Introduction Colorectal cancer (CRC), a major cause of cancer-related mortality, is associated with iron deficiency anaemia (IDA) and is typically treated with oral iron. Iron is an essential nutrient element that is required for a diverse range of biological activities including the immune function (1). However, studies in animal and cell line models have shown that accumulation of iron in the gut can generate toxic reactive oxygen species and proinflammatory cytokines that results in tissue damage and CRC progression (2). We studied, for the first time in humans, the effect of oral (OI) versus intravenous iron (IVI) treatment on iron distribution, immune cell infiltration and systemic cytokine profile in CRC patients with IDA.

Methods Patients with CRC and IDA received oral-ferrous sulphate (n=20) or intravenous ferric carboxymaltose (n=20) for 2 weeks. Tissue was analysed for iron loading using Prussian-Blue staining. Tissue cytokine and immune cell distribution was determined using immunohistochemistry. Systemic cytokine production was evaluated by multiplex-cytokine assays.

Results Iron expression was distributed to the epithelium of tumour tissues in OI treatment (p<0.001) and to the tumour stroma and the macrophages in IVI treatment (p<0.01). OI treatment significantly increased the production of the systemic pro-inflammatory cytokines; IL-6 (p<0.02), IL-12 (p<0.03), IL-17 (p<0.04), GM-CSF (p<0.02) and IFN-γ (p<0.03). Moreover, OI treatment decreased the anti-inflammatory cytokine IL-4 (p<0.01) and IVI increased the anti-inflammatory cytokine IL-10 (p<0.003) production in the serum. Immunoreactivity of IL-12 levels was higher in tissues from patients treated with OI and distributed to the epithelium. However, there were no significant differences in immunoreactivity of tissue IL-10 between the treatment groups. Inflammatory cell (lymphocytes and granulocytes) infiltration was higher in the OI treatment group.

Conclusions Intravenous iron is compartmentalised to non-epithelial cells indicating that iron is potentially less bio-available to the tumour cells. Oral iron treatment induces inflammatory immune responses both systemically and within the tumour microenvironment. Further functional studies are ongoing to evaluate the mucosal immune response to differential iron loading.

References

1. Bergman M, et al., Biomed Pharmacother. 2005;59(6):307.

2. Glei M, et al., Mutat Res. 2002 26;519(–):151.