The primary thematic idea that the local and systemic oxidant balance is a key determinant for the initiation, progression and metastatic conversion of colon and breast cancers. Potential to modulate local and systemic oxidant balance with diet will be investigated to determine the genetic and functional consequences for cancer progression. Selective cancer models which appropriately define in situ transformation, proliferation, invasion and metastasis will be used in conjunction with genetic and functional analyses to clearly define these events in cancer progression. Part of the program will be directed towards defming diet-induced changes in cancer gene expression that correspond to particular steps in the cancer progression pathway. Specific gene regulating events may be delineated as positive or negative effecters of tumorigenesis, invasion or metastasis. Reproducible gene expression changes observed in tumor cells or the host and can be correlated to pro- or anti-oxidant status, will then be further developed as independent biomarkers of oxidant balance-dependent tumorigenic events. Biomarkers of oxidant status will be determined to establish baseline oxidant balance at the site of tumor initiation and progression as well as in the circulation over the entire time course of each tumor progression model. Dietary interventions will be employed as pro- and anti-oxidant treatments to determine their contribution or alteration to both the level of oxidant balance observed and the corresponding tumor progression events. The overall programatic approach will necessarily define the particular positive and negative events for which dietary constituents, especially those that affect local or overall oxidant balance, will have on select tumorigenic events. Application of oxidant biomarker screening methods defined in these models will then be applied to human tumors (i.e. local oxidant balance), as well as circulating serum levels will be correlated to tumor status and diagnosis. Thus, a long-term goal of this collaboration will be to define baseline oxidant status for human patients depending on their tumor type, current treatment, diet and lifestyle factors. In addition, continued oxidant balance monitoring through the course of treatments, such as chemo and radiotherapies, new therapeutics and changes in diet in lifestyle which may be employed are additive long term goals of the program.
| Stevens, Richard G; Morris, James E; Cordis, Gerald A et al. (2003) Oxidative damage in colon and mammary tissue of the HFE-knockout mouse. Free Radic Biol Med 34:1212-6 |
