![[Feedback]](/icons/banner/feedbackACT.gif){kind=icon}
![[For Subscribers]](/icons/banner/subscriberACT.gif){kind=icon}
![[Archive]](/icons/banner/archiveACT.gif){kind=icon}
![[Search]](/icons/banner/searchACT.gif){kind=icon}
![[Contents]](/icons/banner/tocACT.gif){kind=icon}
|
|
|
|
|
||
Vitamin D and Cancer Risk: What Do We Know? Kay Colston. St. George's University of London, London, UK.
It is becoming increasingly clear that environmental factors, through interacting with genetic components, play a significant role in the development of cancer. The impact of diet on cancer risk has recently come significantly to the fore with a number of studies establishing relationships between diet and cancer initiation and progression. Members of the nuclear receptor superfamily of transcription factors bind to lipid-derived hormonal and dietary factors and regulate gene targets. The vitamin D receptor was originally described for its central endocrine role in the maintenance of serum calcium levels, but the expression of this receptor protein in nonclassical tissues such as the prostate and breast suggests a broader role. A large body of evidence has clearly shown that the active form of vitamin D, 1,25-dihydroxyvitamin D [1,25(OH)2D] and its synthetic analogs have antiproliferative effects in a wide variety of cancer cell lines. Such actions are associated with regulation of cell cycle progression and induction of apoptosis. Parallel studies examined the ability of dietary and pharmacological vitamin D compounds either to prevent tumor formation in animal models or inhibit progression of established tumors. Epidemiological studies demonstrated that the intensity of local sunlight is inversely correlated with risk of certain cancers including breast, prostatic, and colorectal carcinoma. These findings suggest that decreased availability of vitamin D or its active metabolite may lead to increased risk for the development of these cancer types. Concentrations of 25OHD3, the major circulating metabolite of vitamin D, are directly related to dietary vitamin D intake and cutaneous synthesis in response to sunlight exposure and serve as an index of vitamin D status. Low circulating concentrations of 25OHD have been associated with risk of a number of cancer types including breast and prostate. A proposed mechanism for the protective effects of sunlight on prostate and breast cancer risk involves the generation of 1,25(OH)2D from 25OHD in breast and prostate cells. Evidence also shows that genetic variation in the vitamin D receptor may modify risk for these cancers. Taken together, these various studies suggest a relation between adequate vitamin D status and lower risk of certain cancers.
Obesity and Cancer Risk: An Overview. Eugenia E. Calle. American Cancer Society, Atlanta, GA.
The prevalence of obesity is increasing rapidly in the United States and globally. Although the effects of obesity on all-cause mortality, cardiovascular disease, and diabetes are well described, the relation of excess body weight to specific cancers and to the overall cancer burden is not fully characterized. Associations between obesity and human cancer have been recognized for endometrial cancer (1960s); postmenopausal breast cancer (1970s); adenocarcinoma of the esophagus (1980s); and cancers of the colon, kidney, and gallbladder (1990s). More recent epidemiologic evidence suggests that cancers of the liver and pancreas are obesity related and that obesity might also increase risk of hematopoietic cancers and aggressive prostate cancer. In a large American Cancer Society cohort study of over 900,000 adults, the heaviest men and women (body mass index 
40) had death rates from all cancers combined that were 52–62% higher than rates in normal-weight men and women. Based on associations observed in that study, we estimate that current patterns of overweight and obesity in the United States could account for 14% of all cancer deaths in men and 20% in women and that maintenance of optimal body weight throughout adult life could prevent 90,000 cancer deaths annually in the United States. Studies examining the specific effect of adiposity on prognostic factors, recurrence, and survival are most prevalent for cancer of the female breast and, more recently, prostate cancer. Studies of adiposity and prognosis are scarce for other sites. The mechanisms by which obesity is postulated to induce or promote tumorigenesis vary by site. For cancers of the breast (in postmenopausal women) and endometrium, the effects of overweight and obesity on cancer risk are largely mediated by increased estrogen levels. However, insulin resistance may also play a role in the development of breast cancer in premenopausal women and in the progression of disease. Insulin resistance develops as a metabolic adaptation to increased levels of circulating free fatty acids released from adipose tissue, especially intraabdominal adipose. This is generally compensated by increased pancreatic insulin secretion. Mounting epidemiologic evidence indicates that chronic hyperinsulinemia increases risk of cancers of the colon and endometrium and probably other tumors (e.g., of the pancreas and kidney). Localized inflammation causes the development of Barrett's esophagus and adenocarcinoma of the distal esophagus as a result of gastroesophageal reflux of gastric acid and bile into the esophagus. Chronic cholecystitis from gallstones promotes the development of biliary tract cancers. The role that leptin, adiponectin, and other proteins secreted by adipocytes may have in the development and progression of tumors is an active area of research.
