Photocarcinogenesis and diet

Nearly 50 years ago the first reports appeared that cast suspicion on lipids, or peroxidative products thereof, as being involved in the expression of actinically induced cancer. Whereas numerous studies have implicated lipids as potentiators of specific chemical-induced carcinogenesis, only recently has the involvement of these dietary constituents in photocarcinogenesis been substantiated. It has now been demonstrated that both level of dietary lipid intake and degree of lipid saturation have pronounced effects on photoinduced skin cancer, with increasing levels of unsaturated fat intake enhancing cancer expression. The level of intake of these lipids is also manifested in the level of epidermal lipid peroxidation. Conversely, dietary antioxidants inhibit both lipid peroxidation and photocarcinogenesis, the degree of inhibition of the latter being roughly equivalent to the degree of cancer enhancement evoked by the respective level of dietary lipid. The apparent similarities of lipid effects on both chemical and photoinduced carcinogenesis suggest a common underlying role for these dietary constituents in the carcinogenic process. This role may involve free radical-mediated lipid peroxidative reactions. Regardless of the mechanism, it is obvious that both dietary lipid and antioxidants can modify the photocarcinogenic response of skin.     

Relationship between dietary fiber and cancer: metabolic, physiologic, and cellular mechanisms

The relationships between fiber consumption and human cancer rates have been examined, together with an analysis of the effects of individual dietary fibers on the experimental induction of large bowel cancer. The human epidemiology indicates an inverse correlation between high fiber consumption and lower colon cancer rates. Cereal fiber sources show the most consistent negative correlation. However, human case-control studies in general fail to confirm any protective effect due to dietary fiber. Case-control studies indicate that if any source of dietary fiber is possibly antineoplastic then it is probably vegetables. These results may mean that purified fibers alone do not inhibit tumor development, whereas it is likely that some other factors present in vegetables are antineoplastic. Experiments in laboratory animals, using chemical induction of large bowel cancer, have in general shown a protective effect with supplements of poorly fermentable fibers such as wheat bran or cellulose. In contrast, a number of fermentable fiber supplements including pectin, corn bran, oat bran, undegraded carageenan, agar, psyllium, guar gum, and alfalfa have been shown to enhance tumor development. Possible mechanisms by which fibers may inhibit colon tumorigenesis include dilution and adsorption of any carcinogens and/or promoters contained within the intestinal lumen, the modulation of colonic microbial metabolic activity, and biological modification of intestinal epithelial cells. Dietary fibers not only bind carcinogens, bile acids, and other potential toxins but also essential nutrients, such as minerals, which can inhibit the carcinogenic process. Fermentation of fibers within the large bowel results in the production of short chain fatty acids, which in vivo stimulate cell proliferation, while butyrate appears to be antineoplastic in vitro. Evidence suggests that if dietary fibers stimulate cell proliferation during the stage of initiation, then this may lead to tumor enhancement. Fermentation also lowers luminal pH, which in turn modifies colonic microbial metabolic acidity, and is associated with increased epithelial cell proliferation and colon carcinogenesis. Because dietary fibers differ in their physiochemical properties it has been difficult to identify a single mechanism by which fibers modify colon carcinogenesis. Clearly, more metabolic and physiological studies are needed to fully define the mechanisms by which certain fibers inhibit while others enhance experimental colon carcinogenesis.     

