Iron and Chronic Inflammation in Obese and Lean Men with Colon Cancer: The Link with Hepcidin

Obesity and excessive iron are independently associated with increased risk for colorectal cancer (CRC). Serum hepcidin, the primary regulator of iron metabolism, is elevated during obesity and results in reduced iron absorption, higher iron in the fecal stream and the implications for CRC risk remains unknown. The main objective of this study was to explore the link with obesity and iron in men with CRC. Incident CRC cases (n=20) and healthy controls (n=20) were recruited to obtain colonic mucosa (tumors for cases; healthy mucosa for controls), serum, dietary intake and medical history. Iron accumulation was assessed by Perl’s Prussian Blue staining. messenger ribonucleic acid (mRNA) expression of hepcidin, divalent metal transporter-1 (DMT-1), ferroportin (FPN) and interleukin-6 (IL-6) were measured in colonic mucosa using rt-PCR. Serum parameters were analyzed by enzyme-linked immunosorbent assay (ELISA) for serum transferrin receptor (sTfR), hepcidin, c-reactive protein (CRP), tumor necrosis-alpha (TNF-α). Obesity was measured with waist circumference (WC) and defined as WC> 102 cm (Obese) or WC<102 cm (Lean). To control for the influence of iron status in the analysis, cases (n=16) and controls (n=15) were matched on hemoglobin and waist circumference. Cases had higher iron accumulation (30%) compared to controls (5%). Cases had lower colonic mRNA expression of hepcidin (2.9 fold; p=0.01) and higher IL-6 (9.40 fold; p=0.001) compared to controls. No significant difference with DMT-1 or FPN was observed between groups. Cases had lower iron status (higher sTfR; p=0.004) and higher circulating markers of inflammation (CRP, p=0.01) compared to controls. Although cases had lower serum hepcidin (p=0.02) compared to controls, levels were within the normal range for adult men. No associations were found by obesity and serum hepcidin in cases or controls. Findings remained similar after matching on hemoglobin and waist circumference. Colonic hepcidin does not contribute to tumor iron retention. The inappropriately normal serum hepcidin in cases is likely due to tumor driven inflammation rather than iron status which suggests 1) decreased duodenal iron absorption resulting in higher iron in fecal stream and colonic exposure 2) increased tumor iron retention. Overall, these findings may have clinical implications for oral iron supplementation during CRC.