ß-Carotene, Smoking, and Lung Cancer. Margaret E. Wright and Demetrius Albanes. Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, MD.
Over the past 2 decades, there has been considerable controversy regarding the chemopreventive efficacy of ß-carotene, particularly with respect to lung carcinogenesis. A wealth of observational data indicate that higher dietary intakes and serum levels of ß-carotene, as well as increased consumption of foods rich in ß-carotene, are associated with reductions in lung cancer risk; this has been observed in men and women; in nonsmokers, former smokers, and current smokers; and for all histological types of lung cancer. Three well-designed, randomized controlled trials, the Physician's Health Study I (PHS), the 
-Tocopherol, ß-Carotene Cancer Prevention (ATBC) Study, and the Carotene and Retinol Efficacy Trial (CARET), however, failed to confirm these findings, with the latter 2 showing unexpected increases in lung cancer incidence, particularly in the heaviest smokers. It is unclear why the observational and trial data yielded divergent results, although differences may be caused by 1) use of single-nutrient supplements versus nutrients obtained in combination from foods, 2) several years of intervention later in life versus habitual dietary intake, and 3) methodological issues related to study design (e.g., confounding and measurement error in observational studies). In vitro and animal studies, particularly those conducted in ferrets, have begun to yield potential biological explanations for the aforementioned adverse effects in the controlled clinical trials. Although ß-carotene is a powerful antioxidant nutrient at low doses, such as those obtained through the diet, it appears to exert different biological effects at higher concentrations, including induction of cytochrome P450 enzymes and down-regulation of retinoic acid signaling. We are investigating these findings in lung tumors from the ATBC Study. Using immunohistochemical approaches, we are comparing the expression of various molecular markers of lung carcinogenesis in tumors and adjacent nontumor lung tissues among men who were randomly assigned to the placebo or ß-carotene trial groups. Future research should continue to elucidate the molecular mechanisms underlying the paradoxical effects of ß-carotene and whether other phytochemicals found in carotenoid-rich foods, either alone or in combination, may be more efficacious chemopreventive agents.
Alteration of Retinoid Metabolism and Signaling by Tobacco Smoke and Alcohol Consumption: Implications for Cancer Risk. Xiang-Dong Wang. Nutrition and Cancer Biology Laboratory, Jean Mayer USDA Human Nutrition Research Center on Aging at Tufts University, Boston, MA.
Disruption in retinoid metabolism and signaling may play a key role in the process of carcinogenesis. An understanding of the metabolic and molecular details behind the altered homeostasis of retinoids by cigarette smoke and excessive alcohol consumption may yield insights into pathophysiologic processes in related cancers. Exposure to smoke, alcohol, or both subjects tissues to increased reactive oxygen species, which can induce cytochrome P450 enzymes and result in the degradation of retinoic acid, the bioactive form of vitamin A. Furthermore, alcohol and acetaldehyde, the first metabolite of ethanol and a constituent of tobacco smoke, can act as an inhibitor of vitamin A oxidation to retinoic acid involving alcohol dehydrogenases and acetaldehyde dehydrogenases. Impaired retinoid homeostasis leads to aberrant retinoid receptor signaling through up-regulation of the mitogen-activated protein kinase signaling pathways. The overall effect of both cigarette smoke and excessive alcohol intake is dysregulated apoptosis and cellular proliferation, which can promote the process of carcinogenesis. Nutritional interventions that restore normal retinoid signaling and functioning may offer protection at the cellular level and represent a means to modify cancer risk in high-risk human populations. However, special attention should be paid to the potential detrimental effects of polar metabolites of retinoids generated during smoke exposure and alcohol drinking. In considering the efficacy and complex biological functions of retinoids and provitamin A carotenoids in human cancer prevention, nutritional intervention using combined agents that target different signaling pathways could provide complementary or synergistic protective effects against tobacco and alcohol-related cancer risk.