Update on the effects of vitamins A, C, and E and selenium on carcinogenesis

The effects of vitamins A, C, and E and of selenium on carcinogenesis are briefly summarized and updated. These vitamins and minerals were selected because they have been studied extensively in recent years with a variety of carcinogenesis models. The consumption of vitamin A and its precursors (carotenoids) has been negatively correlated with cancer at a number of sites, particularly the lung. Animal investigations on vitamin A involvement in carcinogenesis have generally been of three types: those assessing the effect of vitamin A deficiency, the effect of excess vitamin A, or the effect of supplementation with synthetic analogs of vitamin A. Vitamin A deficiency had no effect on salivary gland carcinogenesis, enhanced urinary bladder, lung, and liver carcinogenesis, and inhibited colon carcinogenesis. Excess of various forms of vitamin A enhanced or inhibited skin tumorigenesis, inhibited mammary carcinogenesis in rats (but not in mice), and carcinogenesis of the forestomach, liver, and urinary bladder (with one model, but not with another), or enhanced or did not influence lung carcinogenesis. Vitamin A analogs have enhanced or inhibited skin tumorigenesis, inhibited salivary gland, mammary, and urinary bladder carcinogenesis, enhanced tracheal and liver carcinogenesis, and either enhanced or inhibited pancreas carcinogenesis, depending upon the model employed. Although retinoids have been shown to inhibit carcinogenesis at many sites, numerous negative studies have been reported and some reports have indicated enhanced carcinogenesis. The most convincing evidence for the involvement of vitamin C in cancer prevention is the ability of ascorbic acid to prevent formation of nitrosamine and of other N-nitroso compounds. In addition vitamin C supplementation was shown to inhibit skin, nose, tracheal, lung, and kidney carcinogenesis, to either not influence or enhance skin, mammary gland, and colon carcinogenesis, and to enhance urinary bladder carcinogenesis, when given as sodium ascorbate, but not when given as ascorbic acid. Like vitamin C, vitamin E can inhibit nitrosation. Vitamin E was shown to inhibit skin, cheek pouch, and forestomach carcinogenesis, to enhance or inhibit colon carcinogenesis, and to have no effect on or to inhibit mammary gland carcinogenesis, depending upon the method of vitamin E administration or the level of dietary selenium or dietary fat. Selenium effects on carcinogenesis have been recently reviewed and the present discussion only updates this area by indicating that enhancement of carcinogenesis by dietary selenium supplements has been observed in the liver, pancreas, and skin.(ABSTRACT TRUNCATED AT 400 WORDS)     

Nutritional factors in lung, colon, and prostate carcinogenesis in animal models

Dietary factors are now considered to be among the most important environmental risk determinants for cancer. In addition to epidemiological studies, experimental animal studies are an important tool to investigate dietary modulation in carcinogenesis. Results of recent experimental studies on the effect of some nutrients indicate that vitamin A did show an inverse relation with the occurrence of preneoplastic respiratory lesions but not with respiratory tract tumors in benzo[a]pyrene-induced respiratory carcinogenesis. Dietary fat increases respiratory tract tumors and preneoplastic lesions. In colon carcinogenesis, a fat-fiber interrelation was noticed in 1,2-dimethyl-hydrazine- and N-methyl-N'-nitro-N-nitrosoguanidine-induced tumors. Preliminary results in prostate carcinogenesis indicate that dietary fat did not influence the incidence of prostate cancer in a recently developed rat model. Some possible mechanisms in colon and prostate carcinogenesis are discussed.     

Dietary fibre and colon cancer: epidemiologic and experimental evidence.

Epidemiologic studies have identified two dietary factors, a relatively high intake of fat and a relatively low intake of fibre, that are associated with colon cancer in humans. However, a recent study has shown a low risk of large bowel cancer in a rural Finnish population with a high dietary intake of fat, but also a high intake of fibre. Observations in humans and studies in animals have indicated that dietary fibre may protect against colon carcinogenesis by binding bile acids in the intestinal tract, by a direct effect on the colonic mucosa and by an indirect effect on the metabolism of carcinogens. The strength of protection varies with the type of fibre.     

Minireview possible roles of dietary fats in carcinogenesis

Epidemiological data have implicated dietary fat as an important factor in the aetiology of various cancers in humans. This suggestion is supported by the results of experiments with animals which have shown that increased amounts of dietary fat, in particular polyunsaturated fat, increase the incidence of some spontaneous and induced tumours. The enhancement of carcinogenesis by dietary fats appears to be exerted at the promotional stage of carcinogenesis. Changes induced by dietary fats in several biological systems involved in carcinogenesis may well indicate the underlying mechanisms responsible for the results of these experiments. These include the effects of dietary fats on the metabolism of chemical carcinogens, the structure and function of membranes, immunocompetence, DNA repair potential and endocrine function.     

