Diet and cancer

Most common cancers

Men: prostate, lung, colorectal
Women: breast, colorectal, lung

What is cancer?

An acquired genetic disorder of somatic cells, causing a normal cell to give rise to one which is abnormal in form or function

• The normal control of cell division is lost, an individual cell multiplies inappropiately to form a tumor

• The abnormal cells fail to response to some or all of the regulatory signals and immune system that normally controls cell division, differentiation and programmed cell death (apoptosis)

• Tumor interferes with normal function of the tissue or organ where it grows

Tumor growth requires nutrients, an increased catabolism will lead to weight loss. There is genetic predisposition for certain cancers.

Causes: tobacco, alcohol, ionising radiation, ultraviolet light, certain infections and hormones

Environmental factors (including diet) can contribute to initiating cancerous change, to the rate of growth and metastasis and to responses in treatment

Incidence of cancer

Africa, Asia and Latin America: higher rates of cancers of upper respiratory and digestive systems (mouth, pharynx, larynx, oesophagus), stomach, liver and cervix

Europe, North America and Australia: higher rates of breast, endometrium, prostate, colon and rectum cancer

Research: different types of tests

Descriptive epidemiology: variations of cancer rates with space and time

Ecological studies (correlation studies): food intake in different populations are compared with their cancer rates

Observational studies: compare diets of individuals who develop cancer with diets of those who remain cancer free

Randomised trials: test the effect of dietary supplements or dietary change on cancer incidence (e.g. beta carotene lowers the risk for developing lung cancer, but in smokers an increase in the risk for lung cancer was observed)

Experiments in animals and in the lab: provide hypothesis of effects in humans and of mechanisms

Diet and cancer

Diet contributes to the development of cancer in a number of ways:

• Foods may be a source of pre-formed carcinogens (or precursors)

• Nutrients may affect the formation, transport, deactivation or excretion of carcinogens

• Nutrients may affect the body’s resistance to carcinogens and therefore be important protective factors

Dietary mutagens directly damage the DNA of the host:

• Aflatoxin: liver cancer

• N-nitrosocompounds?

• Salt, nitrites, nitrates: stomach cancer?

  • Nitrates → nitrites → nitrosamines: carcinogenic

  • This conversion occurs in the stomach with low pH

  • Vitamin C prevents the formation of nitrosamines

• Heterocyclic amines and polycyclic aromatic hydrocarbons of cooked meat and fish: colorectal cancer

Wholegrains, vegetables, fruit and cancer risk

Wholegrains decrease the risk of colorectal cancer

Foods containing dietary fibre decrease the risk of colorectal cancer. Dietary fiber minimizes the absorption of carcinogens:

• Reducing transit time

• Dilution of the gut content

• Binding the carcinogens

• Production of butyrate: anti-proliferative and differentiating agent, induces apoptosis (= programmed cell death)

• Lowering pH: more aerobic bacteria that don’t produce carcinogenic products from bile acids, bile acids will bind with calcium

Beta-carotene in foods or supplements is unlikely to have a substantial effect on the risk of prostate cancer

Foods contaminated by aflatoxins increase the risk of liver cancer

Foods preserved by salting increase the risk of stomach cancer

Plant anti-carcinogens:

• Flavonoids: quercetin in apples, onions and tea

• Carotenoids: lycopene and lutein in tomato products and green vegetables respectively, but beta carotene supplements increase the risk of lung cancer

• Isothiocynates: in cruciferous vegetables

• Sulphur-containing compounds in garlic, onions and leeks

• Phytosterols

• Phytoestrogens reduce breast cancer risk: isoflavones in soybeans, lignans in whole grain products

Meat, fish, dairy and cancer risk

Red meat increases the risk of colorectal cancer

Processed meat increases the risk of colorectal cancer

Contonese-style saled fish increases the risk of nasopharyngeal cancer

Dairy products decrease the risk of colorectal cancer

Milk:

• Calcium binds fatty acids and bile salts in the colon: prevention of producing damaging compounds

• Vitamin D: control of cell differentiation

• Whey proteins: precursor of antioxidant glutathione

• Lactoferrin binds iron → less available as a pro-oxidant

Potential carcinogenic compounds in red and processed meat: Haem iron can induce DNA damage in cells. This can result in mutation if it is not repaired. If this cell does not undergo apoptosis, if it proliferates, it may result in a tumor that can become malignant. Animal studies firmly suggest that haem iron is carcinogenic in doses relevant for humans. Epidemiological studies indicate that other causes are much more important than haem iron from meat.

Nitrate, nitrite, N-nitroso compounds: Nitrate (not a carcinogen) can be reduced by micro-organisms to nitrite. Nitrite can react with amines to form N-nitroso compounds of which many are potent carcinogens. The endogenous formation is limited, but it is performed in cured meat. This is way the addition of nitrite is limited, the addition of ascorbic acid can reduce nitrosamine levels.