Diet, Human Papillomavirus, and Cervical Cancer. Carlos A. González. Catalan Institute of Oncology, Barcelona, Spain.
Persistent infection by certain human papillomavirus (HPV) genotypes is a recognized necessary cause for the development, maintenance, and progression of cervical intraepithelial neoplasia (CIN) and cervical cancer. However, HPV infection is most likely not a sufficient cause of cervical cancer because only a small fraction of infected women develop cervical cancer. Dietary intake and nutrient status are considered cofactors that may influence HPV persistence and progression to cervical cancer. There are several plausible biological mechanisms by which dietary factors may protect from progression of transient to persistent HPV infection, CIN, and invasive carcinoma: antioxidant vitamins enhancing mucosal immune response to infections or by scavenging mucosal oxygen free radicals; retinoids modulating epithelial cell growth and differentiation; and folate and related vitamins involved in DNA and RNA methylation, which may play a role in virus integration, HPV expression, and gene stability. No published epidemiologic studies have explored the possible role of diet and nutritional status on the risk of HPV infection acquisition. Studies on HPV persistence showed a possible protective effect of vegetables and fruits, vitamin C, vitamin E, ß- and -carotene, lycopene, lutein, zeaxanthin, and cryptoxanthin. With HPV infection included in the analysis, epidemiologic studies of cervical cancer showed a probable protective effect of folate, retinol, and vitamin E and a possible protective effect of vegetables, vitamin C, vitamin B-12, and certain carotenoids. Results seem not to differ between studies looking at premalignant or invasive lesions. Evidence from chemoprevention trials on dietary supplementation and CIN endpoints is discouraging, but most of these studies had serious limitations in size, duration of treatment, and length of follow-up. Overall, there is not sufficient evidence for an association between diet and cervical carcinogenesis.
Influence of Maternal Diet on the Developmental Potential of the Preimplantation Embryo. Tom P. Fleming. University of Southampton, Southampton, UK.
The cleavage-stage embryo is sensitive to environmental conditions that can change developmental potential, leading to altered fetal and postnatal phenotype. We have developed mouse and rat models in vivo to investigate the effect of a mild form of maternal protein undernutrition exclusively during egg cleavage on long-term developmental potential. Maternal low-protein diet (LPD) during embryonic development leads to significant alteration in fetal and postnatal growth, a sustained increase in systolic blood pressure during adult life, and a changed pattern of anxiety-related behavior compared with controls fed a normal-protein diet during the embryonic period. This long-term patterning of phenotype includes gender-specific components. The sensitivity of embryos in vivo is paralleled by a similar adverse programming of phenotype in response to in vitro culture conditions, demonstrated in several species. Given the health care implications of the data arising from these models, elucidation of underlying mechanisms contributing to environment-induced changes in embryo potential is essential. Studies to date indicate that complex interactions are mediated through altered cell signaling, homeostatic regulation, proliferation, and epigenetics. In vivo programming via maternal LPD may initiate through abnormal cross-talk between maternal and embryonic cells involving amino acid and growth factor signaling, which may lead to altered setting of metabolism and biosynthesis within the embryo. Our data further indicate that in response to poor maternal periconceptional nutrition, the embryo can induce adaptations in nutrient supply during later development via the visceral yolk sac to protect fetal growth. However, such adaptations can be inappropriate and contribute to adverse fetal and postnatal programming when maternal nutrient levels exceed those predicted. Epigenetic changes involving DNA methylation in control regions of growth- and metabolism-regulating genes, including imprinted genes, have been identified in response to embryo in vitro culture conditions and sustained maternal LPD during gestation, representing additional mechanisms contributing to changes in developmental potential. [Research supported by NICHD and MRC (UK).]
