Overview of genes, diet and cancer

Quantitative epidemiological analysis suggests that about one third of the variation in cancer risk can be attributed to variation in dietary exposure but it has proved difficult, using conventional epidemiological approaches, to identify which dietary components, in what amounts and over what time-scales are protective or potentially hazardous. Work in this area has been hampered by the lack of robust surrogate endpoints. However, the rapidly accumulating knowledge of the biological basis of cancer and the application of post-genomic technologies are helping the development of novel biomarkers of cancer risk. Genomic damage resulting in aberrant gene expression is the fundamental cause of all cancers. Such damage includes mutations, aberrant epigenetic marking, chromosomal damage and telomere shortening. Since both external agents and normal cell functions, such as mitosis, subject the genome to frequent and diverse insults, the human cell has evolved a battery of defence mechanisms which (a) attempt to minimize such damage (including inhibition of oxidative reactions by free radical scavenging and the detoxification of potential mutagens), (b) repair the damage or (c) remove severely damaged cells by shunting them into apoptosis. When such defences fail and a tumour becomes established, further genomic damage and further alterations in gene expression enable the tumour to grow, to cope with anoxia, to develop a novel blood supply (angiogenesis), to escape from the confines of its initiation site and to establish colonies elsewhere in the body (metastasis). All of these processes are potentially modifiable by food components and by nutritional status. In addition, interactions between dietary (and other environmental and lifestyle) factors and genetic make-up [seen principally in the assembly of single nucleotide polymorphisms (SNPs) which is unique to each individual] contributes to interindividual differences in cancer risk.     

Human safety controversies surrounding nitrate and nitrite in the diet

Nitrate and nitrite are part of the human diet as nutrients in many vegetables and part of food preservation systems. In the 1950s and 1960s the potential for formation of nitrosamines in food was discovered and it ignited a debate about the safety of ingested nitrite which ultimately focused on cured meats. Nitrate impurities in salt used in the drying of meat in ancient times resulted in improved protection from spoilage during storage. This evolved into their deliberate modern use as curing ingredient responsible for 'fixing' the characteristic color associated with cured meats, creating a unique flavor profile, controlling the oxidation of lipids, and serving as an effective antimicrobial. Several critical reports and comprehensive reviews reporting weak associations and equivocal evidence of nitrite human health safety have fostered concerns and debate among scientists, regulators, press, consumer groups, and consumers. Despite periodic controversy regarding human health concerns from nitrite consumption, a building base of scientific evidence about nitrate, nitrite, heme chemistry, and the overall metabolism of nitrogen oxides in humans has and continues to affirm the general safety of nitrate/nitrite in human health. As nitrite based therapeutics emerge, it is important to consider the past controversies and also understand the beneficial role in the human diet.     

Development of accelerated net nitrate uptake : effects of nitrate concentration and exposure time

Upon initial nitrate exposure, net nitrate uptake rates in roots of a wide variety of plants accelerate within 6 to 8 hours to substantially greater rates. Effects of solution nitrate concentrations and short pulses of nitrate (≤1 hour) upon `nitrate-induced' acceleration of nitrate uptake in maize (Zea mays L.) were determined. Root cultures of dark-grown seedlings, grown without nitrate, were exposed to 250 micromolar nitrate for 0.25 to 1 hour or to various solution nitrate concentrations (10-250 micromolar) for 1 hour before returning them to a nitrate-free solution. Net nitrate uptake rates were assayed at various periods following nitrate exposure and compared to rates of roots grown either in the absence of nitrate (CaSO₄-grown) or with continuous nitrate for at least 20 hours. Three hours after initial nitrate exposure, nitrate pulse treatments increased nitrate uptake rates three- to four-fold compared to the rates of CaSO₄-grown roots. When cycloheximide (5 micrograms per milliliter) was included during a 1-hour pulse with 250 micromolar nitrate, development of the accelerated nitrate uptake state was delayed. Otherwise, nitrate uptake rates reached maximum values within 6 hours before declining. Maximum rates, however, were significantly less than those of roots exposed continuously for 20, 32, or 44 hours. Pulsing for only 0.25 hour with 250 micromolar nitrate and for 1 hour with 10 micromolar caused acceleration of nitrate uptake, but the rates attained were either less than or not sustained for a duration comparable to those of roots pulsed for 1 hour with 250 micromolar nitrate. These results indicate that substantial development of the nitrate-induced accelerated nitrate uptake state can be achieved by small endogenous accumulations of nitrate, which appear to moderate the activity or level of root nitrate uptake.     

