Lactoferrin (Lf), a multifunctional molecule first identified as a major constituent of human milk, has become the subject of intensive and widespread study. Although initially thought to be involved in iron transport and nutrition in the neonate, because of its strong avidity for Fe, it is now apparent that Lf is a key component of the body's first line of defense against infection and other invasive processes. We and others have shown that Lf also has antitumor activity and may be useful as a natural antibiotic. Yet, paradoxically, Lf is consistently re-expressed or ectopically expressed in a substantial proportion of many different cancer types. The significance of this finding has never been systematically examined. The goal of this study is to determine the functional consequences of Lf expression in human cancers. Our hypothesis, which is based on the known molecular properties of Lf and a striking new result obtained in our laboratory, is that Lf expression contributes to resistance of many cancers to oxidative damage that results from growth, local conditions and even treatment by certain chemotherapeutic agents and radiation. We will test this novel hypothesis by first determining the scope and characteristics of Lf-mediated resistance to cell damaging agents. We will then determine the mechanisms by which Lf mediates its effects, and determine whether the properties of Lf-expressing cells also involve activation of additional pathways of cellular resistance to oxidative damage. Finally, we will test whether Lf-mediated resistance in vitro to various chemotherapeutic agents that act at least in part by causing oxidative damage is manifest in resistance to therapy in vivo, using both syngeneic and xenotransplant model systems. The results of these studies could provide useful insights into the pathophysiology and natural history of some human cancers, mechanisms by which they develop resistance to treatment, and markers which may be applicable to predicting treatment response in patients with the disease.