Nutrition, Epigenetics, and Disease Susceptibility. Randy L. Jirtle. Duke University Medical Center, Durham, NC.
Human epidemiologic and animal data indicate that susceptibility to adult-onset chronic conditions such as cardiovascular disease, diabetes, obesity, and cancer is influenced by persistent adaptations to prenatal and early postnatal nutrition (1). We have used the viable yellow agouti (Avy) mouse, which harbors a retrotransposon in the Agouti gene, to investigate the importance of maternal nutrition and DNA methylation in determining the susceptibility of offspring to adult diseases. We have shown that maternal dietary supplementation during pregnancy with either methyl-donating substances (i.e., folic acid, vitamin B-12, choline, and betaine) (2) or genistein (3), a phytoestrogen present in soy products, alters coat color of the offspring by increasing CpG methylation of the transposable element within the Agouti gene rather than by gene mutation. Furthermore, these epigenetic changes reduce the risk of Avy offspring developing obesity, diabetes, and cancer, a clear example of nature via nurture. Such epigenetic information can also be inherited transgenerationally. Therefore, it is now critically important to determine whether similar epigenetically labile genes exist in the human genome and whether micronutrients are useful in counteracting environmentally induced deleterious alterations of the epigenome. [Supported by NIH grants CA25951, ES08823, and ES08823.]
1. Waterland RA, Jirtle RL. Early nutrition, epigenetic changes at transposons and imprinted genes, and enhanced susceptibility to adult chronic diseases. Nutrition. 2004;20:63–8.[Medline]
2. Waterland RA, Jirtle RL. Transposable elements: targets for early nutritional effects on epigenetic gene regulation. Mol Cell Biol. 2003;23:5293–300.
3. Dolinoy DC, Waterland RA, Jirtle RL. Maternal genistein alters coat color and protects Avy mouse offspring from obesity by modifying the fetal epigenome. Environ Health Perspect. 2006;114:567–72.[Medline]
Cancer Survivors: The WHEL Study: Current Evidence Relating Diet to Risk for Recurrence. Cheryl L. Rock. University of California, San Diego, La Jolla, CA.
The majority of women diagnosed with breast cancer will survive at least 5 y postdiagnosis. Risk for recurrence or a second primary cancer is an important issue in their long-term management. Fourteen studies of the relations between intakes of dietary factors and survival after the diagnosis of breast cancer have been reported. Results suggest that intakes of fat (inversely) and vegetables (directly) are possibly associated with likelihood of survival, although the findings are inconsistent. Two studies of the relation between dietary biomarkers and recurrence or survival have been reported. An increased risk of recurrence was observed in patients with higher plasma concentrations of lipoperoxides (a possible biomarker for polyunsaturated fat intake) and -tocopherol. Plasma total carotenoid concentration, a biomarker of vegetable and fruit intake, was recently observed to be directly associated with likelihood of recurrence-free survival in women with a history of breast cancer. Being in the highest versus the lowest quartile of plasma total carotenoid concentration was associated with an estimated 43% reduction in risk for a new breast cancer event when covariates influencing breast cancer prognosis were controlled for. The Women's Healthy Eating and Living (WHEL) Study is testing whether change in diet can reduce risk for recurrence and increase survival in women who have been diagnosed with early breast cancer. The target group consists of 3088 women diagnosed within the preceding 4 y who were randomly assigned to groups after completing initial therapies. Two-thirds of these women were <55 y old at randomization. The major emphasis of the WHEL Study diet intervention is on increased vegetable intake. A comprehensive intervention program that includes intensive telephone counseling, cooking classes, and print materials has promoted a major change in the dietary pattern of women in the intervention group. As previously reported, interim findings suggest that the intervention results in a substantial increase in vegetable and fruit intake, evident in the increased plasma carotenoid concentrations (particularly -carotene, ß-carotene, and lutein). Results from the WHEL Study are anticipated by 2008. In conclusion, observational studies suggest that diet composition may affect breast cancer outcomes, and the WHEL Study is addressing this research question.
 |
FOOTNOTES |
|---|
| ||||||||||||||||||||||||||||||||||||||||||||
