Iron Cell Proliferation and Iron Withholding

In addition to its ability to increase oxidative damage, excess iron is detrimental because iron is needed for proliferation of bacteria and many other organisms, including most if not all cancer cells. In particular, iron is needed for the enzyme ribonucleotide reductase, which plays an essential role in DNA synthesis. In fact, iron availability is commonly growth-limiting for many organisms. Since bacteria need iron, the body has developed ways to withhold iron when faced with infection. A large body of evidence demonstrates that one of the first responses to infection in animals is iron withhold-ing.76 The iron-withholding system can thus be considered part of the natural immune system. Many studies have reported that iron withholding reduces the severity of infection and that high iron levels favor more severe and more frequent infections.

Not surprisingly, the body responds to cancer in the same way it responds to infection—by withholding iron. Because of this response and the relationship between cancer, the immune system, and iron, it is useful to explore how iron withholding works, how excess iron affects the immune system, and how cancer cells strive to obtain iron.

There are at least three ways the body withholds iron. First, iron is sequestered in macrophages. In response to infection, immune cells secrete nitric oxide (NO) and other compounds that cause pathogens to export iron; the iron they release, along with that released from damaged cells, is picked up by iron-binding proteins secreted from neutrophils. One such protein is the multipurpose protein lactoferrin.a The iron-loaded lactoferrin is eventually ingested by macrophages. If iron levels are not too high, macrophages safely store the excess iron they ingest. In fact, in moderate amounts this iron can assist macrophages to produce ROS.77 Ingestion of excessive amounts of iron, however, reduces their effectiveness and their ability to sequester additional iron. Thus very high iron levels can overwhelm storage capacity and have detrimental consequences for the immune system.

Second, the body controls iron availability during infection by reducing iron absorption in the intestines and by synthesizing immunoglobulins that attack the receptors for iron-binding proteins located on the surface of microbe cells.78

Lastly, the body regulates iron availability through synthesis of the iron-binding protein transferrin. Although transferrin also serves as an iron-supplying protein, it does play a role in removing iron from use.

Assays that measure the iron saturation level of trans-ferrin are useful in determining the amount of available iron. The normal iron saturation level is about 30 percent, and levels at or below this point are helpful in fighting infection. In response to infection, iron-

a Mother's milk has a high concentration of lactoferrin, which may help reduce the risk of infection in a child.

withholding systems can lower transferrin saturation levels to about 15 percent, and serum iron can drop from a normal of about 18 mM down to about 5.3 mM.76 In chronic infection, however, this self-induced drop in iron is prolonged and is responsible for the well-known anemic condition called the "anemia of chronic disease."

Iron withholding limits the ability of microbes to obtain needed iron; it also limits the same ability in cancer cells. Some cancer cells, however, have adapted to this limitation by producing iron-binding peptides that deliver iron to the cancer cell.79'a Still, in many cancer cell lines, proliferation is inhibited by iron withholding.

It is tempting to speculate that the spontaneous regressions seen in some cancer patients after severe infection and/or fever could be related at least in part to reductions in iron availability.80-83 Not only does infection increase iron withholding, as discussed above, but fever, among its many effects, reduces the ability of pathogens and cancer cells to synthesize iron-binding proteins and their receptors.84 Increased iron withholding, possibly in association with fever, may also be partly responsible for the antitumor effects of some bacterial injections.76

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