Dissimilatory nitrate reduction to nitrate, nitrous oxide, and ammonium by Pseudomonas putrefaciens.

The influence of redox potential on dissimilatory nitrate reduction to ammonium was investigated on a marine bacterium, Pseudomonas putrefaciens. Nitrate was consumed (3.1 mmol liter-1), and ammonium was produced in cultures with glucose and without sodium thioglycolate. When sodium thioglycolate was added, nitrate was consumed at a lower rate (1.1 mmol liter-1), and no significant amounts of nitrite or ammonium were produced. No growth was detected in glucose media either with or without sodium thioglycolate. When grown on tryptic soy broth, the production of nitrous oxide paralleled growth. In the same medium, but with sodium thioglycolate, nitrous oxide was first produced during growth and then consumed. Acetylene caused the nitrous oxide to accumulate. These results and the mass balance calculations for different nitrogen components indicate that P. putrefaciens has the capacity to dissimilate nitrate to ammonium as well as to dinitrogen gas and nitrous oxide (denitrification). The dissimilatory pathway to ammonium dominates except when sodium thioglycolate is added to the medium.     

Honey bee‐collected pollen in agro‐ecosystems reveals diet diversity,diet quality,and pesticide exposure

European honey bees Apis mellifera are important commercial pollinators that have suffered greater than normal overwintering losses since 2007 in North America and Europe. Contributing factors likely include a combination of parasites, pesticides, and poor nutrition. We examined diet diversity, diet nutritional quality, and pesticides in honey bee‐collected pollen from commercial colonies in the Canadian Maritime Provinces in spring and summer 2011. We sampled pollen collected by honey bees at colonies in four site types: apple orchards, blueberry fields, cranberry bogs, and fallow fields. Proportion of honey bee‐collected pollen from crop versus noncrop flowers was high in apple, very low in blueberry, and low in cranberry sites. Pollen nutritional value tended to be relatively good from apple and cranberry sites and poor from blueberry and fallow sites. Floral surveys ranked, from highest to lowest in diversity, fallow, cranberry, apple, and blueberry sites. Pesticide diversity in honey bee‐collected pollen was high from apple and blueberry sites and low from cranberry and fallow sites. Four different neonicotinoid pesticides were detected, but neither these nor any other pesticides were at or above LD₅₀ levels. Pollen hazard quotients were highest in apple and blueberry sites and lowest in fallow sites. Pollen hazard quotients were also negatively correlated with the number of flower taxa detected in surveys. Results reveal differences among site types in diet diversity, diet quality, and pesticide exposure that are informative for improving honey bee and land agro‐ecosystem management.     

Human exposure to metals through the diet in Tarragona, Spain

The concentrations of arsenic (As), beryllium (Be), cadmium (cd), chromium (Cr), mercury (Hg), manganese (Mn), nickel (Ni), lead (Pb), tin (Sn), thallium (Tl), and vanadium (V) were determined in a number of food items purchased in zones of Tarragona, County (Catalonia, Spain) near a hazardous waste incinerator (HWI), which has been operating since 1999. Food samples corresponded to the following groups: meat, fish and seafood, pulses, cereals, vegetables, fruits, tubers, whole milk, yogurt, eggs, and sugar. Be and Tl were under their respective limits of detection in all samples. For the analyzed trace elements, the dietary intake by the general population of Tarragona was 458.5 μg/d for As, 14.3 μg/d for Cd, 88.3 μg/d for Cr, 5.3 μg/d for Hg, 2421.4 μg/d for Mn, 138.3 μg/d for Ni, 44.8 μg/d for Pb, 34.6 μg/d for Sn, and 28.9 μg/d for V. Results were compared with those found in a baseline survey carried out in the same area during the construction of the HWI (1996–1998). In general terms, the dietary intake of metals in 2003 was comparatively similar to those found in the baseline survey. For the most toxic elements (As, Cd, Hg, and Pb), it was under their respective Provisional Tolerable Weekly Intake (PTWI) estabished by the FAO/WHO.     