Specific versus non-specific effects of dietary fat on carcinogenesis

It will be apparent from this review that dietary fat can exert both specific and non-specific effects on carcinogenesis, at least in experimental animals. The non-specific effects appear to be related primarily to effects of dietary fat on energy balance. Although a positive energy balance can be achieved on a high-carbohydrate low-fat diet, it is much more likely to occur on a high-fat diet because of the high energy density of fat [101] and the fact that dietary fat is less capable of imparting a sense of satiety [102]. A continuing state of positive energy balance leads to obesity which has been associated with increased risk of cancer at a number of sites, including endometrium [103-106], postmenopausal breast cancer [107-113], renal cancer [114,115] and possibly cancers of the colorectum [116-122], pancreas [103,123] and prostate [124]. Whereas the non-specific effects of dietary fat appear to be deleterious for cancer, the specific effects in some cases can be beneficial. Examples are long-chain n-3 polyunsaturated fatty acids. CLA and tocotrienols. It is still too early to predict whether these may be of value in the prevention and/or treatment of human cancer but they seem worthy of further investigation. Knowledge of their mechanism of action may suggest novel approaches to the cancer problem and, as in the case of vitamins A and D, it may be possible to find analogues with more potent anti-cancer activity.     

Body mass and prostatic cancer: a prospective study.

Previous studies have suggested that increased body mass is associated with an increased risk of prostatic cancer, but these studies have been limited by the fact that they were based on a few simple measurements such as height and weight. Similar results were found in a prospective study of the incidence of prostatic cancer in a cohort of Japanese men born in 1900-19 and living in Hawaii. Further evaluation of the extensive anthropomorphic measurements made in this cohort suggested that the association between measures of body mass and prostatic cancer might be accounted for more by lean tissue than by fat tissue. There was a significant positive association of the risk of prostatic cancer with area of muscle in the arm but not with area of fat in the arm. Further research is needed on the biological mechanisms of carcinogenesis that may be related to both lean and fat tissue and the development of prostatic cancer.     

Effects of red meat and fiber in high fat diet on activities of sphingomyelinase,ceramidase and caspase-3 in rat colonic mucosa

Red meat and fiber rich foods are the dietary factors most consistently related to colon carcinogenesis. Although several components in these dietary sources may contribute, the biochemical mechanism by which red meat and fiber affect colorectal carcinogenesis has not yet been established. Sphingomyelin metabolism is a novel signal transduction pathway that may have an impact on colonic tumorigenesis. The present study investigated the activity changes of sphingomyelinase (SMase), ceramidase and caspase-3 in colonic mucosa of rats fed on a high fat control diet, the control diet with beef and the control diet with fiber (cellulose). After a three week feeding period the colonic mucosa were scraped and homogenized and enzyme activities were determined. The fiber diet significantly increased the activities of neutral and acid SMases but had no effect on those of alkaline SMase and neutral ceramidase. The beef diet, on the other hand, significantly reduced neutral ceramidase activity, but had no effect on the activities of any SMase. In addition, the beef diet significantly reduced and the fiber diet increased caspase-3 activity in the colonic mucosa when compared with the control diet. The changes of caspase-3 activities were abolished by preincubating the samples with caspase-3 inhibitor. No significant changes of intestinal alkaline phosphatase could be found among the three dietary groups. In conclusion, fiber and red meat in the high fat diet affected in an opposite way the enzymes responsible for sphingomyelin metabolism and apoptosis in the colon. The effects may have implications in colorectal tumorigenesis.     

A carcinogenic western diet does not induce somatic mutations in various target tissues of transgenic C56BL/6 mice

Although the importance of diet in human cancer is clear, most dietary studies of carcinogenesis in laboratory rodents have involved the use of large doses of a carcinogen, which is not comparable to the human situation. The use of carcinogens has been necessary because laboratory rodents have extremely low spontaneous rates of colon cancer. Newmark et al. (2001) showed, however, that a radical dietary manipulation sufficed to induce high rates of colon cancer in C57BL/6 mice. Here we report an investigation into whether or not this dietary manipulation acts by altering somatic mutation rates. We used the transgenic lambda cII locus of F₁ pups (C57BL/6 × Big Blue^®) with the same C57BL/6 genetic background. The same diet (ND), high in fat, and low in calcium, vitamin D, folic acid, choline, and fibre, that was used by Newmark et al. (2001) was fed ad libitum to dams during pregnancy and lactation in order to examine its effect on mutagenesis in development and growth. There was no significant difference in mutant frequency in the small intestine (P = 0.82), or bone marrow (P = 0.95) of pups fed a ND versus the control diet. To investigate the effect of a ND during adulthood, 6-week-old F₁ pups were fed a ND ad libitum for 6, 12 and 19 weeks. There was no significant difference in mutant frequency in the small intestine (P = 0.66) or colon (P = 0.49) at the cII locus with no significant difference in body weight. These results indicate that Western diet-induced carcinogenesis is not mediated by alterations in mutation rate and thus may act at the promotion rather than at the initiation stage of carcinogenesis.     

