation in mouse models of colitis, its impact on colorectal cancer risk remains unclear. The aim of this study was to investigate the effect of oral iron on inflammation, iron homeostasis and carcinogenesis in a mouse model of colitis-associated cancer (CAC).

Methods: Colonic inflammation and tumours were induced by the administration of azoxymethane (AOM) and dextran sodium sulphate (DSS) to mice fed either a carbonyl iron supplemented or a normal diet (1% vs. 0.01% iron). Inflammation and tumourigenesis were monitored and scored via mini-endoscopy. Plasma transferrin saturation and liver iron were measured biochemically, ferritin levels were assessed by immunohistochemistry and colonic iron by Perl's Prussian blue. Cytokine gene expression was measured by real-time PCR and pSTAT3 phosphorylation by western blotting.

Results: Oral iron increased iron stores in the intestinal epithelium, mucosal macrophages and hepatocytes. In iron-treated mice intestinal macrophages secreted IL‑6 and colonic STAT3 phosphorylation was elevated in the absence of inflammation (p < 0.01) indicating an effect of dietary iron on signalling by members of the IL‑6 family of proinflammatory cytokines. After 7 days of AOM/DSS treatment, endoscopic inflammation scores were higher in iron-loaded, compared to control, mice (p < 0.05). AOM/DSS treatment also led to lower transferrin saturation and higher hepatic iron levels in mice receiving both diets (p < 0.01), changes that are consistent with anaemia of inflammation. Oral iron, however, further enhanced IL‑6, IL‑11 and IL‑17a gene expression and STAT3 phosphorylation in the AOM/DSS-treated mice (p < 0.05). At 5 weeks, endoscopic tumour scores were increased in AOM/DSS treated mice with more and larger colonic tumours developing in iron-loaded compared to control mice (p < 0.05). Oral iron also increased intratumoural IL‑6 and IL‑11 gene expression (p < 0.05).

Conclusions: Oral iron enhances colitis and tumour formation in a mouse model of CAC and anaemia of inflammation. Iron, inflammation and tumourigenesis may be linked through IL‑6/11-STAT3 signalling. Until the impact of oral iron on the risk of colorectal cancer in IBD has been clarified, systemic iron supplementation may be a better option for iron deficient IBD patients.