Research Project: Cancer Prevention via Diet

Location: Jean Mayer Human Nutrition Research Center On Aging

Project Number: 8050-51000-096-000-D
Project Type: In-House Appropriated

Start Date: Oct 1, 2014
End Date: May 13, 2019

Objective:
LAB NAME: Vitamins and Carcinogenesis 1: Define the role that intake, or nutrient status, of each of the one-carbon nutrients plays in determining the risk of common cancers and to examine select environmental and genetic factors that further modify the effects of 1-carbon nutrients. Through the use of cell culture, animal models and human studies, determine the cell-signaling pathways(s) through which the effects of 1-carbon nutrients is exerted, and elucidate genetic and epigenetic mechanisms by which this occurs. In animal models, also examine how parental intake of these nutrients influences cancer risk in offspring. 1.1: Determine the effect of maternal B vitamin intake on tumorigenesis in offspring. 1.2: Determine the effect of paternal B vitamin intake on tumorigenesis in offspring. 2: Define the cellular pathways by which obesity, and related factors, enhance cancer risk and explore means of attenuating that risk. By use of cell culture studies, animal models, and human studies, focus on how the chronic, low-grade inflammation produced by obesity incites molecular processes that lead to cancer. 2.1: Define the effects of obesity-induced elevations of colonic IL-1ß on Wnt and NF'B activation in the colonic mucosa of mice. 2.2: Determine the effect of genetic and immunologic blockade of IL-1ß on obesity-induced tumorigenesis. 2.3: Determine the effects of an orally-available inhibitor of Akt on obesity-promoted tumorigenesis in AOM-treated mice. 2.4: Determine whether obesity in humans raises pro-inflammatory cytokine levels in the colonic mucosa and whether the elevation in cytokines is accompanied by activation of mucosal Wnt and NF'B. LAB NAME: Nutrition and Cancer Biology 1: Determine the ability of carotenoid-enriched food, carotenoids, and apocarotenoids (carotenoid cleavage metabolites by beta-carotene 9’,10’-oxygenase, BCO2) to induce SIRT1 by regulating microRNAs for preventing obesity-related inflammatory responses and cancer development in liver and colon. 1.1: Determine the protective effects of tomato extract, lycopene and apolycopenoids against high-fat diet-induced inflammatory responses and tumorigenesis. 1.2: Investigate the ability of tomato carotenoid and apolycopenoids to modulate SIRT1 and its down-stream effectors as a unique mechanism for preventing inflammation and tumorigenesis. 1.3: Determine whether SIRT1 activity is required for the preventive action of tomato carotenoids and apolycopenoids. 1.4: Investigate the protective effect of beta-cryptoxanthin (BCX, a provitamin A carotenoid) against high sugar diet- induced NAFLD and liver cancer via gut/adipose/liver axis 1.5: Determine the biological functions of intact BCX in absence of carotene cleavage enzymes beta-carotene 15,15'-oxygenase 1 ( BCO1) and beta-carotene 9',10'-oxygenase (BCO2) double knock out (KO) mice. 1.6 Determine the SIRT1 activity as a molecular target for BCX protection against high sugar diet-induced NAFLD and liver cancer.

Approach:
LAB NAME: Vitamins and Carcinogenesis Alterations in dietary and nutritional habits have an important role to play in cancer prevention. The nutrients involved in 1-carbon metabolism (methionine, choline, and the B-vitamins, folate, B2, B6, and B12), as well as obesity have drawn considerable attention in this regard and are the focus of this laboratory. Our mission is to examine the complex roles that obesity and these 1-carbon nutrients play in modifying cellular pathways that lead to human carcinogenesis and thereby define means by which nutrition can be used to reduce the risk of developing cancer. The program of research emphasizes how dietary intake interacts with the genetic background to modify molecular and signaling pathways which alter the development of cancer, and to examine how other exogenous factors, such as alcohol consumption, also play a role. The laboratory focuses on colorectal and breast cancer, and utilizes cell culture studies, animal models, and human studies to accomplish our research goals. LAB NAME: Nutrition and Cancer Biology We will use both C57BL/6J mice and specific genetically-altered carotenoid cleavage enzyme (beta-carotene 9’,10’-oxygenase, BCO2) knockout mice strains to determine whether high-fat diet-induced liver inflammation and tumorigenesis can be prevented by apo-10’-lycopenoid (lycopene cleavage metabolite by BCO2), lycopene or tomato extract supplementation. We will examine the effects of dietary tomato carotenoids on modulating sirtuin 1 (SIRT1, a key metabolic sensor that directly links environmental nutrient signals to amelioration of inflammation as well as tumor development secondary to high-fat diet-induced obesity) expression/activity and its down-stream effectors, as well as its regulation by microRNAs in liver, intestine, colon and adipose tissues. We will use sirt1y/y homozygous mice that ablates the SIRT1 catalytic activity, as compared with their corresponding wild-type littermates, to determine the contribution of the tomato carotenoids and their metabolites to SIRT1 signaling pathway in liver, colon and adipose tissues, thus leading to the prevention of diet-induced obesity associated inflammation and cancer development.