Peripheral oestrogen metabolism in postmenopausal women with or without breast cancer: the role of dietary lipids and growth factors

Studies we have carried out have revealed significant differences in oestrogen production and metabolism between normal women and postmenopausal women with breast cancer. The free, biologically available fraction of oestradiol is elevated in plasma from women with breast cancer and we have found that metabolic clearance rates and production rates of oestradiol are also increased. In vitro studies have suggested that lipids can influence the distribution of sex steroids in plasma and we have therefore examined the effect of dietary lipids on the distribution of sex steroids in plasma in vivo. Consumption of a meal with a high saturated fat content or the oral or i.v. administration of "Intralipid", a stabilised emulsion of soya bean oil that is high in unsaturated free fatty acids, had little effect on the available fractions of oestradiol in plasma. However, results from a preliminary study suggest that long-term changes in dietary fat intake can alter the distribution of steroids in plasma. It is concluded that dietary lipids may influence the availability of sex steroids to tissues. Such a mechanism could account for the significant correlation that has been found between dietary fat consumption and the incidence of breast cancer on a world-wide basis.     

Does chemically induced hepatocyte proliferation predict liver carcinogenesis?

Cell proliferation has long been recognized as having an important role in chemically induced carcinogenesis. Based on findings that certain nongenotoxic chemical carcinogens induced cell proliferation in the same organ that had an increased incidence of tumors, it has been hypothesized that a chemically induced response of enhanced DNA synthesis and cellular division causes cancer by increasing the rate of spontaneous mutations. It was further suggested that there would be no increased human risk of cancer by non-DNA-reactive compounds at doses that do not cause a proliferative response. An evaluation of the literature on the relationship between chemically induced cell proliferation and liver carcinogenesis reveals that very few systematic cell proliferation studies have been conducted over periods of extended exposure, and in many cases the exposure concentrations were not similar to those used in the cancer studies. The proliferative response resulting from exposure to many nongenotoxic carcinogens is not well sustained, whereas the carcinogenic response by these chemicals often requires prolonged exposure. The available literature leads to the conclusion that quantitative correspondences between cellular proliferation and carcinogenic responses have not been demonstrated and do not support the hypothesis that chemically induced cell proliferation is the primary mechanism by which nongenotoxic chemicals cause liver cancer. Studies of liver carcinogenesis in two-stage models point out the need to better understand chemical effects on cell loss as well as on cell replication, and demonstrate that measurements of cell proliferation alone are not sufficient to elucidate mechanisms of tumor development.     

Histone acetylation and cancer.

In the past year, several papers have been published which implicate a link between alterations in chromatin structure and the development of cancer. Both histone hyperacetylation and hypoacetylation appear to be important in the neoplastic process, depending on the target gene involved. In the case of colon cancer, induction of the p21 gene by histone hyperacetylation may be a mechanism by which dietary fiber prevents carcinogenesis.     

Timing of dietary fat exposure and mammary tumorigenesis: Role of estrogen receptor and protein kinase C activity

The possible association between a high fat diet and increased breast cancer risk has remained controversial. This largely reflects the conflicting data obtained from migrant, case control and animal studies, which generally support this association, and cohort studies which often fail to show a link between fat and breast cancer. The mammary gland is particularly sensitive to estrogens during the fetal development, leading us to hypothesize that dietary fat levels during this period may significantly influence breast cancer risk. Using chemically-induced mammary tumors in rats as our experimental model, we have demonstrated the ability of a maternal diet, high in the polyunsaturated fatty acid (PUFA) linoleic acid, to alter mammary gland differentiation, accelerate the onset of sexual maturation, and increase breast cancer risk. The mammary glands of female rats exposed to a highfat diet in utero have more of the undifferentiated structures (terminal end buds) and fewer of the differentiated structures (alveolar buds) than the glands of rats exposed to a low-fat diet in utero. Furthermore, these mammary glands contain lower levels of total estrogen receptors and have reduced total protein kinase C activity. These effects appear to be mediated by an increase in tne serum estradiol levels of pregnancy, which are elevated at least 30% in pregnant dams fed a high fat diet. Furthermore, the administration of estradiol to pregnant dams produce effects on mammary gland development, onset of puberty and sensitivity to chemical carcinogenesis comparable to those seen in the offspring of rats fed a high fat diet during pregnancy. Our results, thus, support the hypothesis based on epidemiological data that high maternal estrogen levels increase daughters' breast cancer risk. The results also suggest that a high-fat diet may be an important factor in increasing pregnancy estrogenic activity.     