Heterocyclic amines (= at least one heterocyclic ring and an amino group attached) are the result of Maillard reactions in heated meat (not only red meat). → heat more gently, additives that inhibit formation of heterocyclic amines, heterocyclic amines bind to some extent fibers which decreases their bioavailability

Polycyclic aromatic hydrocarbons (= 2 or more fused aromatic rings) are made in incomplete combustion or pyrolysis of organic matter. This happens in partial carbonisation when grilling, smoking, high temperature roasting. There are positive associations between cancer and intake of grilled/barbequed meat. Polycyclic aromatic hydrocarbons are genotoxic carcinogens in experimental animals and most likely also in humans.

Proteins and microbiota: Proteolytic fermentation in the colon results in different end products such as ammonia, N-nitrosocompounds, pehnolic and indolic substances and hydrogen sulfide. They generate ROS that lead to genotoxicity and inflamation and thus into carcinogenesis. H2S decreases the intestinal barrier so that intestinal epithelial tissue is exposed to cytotoxic haem. Some bacteria convert latent carcinogens into bioactive compounds (N-nitrosocompounds, PAHs, HCAs) → promote saccharolytic fermentation by eating a lot of fibres which increases butyrate formation, probiotics can help, maintain symbiosis and avoid dysbiosis

Other negative aspects: saturated fatty acids, trans fatty acids, sodium

Recommendations: 500g of red meat per week with very little (if any) processed meat

Beneficial nutrients in meat:

• >= 15% of most vitamins and minerals including vitamin D

• >= 30% of protein, vitamin A, thiamin, niacin, vitamin B12, vitamin B6, zinc, selenium: iron, zinc and vitamin D have a high bioavailability

• All essential amino acids

• MUFAs and PUFAs

Preservation and processing of foods and cancer risk

Processed meat increases the risk of colorectal cancer

Cantonese-style salted fish increases the risk of nasopharyngeal cancer

Foods preserved by salting increases the risk of stomach cancer

Non-alcoholic crinks and cancer risk

Arsenic in drinking water increases the risk of lung cancer, bladder cancer and skin cancer

Maté, as drunk scalding hot in the traditional style in South America, increases the risk of oesophageal squamous cell carcinoma

Coffee decreases the risk of liver cancer and endometrial cancer

Alcoholic drinks and cancer risks

Alcoholic drinks increase the risk of mouth, pharynx and larynx cancers, oesophageal cancer and breast cancer

2 or more alcoholic drinks a day (30g or more) increases the risk of colorectal cancer

3 or more alcoholic drinks a day (45g or more) increases the risk of stomach and liver cancer

Up to 2 alcoholic drinks a day decreases the risk of kidney cancer

Causal risk of alcohol for cancers: oral cavity, larynx, pharynx, esophagus, liver, colorectum, female breast → the more you drink per day, the higher the risks

Vitamins, minerals and other nutrients and cancer risk

Consuming high-dose beta-carotene supplements increases the risk of lung cancer in people who smoke or used to smoke

Consuming beta-carotene in foods or supplements is unlikely to have substantial effect on the risk of prostate cancer

Consuming beta-carotene in supplements is unlikely to have substantial effect on the risk of skin cancer

Consuming calcium supplements decreases the risk of colorectal cancer, however, its best to eat a healthy diet rather than rely on dietary supplements to protect against cancer

Greater glycaemic load of the diet increases the risk of endometrial cancer

For high-dose-beta carotene supplements and calcium supplements, conclusions can be drawn only for the doses that were investigated

Cancers of the stomach and oesophagus in some developing countries is partly due to micronutrient deficiencies

Antioxidants may provide protective effects: vitamin A, C, E

• Retinoids (vitamin A) regulate epithelial cell differentiation

• Carotenoids are powerful quenchers of singlet oxygen and activate the immune system

• Vitamin C inhibits nitrosamine formation in the stomach

Physical activity and cancer risk

Being physically active decreases the risk of colon cancer, breast cancer and endometrial cancer

Vigorous physical activity (running or fast cycling) decreases the risk of pre-and postmenopausal breast cancer

Studies in mice: both increased physical activity and restricting food intake might reduc tumor development

Physical activity promotes the activity of the immune system

Obesity, weight gain and cancer risk

Greater weight gain in adulthood increases the risk of postmenopausal breast cancer

Being overweight or obese as an adult before menopause decreases the risk of premenopausal breast cancer

Being overweight or obese between the ages 18-30 decreases the risk of pre-and postmenopausal breast cancer

Breast cancer is an oestrogen-dependent tumor

Levels of ovarian hormones are influenced by the nutritional status

High energy intake increases the risk of cancer

A high fat diet increases the risk of cancer in the colon, rectum, prostate and endometrium. The hyptohesis for this is that dietary fat causes a greater increase of bile salts that are then fermented by anaerobic bacteria producing mutagenic compounds. Non-starch polysaccharides are protective factors against this mechanism.

