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 ocurrence 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 funtionally 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. Recently, 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. Interventions with berries (Mentor-Marcel et al Nutr Ca 2012) or the flavonoid isorhamnitin (Saud et al Cancer Res 2013) under conditions that prevent colon carcinogenesis in humans or mice revealed potentially predictive biomarkers. In addition emerged the surprising finding that isorhamnitin exerts its chemopreventive activity by targeting the endogenous inhibitor of oncogenic Src CSK. These findings are among the first to demonstrate biomarkers as well as pathways that can identify those likely to benefit from the dietary intervention with reduced colon polyp recurrence.

Agency
National Institute of Health (NIH)
Institute
National Cancer Institute (NCI)
Type
Investigator-Initiated Intramural Research Projects (ZIA)
Project #
1ZIABC011159-05
Application #
8763373
Study Section
Project Start
Project End
Budget Start
Budget End
Support Year
5
Fiscal Year
2013
Total Cost
$191,925
Indirect Cost
Name
National Cancer Institute Division of Basic Sciences
Department
Type
DUNS #
City
State
Country
Zip Code
Mitsunaga, Makoto; Kosaka, Nobuyuki; Choyke, Peter L et al. (2013) Fluorescence endoscopic detection of murine colitis-associated colon cancer by topically applied enzymatically rapid-activatable probe. Gut 62:1179-86
Saud, Shakir M; Young, Matthew R; Jones-Hall, Yava L et al. (2013) Chemopreventive activity of plant flavonoid isorhamnetin in colorectal cancer is mediated by oncogenic Src and *-catenin. Cancer Res 73:5473-84
Young, Matthew R; Ileva, Lilia V; Bernardo, Marcelino et al. (2009) Monitoring of tumor promotion and progression in a mouse model of inflammation-induced colon cancer with magnetic resonance colonography. Neoplasia 11:237-46, 1p following 246
Mentor-Marcel, Roycelynn A; Bobe, Gerd; Barrett, Kathleen G et al. (2009) Inflammation-associated serum and colon markers as indicators of dietary attenuation of colon carcinogenesis in ob/ob mice. Cancer Prev Res (Phila Pa) 2:60-9
Zhao, Chen; Ivanov, Ivan; Dougherty, Edward R et al. (2009) Noninvasive detection of candidate molecular biomarkers in subjects with a history of insulin resistance and colorectal adenomas. Cancer Prev Res (Phila Pa) 2:590-7
Kim, Young S; Young, Matthew R; Bobe, Gerd et al. (2009) Bioactive food components, inflammatory targets, and cancer prevention. Cancer Prev Res (Phila Pa) 2:200-8
Bobe, Gerd; Barrett, Kathleen G; Mentor-Marcel, Roycelynn A et al. (2008) Dietary cooked navy beans and their fractions attenuate colon carcinogenesis in azoxymethane-induced ob/ob mice. Nutr Cancer 60:373-81