Effects of diet on biomarkers of exposure and effects, and on oxidative damage

Modification of DNA is believed to be a key step in carcinogenesis, and therefore DNA adducts have been proposed as predictive biomarkers of human cancer. Smoked and grilled foods are important contributors of PAH-DNA adduct levels, while the consumption of flavonoids and other antioxidants seems to decrease the level of DNA adducts. The aim of this study was to assess the effect of each group of foods and of different dietary profiles on the DNA adducts levels and on oxidative damage to DNA. Occupationally exposed men were recruited in Czech Republic, Slovak Republic and Bulgaria. Non-occupationally exposed subjects were matched on age and gender to PAH-exposed workers. Three hundred and fifty-six subjects who completed the questionnaire for dietary information and had a measurement of DNA adduct levels and oxidative damage to DNA were included in this study. No food item seemed to be individually associated with markers of exposure or DNA damage. Total DNA adducts levels were significantly higher for subjects who had eaten, in the previous 24 h, smoked or fried food. A Principal Components Analysis was performed to identify groups of subjects with similar dietary profiles: no significant differences in biomarker levels were observed among the groups defined according to dietary profiles. In conclusion, this study did not show any significant association between diet and biomarkers of DNA damage, oxidative damage to DNA and chromosomal aberrations, neither when each food was considered separately, nor when the effect of different dietary profiles was tested. The recent consumption of smoked or fried food was associated with an increase in total DNA adducts levels.     

Gastric cancer: clinical aspects, epidemiology and molecular background

The validity and usefulness of the 7th edition of the UICC tumor node metastasis classification in the context of clinical management of gastric cancer are discussed. The most relevant new agent in gastric cancer therapy is trastuzumab for HER2-positive gastric carcinomas. This marks the success of continuous effort of translational research. Trastuzumab, initially applied in palliative settings, is currently being evaluated also in neoadjuvant treatment regimens. Several new meta-analyses support the carcinogenic effect of high salt intake and smoking in the context of Helicobacter pylori infection. Further data have become available on the efficacy of protective agents, acetyl salicylic acid/nonsteroidal anti-inflammatory drugs, and antioxidants. In search for a successful prevention strategy, the focus is on the identification of individuals at high risk who demand screening (testing) and surveillance. Serological assessment of gastric mucosal abnormalities with increased risk for gastric cancer development is extensively studied, and new data are presented from Asia as well as from Europe. New high-throughput techniques combined with bioinformatic vector analysis open the gate to the identification of new potential diagnostic and therapeutic targets. Furthermore, these approaches allow us to elucidate the interplay of bacterial virulence factors and the host's immune response as well as H. pylori-associated alterations of mucosal gene expression.     

Electromagnetic-field exposure and cancer

Electromagnetic fields are a ubiquitous part of man's environment. Natural sources of energy have been present, and possibly have contributed to the processes of the evolution of living forms. In very recent time, however, exploitation of the properties of the electromagnetic spectrum, has added variables in intensity, frequency, modulation frequency, and alterations in contributions of electrical and magnetic components. Biological impact has been little studied and poorly defined. Animal carcinogenesis studies and human epidemiological data indicate that exposure to nonionizing radiation can play a role in cancer causation. Numerous effects at the physiological and biochemical level have been reported; many are of such a nature that a relationship to the causation of neoplastic transformation can rationally be hypothesized. Many bioeffects of electromagnetic fields can be adequately and economically explained in terms of heat effects alone. However, observations of frequency-, pulse form or modulation-, and intensity-specificity as well as effects opposite to that known for temperature-rise, imply direct interaction of radiant energy with biomolecules. The possibility of such direct interaction has been shown in quantum mechanical models.     

Gastric cancer: a curable disease in Britain.

