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. Determine how genetic differences interact with dietary antagonists of one-carbon nutrients in determining cancer risk. (PDRAM NAA09). 3. To determine how obesity enhances the risk of cancer, to find means of ameliorating this risk, and to define other factors that interact with obesity to further modify its effects. 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), 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 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 dietary intake interacts 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 progress report includes the work of two subordinate projects at the HNRCA funded through a Specific Cooperative Agreement with TUFTS UNIVERSITY. For further information and progress reposrts, 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 carcinogeneis).
1. LAB: Vitamins and carcinogenesis: A mild depletion of B vitamins activates the pro-cancerous Wnt signaling pathway and increases intestinal tumor development. There is overwhelming evidence from human studies that inadequate amounts of dietary folate—and perhaps some of the other B vitamins as well—increase the risk of colon cancer. However, the cellular pathway(s) responsible for mediating this effect is unknown. Previously, various cellular pathways have been cited as candidates but no compelling proof of a particular operable pathway has been published. ARS-funded researchers at JMUSDA-HNRCA at Tufts University in Boston, MA have demonstrated, for the first time, definitive evidence in intact laboratory animals that the pro-cancerous Wnt pathway is activated by B vitamin depletion in the colon and is accompanied by increased tumor development. Knowledge of the pathway responsible for this effect assists in the development of strategies that aim to reduce the burden of this cancer in our society.
2. LAB: Vitamins and carcinogenesis: Folate concentration in the human breast correlates with several molecular and clinical determinants of cancer risk. Epidemiological evidence suggests that in take of the B-vitamin folate may be a determinant of breast cancer risk, particularly among women who regularly imbibe alcohol. ARS-funded researchers at JMUSDA-HNRCA at Tufts University in Boston, MA measured folate levels in the breasts of approximately 150 women undergoing routine mammoplasty and found that the concentration of folate in the breast was inversely related to the cancer risk factors of alcohol and family history of breast cancer. Such a relationship was not evident with blood folate. Moreover, two common genetic variants in critical folate-dependent enzymes—when present in conjunction with low breast folate—was highly linked to abnormal and procancerous methylation of cancer-relevant genes in the breast tissue. These observations provide several new and potentially important insights into how low folate intake might increase the risk of breast cancer.
3. LAB: Vitamins and carcinogenesis: Caloric restriction attenuates alterations that age produces in gene methylation. Age is a major risk factor for several common cancers, and therefore considerable interest rests in determining how diet might attenuate those age-related factors that predispose to cancer. ARS-funded researchers at JMUSDA-HNRCA at Tufts University in Boston, MA conducted a mouse study that examined aging and caloric restriction as combined and independent factors. They examined critical sites of methylation (an important chemical modification of DNA that controls which genes get ‘turned on’) in approximately 23,000 genes and found that aging was associated with sizeable changes in methylation in selected sites. Among the most commonly affected genes were those involved in the processing of carbohydrates and fats. In most instances, caloric restriction significantly lessened, or entirely prevented, the age-related changes in methylation. Since aberrant methylation of critical genes is thought to be an important avenue by which some tissues become cancerous, this study suggests that caloric restriction can attenuate age-related cancer risk by preventing those age related changes.
4. LAB: Nutrition and cancer biology: Lycopene possesses anti-fatty liver and anti-cancer activity. One of the consequences of the current obesity epidemic is an increased prevalence of fatty liver disease. ARS-funded researchers at the JMUSDA-HNRCA at Tufts University in Boston, MA, provided strong evidence demonstrating that lycopenoic acid, a breakdown product of the lycopene, is protective against high fat diet-induced fatty liver. For the first time, research has demonstrated that the anti-fatty liver effect of lycopenoic acid was associated with the higher activity of the enzyme called SIRT1, which plays a key role in increasing fat oxidation and decreasing fat synthesis. This data indicates a novel role of the lycopenoic acid in the regulation of lipid metabolism in the liver. These findings have led to greatly increased interest in the role of tomato and tomato products for prevention of obesity associated pathologies, such as utilizing tomato products to prevent high fat diet/obesity related insulin resistance, oxidative stress, inflammation and cancers.
Liu, Z., Brooks, R., Ciappio, E., Kim, S., Crott, J., Bennett, G., Greenberg, A., Mason, J. 2011. Diet-induced obesity elevates colonic TNF-alpha in mice and is accompanied by an activation of Wnt signaling: a mechanism for obesity-associated colorectal cancer. Journal of Nutritional Biochemistry. Available: www.sciencedirect.com.