Dietary fats and cancer

The present review addresses the evidence for a possible link between dietary fat and cancer. International comparisons suggest that a high-fat diet may increase cancer risk, and this hypothesis is supported by animal experiments. However, epidemiological studies within populations show little or inconsistent associations. Taken together, the available evidence for a relation between dietary fat and cancer is weak.     

HPV-DNA integration and carcinogenesis: putative roles for inflammation and oxidative stress

HPV-DNA integration into cellular chromatin is usually a necessary event in the pathogenesis of HPV-related cancer; however, the mechanism of integration has not been clearly defined. Breaks must be created in both the host DNA and in the circular viral episome for integration to occur, and studies have shown that viral integration is indeed increased by the induction of DNA double strand breaks. Inflammation generates reactive oxygen species, which in turn have the potential to create such DNA strand breaks. It is plausible that these breaks enable a greater frequency of HPV-DNA integration, and in this way contribute to carcinogenesis. Consistent with this idea, co-infections with certain sexually transmitted diseases cause cervical inflammation, and have also been identified as cofactors in the progression to cervical cancer. This article examines the idea that inflammation facilitates HPV-DNA integration into cellular chromatin through the generation of reactive oxygen species, thereby contributing to carcinogenesis.     

Ubiquinol and the papaverine derivative caroverine prevent the expression of tumour- promoting factors in adenoma and carcinoma colon cancer cells induced by dietary fat

High consumption of dietary fat promotes colon carcinogenesis. While this effect is well known the underlying mechanism is not understood. Fatty acid hydroperoxides (LOOH) arise from unsaturated fatty acids in the presence of oxygen and elevated temperature during food processing. An approach was made starting from the assumption that LOOH are present in dietary fats as a result of boiling. LOOH undergoes homolytic cleavage in the presence of iron. We studied their effects on gene expression in colorectal tumour cells using linoleic acid hydroperoxide (LOOH) as model compound. Addition to the medium of LT97 adenoma and SW480 carcinoma cells enhanced the production of hydrogen peroxide. Both cell lines were observed to increase VEGF and COX-II expression based on mRNA. Expression of VEGF was inhibited by caroverine and ubiquinon.     

The role of Sulforaphane in cancer chemoprevention and health benefits: a mini-review

Cancer is a multi-stage process resulting from aberrant signaling pathways driving uncontrolled proliferation of transformed cells. The development and progression of cancer from a premalignant lesion towards a metastatic tumor requires accumulation of mutations in many regulatory genes of the cell. Different chemopreventative approaches have been sought to interfere with initiation and control malignant progression. Here we present research on dietary compounds with evidence of cancer prevention activity that highlights the potential beneficial effect of a diet rich in cruciferous vegetables. The Brassica family of cruciferous vegetables such as broccoli is a rich source of glucosinolates, which are metabolized to isothiocyanate compounds. Amongst a number of related variants of isothiocyanates, sulforaphane (SFN) has surfaced as a particularly potent chemopreventive agent based on its ability to target multiple mechanisms within the cell to control carcinogenesis. Anti-inflammatory, pro-apoptotic and modulation of histones are some of the more important and known mechanisms by which SFN exerts chemoprevention. The effect of SFN on cancer stem cells is another area of interest that has been explored in recent years and may contribute to its chemopreventive properties. In this paper, we briefly review structure, pharmacology and preclinical studies highlighting chemopreventive effects of SFN.     

Genistein,an epigenome modifier during cancer prevention

Dietary compounds have been observed to have a great potential to regulate the epigenome, which is disrupted and reprogrammed during carcinogenesis. Because of their close association with cancer development, DNA methylation patterns have been used as a crucial marker for the study of cancer-related epigenetics. There is immense evidence indicating that dietary components play a critical role in cancer development. Genistein, one of the soy-derived bioactive isoflavones, affects tumorigenesis through epigenetic regulations. By modulating chromatin configuration and DNA methylation, genistein activates tumor suppressor genes and affects cancer cell survival. Here, we summarize and discuss both in vitro and in vivo studies in the field that investigate the effect of genistein on histone modifications and DNA methylation. The promising role of genistein in cancer prevention and therapeutic applications will be discussed from an epigenetic point of view.