OBJECTIVE--To determine whether more vigorous efforts aimed at earlier diagnosis allied to radical surgical resection lead to improved survival of patients with gastric cancer. DESIGN--Prospective audit of all cases of gastric cancer treated during 1970-89. SETTING--Department of surgery, general hospital. SUBJECTS--493 consecutive patients with gastric adenocarcinoma. MAIN OUTCOME MEASURES--Operative mortality, postoperative morbidity, and five year survival after radical potentially curative resection. RESULTS--207 (42%) patients underwent potentially curative resection. The proportion of all patients in whom this was possible increased significantly (p < 0.01) from 31% in the first five year period to 53% in the last five year period. The proportion of patients who had early gastric cancer rose from 1% to 15% (p < 0.01) and stage I disease rose from 4% to 26% (p < 0.001). After potentially curative resection, mortality 30 days after operation was 6%. Operative mortality decreased from 9% in the 1970s to 5% in the 1980s. Likewise, the incidence of serious postoperative complications decreased from 33% in the 1970s to 17% in the 1980s (p < 0.01). Five year survival was 60% in patients who underwent curative resection, 98% in patients with early gastric cancer, and 93%, 69%, and 28% in stage I, II, and III disease respectively. By the late 1980s five year survival after operation was about 70%. CONCLUSIONS--These findings suggest that an increasing proportion of patients with gastric cancer could be diagnosed at a relatively early pathological stage when about two thirds are curable by means of radical surgery.     

Carcinogens in the diet vs. overnutrition. Individual dietary habits, malnutrition, and genetic susceptibility modify carcinogenic potency and cancer risk.

Chemical carcinogens in the diet cannot explain the cancer incidence attributed by epidemiologists to dietary factors when the calculation is based on average exposure levels and conservative estimates of carcinogenic potencies. In a previous review, the discrepancy was explained primarily by overnutrition to which a carcinogenic potency was assigned from dietary restriction experiments and the associated reduction in spontaneous tumor incidence (W.K. Lutz and J. Schlatter, Chemical carcinogens and overnutrition in diet-related cancer, Carcinogenesis 13 [1992] 2211-2216). Here, additional aspects are introduced. They focus on using individual rather than averaged data, both for exposure and susceptibility. First, under conditions of a sublinear (convex) dose-response, the cancer incidence obtained by using an average exposure level is lower than if individual exposure levels associated with particular dietary habits are taken into account. Second, carcinogenic factors, including those unrelated to the diet (e.g., smoking), can act synergistically. Third, the potency of dietary carcinogens is increased under conditions of malnutrition in the sense of a deficiency of protective factors, such as those available with fruits, vegetables, and fibers. Quantitatively, this aspect may be particularly important because it simultaneously increases the efficacy of a multitude of carcinogens. It is concluded that chemical carcinogens could be as important as overnutrition for diet-related cancer.     

Effects of gender,diet, exogenous melatonin and subchronic PCB exposure on plasma immunoglobulin G in mink

Effects of different fish-based diets (freshwater smelt, Baltic herring, marine herring/cod offal or their mixtures), gender, beta-glucan supplement, exogenous melatonin, and PCB exposure (Aroclor 1242((R)), 1 mg per animal per day in feed) on plasma immunoglobulin G (IgG) in the mink (Mustela vison) were studied. The aims of the study were to find out whether plasma IgG of the mink is affected by the subchronic PCB exposure, and whether biological, nutritional and hormonal effects are large enough to mask the possible IgG response. The concentration of IgG was determined using enzyme-linked immunosorbent assay (ELISA). Sexual dimorphism was detected, the males having higher levels of plasma IgG. In addition, melatonin tended to decrease IgG in females but not males. Diet also affected the humoral immune arm; the mixed-fish diets caused an unfavorable ratio of the oxidation products of lipids vs. vitamin E in liver, and resulted in low IgG concentration in plasma. In males fed Baltic herring, the beta-glucan supplement also lowered IgG levels. The PCBs failed to affect the plasma IgG of the smelt-fed female mink, and IgG concentration was not correlated with increased hepatic EROD activity or with the decreased total retinol in the liver of exposed mink. It is concluded that hormonal/seasonal and dietary factors affect the plasma IgG levels to such an extent that possible change in plasma IgG level due to PCBs in wild populations of mink is difficult to detect without a large amount of reference data.