Ironing out cancer

Abstract

New insights into the roles of proteins that regulate cellular iron in cancer growth, angiogenesis, and metastasis have recently emerged. Discoveries of the roles of ferroportin, hepcidin, lipocalin 2, and members of the six transmembrane epithelial antigen of the prostate (STEAP) and iron regulatory protein (IRP) families in cancer have provided specificity and molecular definition to the role of iron homeostasis in cancer growth and metastasis. A number of studies directly support a role of these proteins in modifying bioavailable iron, whereas other studies suggest that at least some of their effects are independent of their role in iron biology.

Figure 1. Potential mechanisms for alteration of iron homeostasis in the breast tumor environment

Left: Normal breast epithelial cells express low levels of transferrin receptor 1, STEAP proteins, and hepcidin and high levels of ferroportin, which collectively lead to a small pool of labile iron. Lcn2 complexed with a siderophore may further reduce levels of intracellular iron by capturing and effluxing siderophore-bound iron from these cells, although this is currently hypothetical. Right: Breast cancer cells show increased expression of transferrin receptor 1, certain STEAP family members, and hepcidin and low levels of ferroportin, which lead to an increased labile iron pool. In these cells, Lcn2 complexed with siderophore bound iron may serve as a further source of iron. Tumor–associated macrophages in the tumor environment may serve as an additional source of iron for these cells.