Abstract
A major opportunity for discovery in cancer prevention research is the identification of predictive biomarkers that can match the intervention with the patient likely to benefit. Dietary interventions that prevent carcinogenesis are thought to work by hitting multiple important molecular drivers. Such interventions include curry-derived curcumin and red wine-derived resveratrol as well as flavonol-containing legumes. Translational prevention studies by our team focus on dietary interventions to prevent colon carcinogenesis and discover predictive biomarkers in mice and humans. Bean-based diets shown to reduce adenoma recurrence in the Polyp Prevention Trial (Lanza et al 2006) also show chemopreventive activity in Ob/Ob and AOM/DSS induced mouse models. New intervention studies in genetically obese mice employ a bean-based diet being tested for attenuation of colon carcinogenesis following exposure to azoxymethane. The bean-based diet was chosen to mimic conditions in the recently completed polyp prevention trial in which human subjects consuming the highest quartile of beans (navy, lima, kidney, black etc) showed a 3-fold reduction in occurrence of advanced adenoma (E. Lanza and coworkers 2006, 2009). The whole beans and two bean fractions showed efficacy in attenuating tumor multiplicity (Bobe et al, Nutr Ca 2008). Recent studies have identified inflammation-associated cytokines including IL-6 as indicators of bean-diet efficacy (Mentor-Marcel et al Ca Prev Res 2009). Current studies are aimed at identifying functionally significant molecular targets of the bean diets under conditions of efficacy as well as predictive biomarkers. Non-invasive gene expression profiling of fecal colonocytes has revealed sets of 2 to 3 genes whose changes are indicative of risk (Zhao et al Ca Prev Res 2009). In collaboration with the Small Animal Imaging facility at NCI Frederick we have demonstrated with magnetic resonance imaging that the endpoints of inflammation, tumor promotion and tumor progression can be monitored during colon carcinogenesis in a mouse model (Young et al Neoplasia 2009). These imageable markers are being used to compare the effects of short term exposure to dietary interventions in preclinical studies. Short term human studies with the bean intervention showed significant improvements in serum markers of inflammation and insulin resistance (Hartman et al 2009-2011). In collaboration with Terry Hartman and coworkers (Penn State Univ) we have queried serum biomarkers for predictive value in short term controlled feeding intervention studies of men at risk of polyp recurrence in the Legume Intervention Feeding Experiment (LIFE) study. Serum levels of proinflammatory proteins decreased and serum lipid profiles improved in response to the bean-based diet (Hartman et al J Nutr 2010; Zhang Z et al Lipids 2010). The Obese mouse bean intervention study of biomarkers (Mentor-Marcel) turned out to agree with a recent analysis of the 4000 participant Polyp Prevention Trial samples. In both cases serum IL-6 levels were elevated in those at greatest risk of polyp recurrence (occurrence) and IL-6 levels were attenuated by the bean based diet in the complier group who benefited (Bobe et al Cancer Prev Res 2010).In the LIFE study the high legume low glycemic index diet reduces plasma leptin (Zhang et al, Eur J Clin Nutr 2011) as well as producing weight loss in overweight men. Ongoing metabolomics studies are expected to reveal not only biomarkers, but also targetable pathways. These findings are among the first to demonstrate biomarkers that can identify those likely to benefit from the dietary intervention with reduced colon polyp recurrence.
Citation Format: Nancy H. Colburn. Dietary interventions to prevent colon cancer and discover biomarkers in mice and humans. [abstract]. In: Proceedings of the Eleventh Annual AACR International Conference on Frontiers in Cancer Prevention Research; 2012 Oct 16-19; Anaheim, CA. Philadelphia (PA): AACR; Cancer Prev Res 2012;5(11 Suppl):Abstract nr ED03-03.
RSS Feeds