1a. Objectives (from AD-416)
Determine the dietary modulation of obesity-related cancer by selenium. Specific objectives include 1) Characterize interactions of energy imbalance and dietary Se status on obesity-promoted carcinogenesis; 2) Elucidate the relationship of body mass index (BMI) and features of Se metabolism in selenoprotein genotypes differing in cancer risk.
1b. Approach (from AD-416)
This project will determine the extent to which Se counteracts the carcinogenic effects of obesity. It will do so by elucidating the effects of Se status on obesity-promoted mechanisms of carcinogenesis, and the relationships of BMI and Se metabolism among individuals of two genotypes known to differ in cancer risk. Two forms of dietary Se will be used: i) SeMet, the dominant form of Se in foods; ii) precursors of CH3SeH - CH3SeCys (catabolyzed to CH3SeH in the cell), the methylseleninic acid (MSeA) (reduced to CH3SeH in the cell), and the combination of SeMet + recombinant methionase (produces CH3SeH). The project utilizes the complementary expertise of the research team in molecular/cell biology and cell signaling (Zeng), experimental tumorigenesis (Yan, Zeng), human Se metabolism (Combs), and chemistry/ biochemistry (Jackson, Combs). The collaborative nature of the project is evident in the CH3SeH metabolism/action theme that connects the two objectives. This research builds on in-depth expertise and existing collaborations to investigate a highly relevant problem hitherto not addressed. The Grand Forks Human Nutrition Research Center provides this team of investigators with an experienced professional infrastructure for the efficient recruitment and management of human subjects and the controlled use of animal and cell models.
3. Progress Report
This is the annual report for the new OSQR-approved Project 5450-51000-045-00D that replaces Project 5450-51000-044-00D. (See separate annual report terminating that project.) This new project focuses on the prevention of obesity-related cancer. We have centered our work on that focus since the project was approved. To determine the extent to which Se reduces/counteracts the effects of obesity related signaling in colon cancer tumorigenesis, we are examining the effect of physical forms (power, pellet) of animal diets on diet-induced obese mice; development of colon xenograft cancer mouse model; selection of the leptin-sensitive colon cells. To determine the extent to which moderate physical activity enhances the protective effect of dietary Se on obesity-enhanced secondary tumorigenesis, we completed animal feeding for 2 experiments on voluntary physical activity and secondary tumor development using an i.v. injection model and an s.c. injection model in mice. Our preliminary results showed that voluntary physical activity (an average run of 5 km/d on an in-cage running wheel) resulted in significant decreases in body weight and abdominal fat weight, but it did not affect the secondary tumor yield compared with sedentary mice. To determine the extent to which Se status is inversely associated with risk factors of obesity, we completed data collection for correlation analysis of Se status and biomarkers of chronic inflammation (preliminary human subject retrospective; Study HS009, GFHNRC). We also finished a human study design and initiated IRB proposal preparation for new human subject cross sectional study. To determine the extent to which obesity exacerbates the altered Se metabolism in individuals, we finished a study design (housed within cross-sectional study, Hypothesis 2.A) and initiated IRB proposal preparation for new human subject cross sectional study; In addition, we initiated data collection for retrospective analysis of the effect of obesity-associated liver dysfunction on Se distribution in archived animal samples derived from previous obesity studies and human liver cell culture experiments.
1. It has been well documented that obesity increases the cancer risk. However, there are very few effective animal cancer models and human bioassays which allow us to study obesity related cancer risk. Recently, we have developed several cancer mouse models (colon and seconday cancer) using transplantable cancer cells. In addition, we have established several new assays to study selenium metabolism in the obese population. These models and human bioassays will allow us to characterize interactions of energy imbalance and dietary Se status on obesity-promoted cancer. The information is useful for policy makers and researchers in identifying effective practices that reduce obesity related cancer risk.
5. Significant Activities that Support Special Target Populations
We found that Se status is inversely associated with risk factors of obesity, and believe that the study on Se status of obese population is urgently needed.