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).
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) 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.
3. Progress Report
Our work continues to be highly consistent with Component 2A of National Program 107. We have also begun work in the past year that is consistent with Component 3A. We have numerous projects designed to define which 1-carbon nutrients modify cancer risk, what underlying cellular pathways mediate these effects, and how other factors such as genetic background, age, and obesity further modulate these relationships. Have extended the scope of our mechanistic animal studies designed to define how B vitamin depletion accelerates colon cancer risk: we have succeeded in demonstrating that mild dietary inadequacies of these nutrients in gravid mice greatly increases the risk of colon cancer in the offspring (a so-called ‘transgenerational effect’), and we have initial evidence that the cellular pathway by which this effect proceeds is via the pro-carcinogenic Wnt signaling pathway, which we have previously shown to be the relevant pathway in intra-generational experiments. Our initial animal experiments designed to examine how the common genetic variant in a pivotal folate-processing enzyme (the ‘MTHFR variant’) modulates cancer risk are completed, and the analyses of endpoints are underway. We have also succeeded in setting up a Nimblegen system in our laboratory that enables us define epigenetic features on a genome-wide basis and are presently utilizing this to determine changes in gene-specific methylation in the murine colon that occur with aging, and with the ‘Western Diet’. Most recently, we have begun to examine mechanisms by which obesity and inflammation in mouse models enhances cancer risk in the colon because both of these factors appear to share a common final pathway with the means by which B vitamin depletion enhances carcinogenesis. To date, we have shown that obesity incites a low-grade inflammatory reaction in the colon, which in turn appears to inappropriately activate Wnt signaling. We are embarking on a translational study in Tufts Medical Center to examine the human relevance of our animal studies on obesity, inflammation and colon cancer risk. Our initial protocol will utilize a cross-sectional examination of lean and obese individuals undergoing routine screening colonoscopies. We have also completed several other translational studies in the past year. One such study aimed at determining whether the functionally important modification of DNA called ‘methylation’, which is diminished among individuals who possess the common MTHFR variant could be corrected with folic acid supplementation. It was found that among individuals already folate-replete, supplementation was ineffective in this regard. We also conducted a study of blood and tissue folate levels among men who had prostate cancer. Excessively high levels of blood folate correlated with exceptionally high levels of cellular proliferation in their prostate tumors. Finally, in a case-control study of cervical cancer we found that low folate levels predicted pre-cancerous and cancerous changes in the cervix, and the relationship was particularly robust among those who had low folate and/or B12 levels and who possessed the common MTHFR variant.
1. 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. 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. 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.