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). 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 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 report, see 1950-51000-074-01S (One-Carbon Nutritients in the Prevention of Cancer) and 1950-51000-074-02S (Nutritional Determinants of Non-Alcholoic Steatohepatitis in Hepatic Carcinogenesis).
1. LAB: Vitamins and Carcinogenesis. Supplementation with B Vitamins in Pregnant Mice Protects Offspring from Intestinal Cancer. Previously, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, indicated that B-vitamin supplementation of pregnant mice protects, while mild depletion enhances, intestinal tumorigenesis in offspring. The investigators have now had the opportunity to explore some of the mechanisms by which this effect appears to be mediated. They have shown that a maternal diet mildly deficient in B vitamins produces alterations in some of the components of the so-called Wnt signaling pathway, a biochemical pathway contained in the cells that line the colon that is pro-cancerous in nature when it is overly activated. They also collaborated with an investigator at another university and examined the same issue in a different mouse model of colon cancer: the same protection against colon cancer with folate supplementation was observed, confirming the validity of the results from the first study. Unraveling the pathways through which the benefits of folate supplementation are mediated should assist in the intelligent design of public health guidelines as to the optimal diet for pregnant women.
2. LAB: Vitamins and Carcinogenesis. A relationship between high folate levels in the blood and the rate of cellular division in prostate cancers. Although adequate intake of folate is felt to protect against cancer in several tissues, it is hypothesized that an excess intake of folate in individuals who already harbor pre-cancerous or cancerous tumors may paradoxically accelerate the course of that cancer. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, in collaboration with investigators at another academic institution, found that blood folate levels correlate well with folate levels in the human prostate. Moreover, among men whose prostates had been removed for cancer, those individuals with the highest levels of blood folate had a much higher rate of cellular proliferation in their tumors, which is a measure of tumor aggressiveness. This observation is consistent with the idea that high intake of folate may accelerate the expansion of prostate cancers in men and indicates that folate supplementation should be avoided in men with a history of prostate cancer.
3. LAB: Vitamins and Carcinogenesis. The association of folate and vitamin B12 levels with cancerous changes in the uterine cervix of Korean women. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, collaborated informally with Korean National Cancer Institute investigators to analyze the data for a multicenter study of approximately 900 Korean women, about half of whom were normal controls and the remainder of whom had various stages of pre-cancerous or cancerous changes in their uterine cervix. A low level of the B vitamin, folate, in the blood was associated with a higher risk of having cervical cancer. Moreover, low blood levels of either folate or vitamin B12 in conjunction with a common genetic variant in an important B-vitamin enzyme were associated with an especially high likelihood of pre-cancerous or cancerous changes in the cervix. The results of this study emphasize the importance of genetic interactions of dietary folate and vitamin B-12 in the cervical cancer development.
4. LAB: Nutrition and Cancer Biology. Tomato possesses anti-inflammatory activity. One of the consequences of the current obesity epidemic is an increased prevalence of nonalcoholic fatty liver disease (e.g., nonalcoholic steatohepatitis), which has paralleled the increased incidence of liver cancer in the USA. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, provided strong evidence demonstrating that tomato extract supplementation is protective against high fat diet-induced inflammation and the development of preneoplastic lesions in the livers. The potential mechanism underlying the anti-inflammatory efficacy manifested by tomato extract is most likely due to a combined or synergistic effect of multiple constituents in tomatoes (e.g., tocopherols, phytoene and phytofluene). This project generated a great interest in role of nutrition in the cancer prevention field to study whether and how tomato extract prevent high fat diet/obesity related insulin resistance, oxidative stress, inflammation and cancers. These data show a high potential of tomato extract in cancer prevention.
5. LAB: Nutrition and Cancer Biology. New pathway of non-provitamin A carotenoid metabolism is discovered: It is acknowledged that for provitamin A carotenoids, such as, beta-carotene, central cleavage by carotene 15,15’- oxygenase is a major pathway leading to vitamin A formation. ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, demonstrated that excentric cleavage of the carotenoid molecule by carotene-9’,10’-oxygenase, is a major metabolic pathway for non-provitamin A carotenoids, such as lutein and lycopene. This work identified a new role of non-provitamin A carotenoids in cancer prevention and opened a new avenue in carotenoid research in mammals.
6. LAB: Nutrition and Cancer Biology. Beta cryptoxanthin is an effective preventive agent against smoke-induced lung inflammation. To determine if carotenoids other than beta carotene may account for the protective effects of fruits and vegetables on lung cancer risk seen in observational studies, ARS-funded researchers at JMUSDA-HNRCA at Tufts University, Boston, MA, demonstrated that one specific carotenoid, beta cryptoxanthin, was significantly associated with reduced risk of lung cancer among smokers. Our studies both in vivo and in vitro also support the notion that the beneficial effects of beta cryptoxanthin in smokers is unique and beta cryptoxanthin is an effective preventive agent, rather than beta carotene or other carotenoids. These findings have significant impact on cancer prevention strategies.
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Sauer, J.A., Hyeran, J., Zimmerly, E., Kim, K., Liu, Z., Chason, A., Smith, D., Mason, J., Friso, S., Choi, S.W. 2010. Ageing, chronic alcohol consumption and folate are determinants of genomic DNA methylation, p16 promoter methylation and the expression of p16 in the mouse colon. British Journal of Nutrition. 104(1):24-30.
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