1a. Objectives (from AD-416)
LAB: VITAMINS & CARCINOGENESIS 1. To define the role that availability of each of the one-carbon nutrients plays in determining the risk of common cancers and to determine the nature of the interactions between these nutrients in this regard. 2. To determine how dietary antagonists (such as alcohol) of one-carbon nutrients further modify the effects of these nutrients in determining cancer risk. 3. To determine how genetic make-up, and other select factors, interact with intake of these nutrients in determining cancer risk. LAB: NUTRITION & CANCER 1. Determine whether high fat diet induced non-alcoholic steatohepatitis is a promoting factor in hepatic carcinogenesis. 2. Determine whether dietary lycopene will protect against high fat diet promoted liver cancer development.
1b. Approach (from AD-416)
LAB: VITAMINS & CARCINOGENESIS Appropriate alterations in dietary and nutritional habits have an important role to play in cancer prevention. The nutrients involved in one-carbon metabolism (methionine, choline and the B-vitamins, folate, B12, B6, and B2) have drawn considerable attention in this regard and are the focus of this laboratory. Our mission is to examine the complex roles that these nutrients play in modifying metabolic and genetic pathways that lead to human carcinogenesis and thereby define the means by which cancers can be nutritionally prevented. The program of research emphasizes how these dietary compounds interact with genetic background to modify molecular and signaling pathways which alter the development of cancers and to examine how other exogenous factors, such as alcohol consumption also play a role. The laboratory focuses on colorectal cancer and breast cancer and utilizes animal studies, cell culture studies, and human studies to accomplish our research goals. LAB: NUTRITION & CANCER We will use both high fat diet-induced nonalcoholic steatohepatitis (NASH) rats and genetically-induced obese mice with injections of liver-specific carcinogen, diethylnitrosamine, followed by treatment with tomato extract or lycopene for both short and long durations. We will focus on the role of the stress-activated protein c-Jun-NH2-kinase (JNK) signaling, a key component mediating the high fat-induced oxidative stress and inflammatory processes, in response to tomato extract and lycopene supplementation on both cell proliferation/apoptosis, inflammation and premalignant and malignant lesions in obesity related hepatic tumorigenesis. We will complement animal study with cell culture studies (e.g., use siRNA silencing of JNK) using human hepatocyte lines and liver cancer cells to facilitate mechanistic studies to determine the contribution of the JNK signaling pathway to lycopene action. Since adiposity contributes to the increased incidence and/or death from liver cancer, we will examine metabolic alteration, including insulin resistance, and pro-inflammatory signaling in intra-abdominal fat tissue and its potential contribution to hepatic carcinogenesis. Once we establish that there is an association between metabolic alteration and hepatic carcinogenesis, we will examine insulin and insulin growth factors (IGF-I/IGF-II) signaling cascades and address their differential activation in NASH and its related hepatic carcinogenesis, as well as potential actions of tomato extract and lycopene prevention against the onset of high fat diet/obesity-related liver disease.
3. Progress Report
This project includes the work of two subordinate projects at the HNRCA funded through a Specific Cooperative Agreement with Tufts University. For further information and progress reports, see 1950-51000-074-01S, (One-Carbon Nutrients in the Prevention of Cancer) and 1950-51000-074-02S, (Nutritional Determinants of Non-Alcoholic Steatohepatitis in Hepatic Carcinogenesis).
1. Higher concentrations of B-vitamins in the human breast are associated with increased activity of an anti-cancer gene (LAB: Vitamins & Carcinogenesis). ARS-funded researchers from Tufts University in Boston, MA examined some of the factors that determine how readily an anti-cancer gene called p16 is expressed in the human breast since adequate expression of this gene is critical in preventing the evolution of cancer. Higher tissue levels of the B-vitamin folate concurred with less inhibition of expression of the p16 gene. Abstinence from alcohol, prior pregnancy, and no family history of breast cancer were each predictive of higher breast folate levels. This provides insight into how adequate amounts of folate in the diet might convey protection against breast cancer.
2. Providing mother mice with supplemental levels of 1-carbon vitamins during pregnancy suppresses the risk of developing intestinal cancer in the offspring. (LAB: Vitamins & Carcinogenesis). ARS-funded researchers from Tufts University in Boston, MA conducted a study in mice that demonstrated that maternal intake of B-vitamins during pregnancy is an important determinant of the risk of developing intestinal cancer in offspring. They demonstrated that it required levels of B-vitamin intake that far exceeded the basal requirement of the adult mouse to optimally suppress tumorigenesis in the offspring. These observations should assist in the future design of optimal diets during pregnancy.
3. Common variants in human genes that determine blood uracil levels do not predict breast cancer risk (LAB: Vitamins & Carcinogenesis). ARS-funded researchers from Tufts University in Boston, MA have previously shown that some common variants in genes that are involved in the cellular disposal of an undesirable building block of DNA, uracil, predict how much uracil is inadvertently incorporated into DNA. A large case-control study of breast cancer was therefore examined and it was found that these common variants (‘polymorphisms’) did not predict the risk of breast cancer. This was true even when folate status, which partly determines uracil levels, was taken into account. In order to efficiently prevent common cancers it is helpful to identify those in the population who have a genetically-based hazard of developing those cancers. This study showed that four gene variants that were candidate risk factors did not, in fact, predict the likelihood of breast cancer and therefore we have shown that they are not suitable indicators of cancer risk.
4. A High-fat Diet May Promote Liver Cancer (LAB: Nutrition and Cancer Biology). One of the consequences of the current obesity epidemic is increased rates of nonalcoholic fatty liver disease, a chronic liver disease in adults and children. This ultimately leads to cirrhosis and end-stage liver disease, such as liver cancer. The increasing incidence of liver cancer in the United States has paralleled the epidemic of obesity. Several large population studies have revealed that obese people have a higher risk of incidence or mortality of liver cancer, however, there is still a need for data on the relationship between inflamed liver, and liver cancer. ARS-funded researchers from Tufts University in Boston, MA were the first to use an animal model to demonstrate that a high-fat diet induced nonalcoholic steatohepatitis (NASH) promotes liver cancer development. This animal study will provide the foundation to develop effective dietary components for the prevention of obesity/NASH related liver disease including cancer.
5. Lycopene, a Nutrient in Tomatoes, May Inhibit Some Forms of Liver Cancer (LAB: Nutrition and Cancer Biology). The beneficial effects of carotenoid-rich fruits and vegetables on cancer risk have been found in many studies, with strong evidence that tomatoes and tomato products as well as tomato carotenoids (lycopene, phytoene, and alpha-tomatine) have important health benefits. Although there is strong supporting evidence from both animal and cell culture studies that these carotenoids inhibit liver tumor growth, our understanding of how carotenoids function against tumorigenesis, particularly against obesity-related hepatic tumorigenesis, is far from complete. ARS-funded researchers from Tufts University in Boston, MA were the first to show in an animal model that lycopene and tomato extract inhibit nonalcoholic steatohepatitis (NASH)-promoted liver cancer. These findings are crucial in order to determine the prevention efficacy of carotenoids in inhibting obesity/high fat diet promoted liver cancer development.Mason, J.B. 2010. Nutritional assessment and management of the malnourished patient. In: Feldman, M., Friedman, L.S., Brandt, L.J., editors. Gastrointestinal and Liver Disease. 9th edition. Philadelphia, PA: Saunders Elsevier. p. 47-75.