Systemic and Tumor Level Iron Regulation in Men With Colorectal Cancer: A Case Control Study

Cenk K Pusatcioglu; Elizabeta Nemeth; Giamila Fantuzzi; Xavier Llor; Sally Freels; Lisa Tussing-Humphreys; Robert J Cabay; Rose Linzmeier; Damond Ng; Julia Clark; Carol Braunschweig

Disclosures

Nutr Metab. 2014;11(21) 

In This Article

Background

Excessive body iron levels are associated with increased risk for colorectal cancer (CRC).[1–6] This is due to the high oxidative potential of iron which can result in the formation of reactive oxygen species and mutate the DNA of key genes involved in cell proliferation.[2] Additionally, since iron is required for cell proliferation, increased iron levels could contribute to tumor promotion.[1]

Iron levels and its tissue distribution in the body are regulated by hepcidin, a hepatic-derived systemic iron regulatory hormone.[7–9] Hepcidin is increased by inflammation and decreased by iron insufficiency and erythropoiesis.[10–12] Mechanistically, hepcidin controls iron release into plasma by degrading the iron exporter ferroportin (FPN) in cells that handle iron, including intestinal enterocytes, hepatocytes, and macrophages.[13] Thus, when concentrations of hepcidin are elevated, FPN expression is low, resulting in reduced dietary iron absorption and impaired mobilization from stores.

Few studies have assessed the role of hepcidin and FPN in cancer.[14,15] Serum hepcidin levels were found to be elevated in some hematologic or nonhematologic cancers, likely because of the presence of inflammation, but the pathophysiological relevance of these findings is unknown.[16,17] For FPN, it was reported that patients with breast cancer had decreased tumor expression of FPN protein compared to non-involved tissue, and that tumor FPN mRNA levels were negatively correlated with advanced staging.[14] This suggested that iron retention by breast cancer cells may affect cancer progression.

Hepcidin may be elevated in persons with CRC due to cancer-induced inflammation.[18,19] However, because CRC patients frequently have anemia or low iron status, hepcidin levels may also be decreased.[20,21] Evaluation of the involvement of hepcidin in regulating systemic and tumor level iron metabolism in CRC is limited to one study.[15] Ward et al. reported that systemic hepcidin is elevated with advanced cancer staging.[15] Additionally, they demonstrated that mRNA expression of hepcidin is detected within a subset (34%) of colonic tumors compared to healthy non-involved mucosa. In a complementary study by Brookes et al., increases in iron acquisition proteins (Divalent metal transporter-1, DMT-1; Transferrin receptor-1, TfR1) and decreases in proteins related to cellular iron efflux (FPN; Hephaestin, Heph) were noted in colonic tumors when compared to non-involved mucosa.[1] The authors suggested that these alterations in iron transport may explain the iron sequestration commonly observed in colonic tumors.[1] What remains unknown is hepcidin's role in regulating colonocyte iron transport and whether it contributes to tumor iron accumulation in persons with CRC.

The purpose of this study was to examine simultaneously systemic and tumor iron status and their regulation in men with CRC compared to controls. This was assessed by measuring: (i) hepcidin, iron status and markers of inflammation in serum and (ii) hepcidin, expression of iron transporters (DMT-1, FPN), inflammation and iron accumulation in colonic mucosa. We hypothesized that CRC would be associated with higher levels of hepcidin in serum and tumor compared to controls and that hepcidin levels would be correlated with markers of inflammation and mucosal iron accumulation.

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