Every year, nearly 300,000 people worldwide are diagnosed with oral cancer. This type of cancer has the highest incidence in people who use tobacco, including cigarettes, but the means by which tobacco promotes the development of oral cancer is unknown. Researchers at the Jean Mayer USDA Human Nutrition Research Center on Aging (USDA HNRCA) at Tufts University are investigating whether nutritional factors may be involved. A causal link has not been established, but their results provide early insights into the complex relationships among oral cancer, smoking, and two groups of nutrients: folates and select antioxidants. Folate levels are different in smokers and non-smokers, according to Joel Mason, MD, director of the USDA HNRCA's Vitamins and Carcinogenesis Laboratory and assistant professor at the Friedman School of Nutrition Science and Policy at Tufts. Mason and colleagues, who reported their results in the American Journal of Clinical Nutrition, analyzed the diets and studied blood and cheek cells of 56 men and women between 30 and 80 years of age. Approximately half of these were chronic smokers, defined by a history of smoking at least 10 cigarettes daily for at least the past year. "Regardless of dietary intake, smokers had lower levels of folate in both blood and cheek cells, compared with non-smokers," says Mason. These findings confirm those of previous studies. Also consistent with previous research results, cheek cells of smokers had significantly more genetic aberrations called micronuclei, which indicate increased risk of oral cancer. Mason notes that these observations raise the question, "does cigarette smoke promote cancer by depleting cells of folate?" Folate is a B vitamin found in leafy green vegetables and fortified foods that not only helps create and preserve cells, but is also critical for synthesis of DNA; the latter serves as a universal set of blueprints for cells and which, if sufficiently altered, often leads to cancer. "It's possible that diminishing folate in cells may cause the cellular milieu to change, inducing the formation of cancerous cells," says Mason. "However, based on our findings," Mason says, "it does not appear that folate depletion induced by smoking is a major avenue for the formation of the genetic aberrations (micronuclei) that increase risk of oral cancer." He explains, "Oral micronuclei and low oral folate are each linked with smoking, but they were not related to each other in this study." Mason notes there are other possibly relevant pathways involving folate, however, which were not examined in this study. In addition to measuring total levels of folate, Mason and colleagues took their analysis a step further. "Folate exists in several different forms, so we also measured the levels of each form present in the cheek cells," corresponding author Jimmy Crott, PhD, scientist in the Vitamins and Carcinogenesis Laboratory at the USDA HNRCA explains. Compared to cheek cells of non-smokers, those of smokers had higher levels of some forms and lower levels of others. Crott stresses that it is not known if the altered distribution of various forms of folate contribute to carcinogenesis. "However," he continues, "it is thought that imbalances in different forms of folate may partly explain why low folate availability enhances cancer risk." Overall, Mason says, "our observations do not support a mechanistic role for folate in development of oral cancer. However, they do not exclude a potential protective role of adequate folate intake or supplementation." He says that "additional studies are clearly needed to elucidate mechanisms responsible for the observed shifts in folate form distribution due to smoking." In a study using the same participants, Elizabeth Johnson, PhD, scientist in the Carotenoids and Health Laboratory at the USDA HNRCA and an assistant professor at the Friedman School, and colleagues, conducted similar analyses looking at nutrients such as carotenoids and vitamin E. Carotenoids, plant pigments found in fruits and vegetables, and vitamin E, a fat-soluble vitamin found in nuts, seeds, and vegetable oils, are both antioxidants, which protect cells from damage. Compared to non-smokers, chronic cigarette smokers had lower levels of carotenoids, such as beta-carotene, in blood and cheek cells. As in the folate study, however, a direct nutrient-cancer link could not be established because the carotenoid levels in the mouth did not correspond with the number of micronuclei, or genetic aberrations, that indicate increased risk of cancer. Johnson and colleagues also found that, in non-smokers, blood and cheek cell levels of carotenoids were correlated. If levels were high in blood, they were also high in oral tissue. This correlation was not found in smokers. Johnson points out that this difference suggests that tobacco may alter the distribution of some nutrients. Further evidence is the finding that smokers tended to have higher levels of a form of vitamin E common in food, called gamma-tocopherol, compared with non-smokers. Levels of alpha-tocopherol, the more easily absorbed form of vitamin E in the body, however, were lower in smokers than in non-smokers. "We can only speculate," Johnson says, "but perhaps this is a protective mechanism in which one form of the antioxidant vitamin goes up when another goes down." The authors note that epidemiologic observations show that smokers tend to eat diets lower in fruits and vegetables than do non-smokers. However, in both the folate study and the antioxidant study, differences detected in nutrient levels between smokers and non-smokers were not attributable entirely to diet. "So," Johnson concludes, "although our results do not support a direct role for these nutrients in oral carcinogenesis, we uncovered some interesting relationships between smoking and nutrient distribution that deserve further exploration." ### Gabriel HE, Crott JW, Ghandour H, Dallal GE, Choi SW, Keyes MK, Jang H, Liu Z, Nadeau M, Johnston A, Mager D, Mason JB. American Journal of Clinical Nutrition 2006 (April); 83(4): 835-841. "Chronic cigarette smoking is associated with diminished folate status, altered folate form distribution, and increased genetic damage in the buccal mucosa of healthy adults." Gabriel HE, Liu Z, Crott J, Choi SW, Song BC, Mason JB, Johnson EJ. Cancer Epidemiology, Biomarkers & Prevention 2006 (May); 15: 993-999. "A comparison of carotenoids, retinoids and tocopherols in the serum and buccal mucosa of chronic cigarette smokers versus non-smokers." If you are interested in learning more about these topics, or speaking with a faculty member at the Friedman School of Nutrition Science and Policy at Tufts University, or another Tufts health sciences researcher, please contact Siobhan Gallagher at 617-636-6586 or Peggy Hayes at 617-636-3707. The Gerald J. and Dorothy R. Friedman School of Nutrition Science and Policy at Tufts University is the only independent school of nutrition in the United States. The school's eight centers, which focus on questions relating to famine, hunger, poverty, and communications, are renowned for the application of scientific research to national and international policy. For two decades, the Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University has studied the relationship between good nutrition and good health in aging populations. Tufts research scientists work with federal agencies to establish the USDA Dietary Guidelines, the Dietary Reference Intakes, and other significant public policies. Contact: Siobhan Gallagher

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