2012 Annual Report
1a.Objectives (from AD-416):
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.
1b.Approach (from AD-416):
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.
We have a number of projects designed to define which of the ‘1-carbon nutrients’ (eg: vitamins B2, B6, B12, folate, methionine and choline) modify cancer risk, what underlying cellular pathways mediate these effects, and how related factors such as genetic background, the stage of the lifecycle, alcohol consumption, and obesity further modulate these relationships. Last year we reported that we had succeeded in demonstrating that mild dietary inadequacies of these nutrients in pregnant mice greatly increases the risk of colon cancer in the offspring (a so-called ‘transgenerational effect’), and we are presently conducting studies to identify the molecular basis of this effect. In addition, we have initiated studies to determine whether inadequate intake of these nutrients in the father also impacts the risk of colon cancer in the offspring. We are also very interested in the other end of the lifecycle: elder age alone, and how dietary intake and elder age interact to determine cancer risk. In this regard we are finishing up analyses of a mouse study in which we examined how the aging process and caloric restriction interact to determine changes at critical sites of methylation across the entire genome.
Over the past two years we have begun to examine mechanisms by which obesity--and the chronic inflammation that accompanies it--enhances cancer risk in the colon. We have shown that obesity incites a low-grade inflammatory reaction in the colon, which in turn appears to inappropriately activate Wnt signaling. Initially we became interested in obesity because it appears to share a cellular pathway with B vitamin depletion in its enhancement of carcinogenesis. However, as a laboratory focused on dietary factors relevant to the U.S. population that impact on cancer risk, we have become interested in obesity as a factor unto itself and we have now submitted a request to add an additional CRIS objective that specifically addresses the issue of obesity-induced cancer. We will undertake additional animal studies and a translational study that will examine the relevance of these mechanistic issues among obese and lean human subjects who are undergoing routine screening colonoscopies.
Folate concentration in the human breast correlates with several molecular and clinical determinants of cancer risk. Epidemiological evidence suggests that intake 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, Massachusetts 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 pro-cancerous 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.
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, Massachusetts 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.
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, Massachusetts 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.