Role of iron in carcinogenesis: cancer as a ferrotoxic disease

Abstract

Iron is abundant universally. During the evolutionary processes, humans have selected iron as a carrier of oxygen inside the body. However, iron works as a double-edged sword, and its excess is a risk for cancer, presumably via generation of reactive oxygen species. Thus far, pathological conditions such as hemochromatosis, chronic viral hepatitis B and C, exposure to asbestos fibers, as well as endometriosis have been recognized as iron overload-associated risks for human cancer. Indeed, iron is carcinogenic in animal experiments. These reports unexpectedly revealed that there are target genes in iron-induced carcinogenesis and that iron-catalyzed oxidative DNA damage is not random in vivo. Several iron transporters and hepcidin, a peptide hormone regulating iron metabolism, were discovered in the past decade. Furthermore, a recent epidemiological study reported that iron reduction by phlebotomy decreased cancer risk in the apparently normal population. These results warrant reconsideration of the role of iron in carcinogenesis and suggest that fine control of body iron stores would be a wise strategy for cancer prevention.

Figure 1

Summary of iron metabolism. Mechanisms and regulation of iron absorption and transport in mammals. HAMP, hepcidin antimicrobial peptide; SLC11A2, natural resistance‐associated macrophage protein 2, divalent metal transporter 1, or divalent cation transporter 1; SLC40A1, iron‐regulated transporter 1 or ferroportin 1. Refer to the text for details.

Figure 2

Macroscopic appearance of iron‐induced animal cancer models. (a) Ferric nitrilotriacetate‐induced renal cell carcinoma (black asterisk) in rat. Mesothelioma (white asterisk) is also observed around the testes. (b) Amosite (asbestos)‐induced malignant peritoneal mesothelioma in rat. Numerous white tumors are observed all over the peritoneal cavity. (c) Ferric saccharate‐induced malignant peritoneal mesothelioma in rat.⁽⁶⁵⁾

Figure 3

Significance of iron‐mediated oxidative stress in carcinogenesis: Schematic view.

Figure 4

Concept of oxygenomics to understand the non‐random nature of oxidative DNA damage. PCR, polymerase chain reaction.