Project Number: 1950-51000-064-00
Project Type: Appropriated

Start Date: May 01, 2004
End Date: Apr 30, 2009

Objective:
LAB:Vitamins and Carcinogenesis To determine the complex roles the 'one-carbon nutrients', (methionine, choline and the B-vitamins, folate, B12, B6, and B2), as well as components of the diet that are one-carbon antagonists (such as alcohol) play in modifying metabolic and genetic pathways that lead to human cancer. To define how the mechanistic knowledge acquired through objective #1 should be used to modify dietary habits, nutritional supplementation, and other nutritional interventions in order to prevent cancer. New advances made by this laboratory can thus be translated into public health initiatives that effectively reduce the burden of cancer in our society. To define the biochemical, molecular and pathophysiologic processes that underlie the apparent effects of vitamin D and calcium in the modulation of cancer development, and to examine how genetic background and environmental factors further impact these effects. Lab: Cancer Biology To establish the dose response effects of lycopene in plasma and lung tissue with and without smoke exposure. To establish the potential for lycopene inhibition of smoke-induced lung lesions and mechanism(s) of action To charecterize both the expression and activity of carotene 9', 10'-monooxygenase in the metabolism of lycopene with and without smoke exposure, and the biological effect of the metabolite(s) of lycopene.

Approach:
LAB:Vitamins and Carcinogenesis Mechanistic questions will largely be examined in studies utilizing cell cultures and animal models. We have several cell lines derived from normal human colonic epithelial cells. The availability of one-carbon nutrients for these cells can easily be manipulated to examine the consequences of limited, or supplemental, levels of nutrient availability. A variety of mouse models will also be used to examine the consequences of limited nutrient availability, including genetically engineered animals who either have a predisposition towards colon cancer or a polymorphism in a folate-dependent enzyme. Studies conducted in human volunteers, in which they undergo folate depletion for several weeks, will also be used to examine mechanistic questions, whereas intervention trials, where people at enhanced risk of colon cancer are randomly chosen to receive folate or placebo, will be used to translate this mechanistic work into answers regarding the possible utility of folate in the prevention of cancer. LAB:Nutrition and Cancer Biology We will investigate the chemopreventive efficacy of lycopene against lung and prostate carcinogenesis in a ferret model (which is highly analogous to humans) under a variety of different circumstances (low and high doses of lycopene, with and without exposure to tobacco smoke, lung vs. prostate). We then would like to extend our work to an in vitro cell culture model, which allows in-depth mechanistic studies and examines whether the induction of IGFBP-3 with lycopene or its metabolites affect kinase activity in the IGF-I/Ras/PI3K/Akt or MAP Kinase pathways. Lastly, we will examine lycopene metabolism in different tissues (lung, liver, prostate, colon and stomach) and in the lycopene treated lung cells (normal cells vs. transformed cells) by examining carotene 9',10'-monooxygnase expression/function and its regulation by varying treatments.