Animals studies have shown the promoting effect of omega 6 FA and inhibitory effect of omega 3 FA on mammary tumor growth

Height and birthweight and cancer risk

Developmental factors leading to greater growth in lenth in childhoud increase the risk of cancers of the following types: pancreas, colorectum, endometrium, ovary, prostate, kidney, skin and breast

Factors that lead to a greater birhtweight or its consequences increase the risk of premenopausal breast cancer

Lactation and cancer risk

Breastfeeding decreases the risk of breast cancer in the mother

Alcohol absorption

20% is abosrbed in the stomach: how much is absorbed depends on how full the stomach is: if you have eaten, alcohol will be absorbed slower (recommended to not drink on an empty stomach)
→ Quick absorption with empty stomach: 15-30 minutes vs 1-3h

80% is absorbed in the small intestine: if you ate a fatty meal, it will be absorbed slower

Alcohol is spread over all fluid-containing compartments of the body: because women have less body fluid, they can’t drink as much as men

Other factors: purity of alcohol, speed of drinking, capacity of stomach and intestines

Metabolization of alcohol happens in the liver, absorption is quick and easy. After metabolization, small molecules can cross the blood-brain barrier → alcohol can affect brain function

Alcohol metabolism

In liver cells, in cytosol (also partly in the digestive tract)

Main pathway: Alcohol dehydrogenase converts ethanol into acetaldehyde which is toxic. Acetaldehyde dehydrogenase then converts acetaldehyde into acetyl CoA. If you have a form of acetaldehyde dehydrogenase that is not soo active, more acetaldehyde will remain present and you have a higher cancer risk. Little acetyl CoA enters the citric acid cycle and is then via the electron transport chain converted into 12 ATP. The rest of acetyl CoA is converted into fatty acids and stored as triglycerides (fat). So when you consume a lot of alcohol, you synthesize fatty acids, this can result in a fatty liver.

Alternative pathway (= MEOS overflow pathway). This pathway is activated when large amounts of alcohol are consumed. Alcohol is then converted into acetaldehyde via an alternative pathway in which energy is consumed (costs 3 ATP to produce acetaldehyde). This happens in the microsomes and peroxisomes of liver cells. High amounts of alcohol are further converted into acetate and ketones. Drugs are also metabolized via this pathway, this is why you should not consume alcohol in combination with drugs since this pathway is then already activated.

Alcohol oxidation is preffered above the oxidation of other energy-compounds, this produces heat. Alcohol has an energy density of 7 kcal/g but part is exhaled or leaves through urine (alcohol testing)

Alcohol intoxication

Alcohol affects the nervous system and the control functions of the brain:

• loss of memory, discrimination, concentration, insight

• increased exuberance, talkativeness, urge to move, emotional outbursts

• sleepiness, coma, suppression of breathing

Sings of alcohol intoxication at 1 g/l, lethal at 4 g/l

Alcoholism

= chronic alcohol use, physiological dependence of alcohol

Withdrawal symptoms: trembling, hallucination

Health problems:

• Liver: hepatitis, livercirrosis, carcinome (different stages of liver disease)

• Gastro-intestinal tract: esophageal carcinome, gastritis, pancreatitis, diarrhea

• Metabolism: high levels of TAG in liver and blood, reduced gluconeogenesis → hypoglycaemia (low blood sugar levels), increased lactate, reduced uric acid excretion, hyperuricaemia, gout

• Cardiovascular: hypertension and cardiomyopathy

• Nerve damage, polyneuritis, encephalopathy of Wernicke, korsakovpsychose (cerebellary degenaration), demention

Dietary effects: reduced levels of vitamin B, zinc and magnesium, high levels of iron

High consumption during pregnancy leads to fetal alcoholsyndrome: growth retardation (60-75% lower bodyweight expected), small head, mental retardation (reduction in IQ of 30%)

Alcohol + carbohydrate intake: increased effect of insulin → this stimulates the absorption of glucose from the blood → hypoglycaemia

Alcohol intake

U- or J-curve in alcohol use and mortality: 1-2 units/day for women, 2-4 units/day for men but from 1,5 glass/day there is an increase in the risk of strokes and cancer in the gastrointestinal tract. Low consumption of alcohol decreases mortality, but this is probably because these people have a healthier overall lifestyle

Positive effects are not understood (only seen for wine consumers)

Based on epidemiological studies (association)

WHO does not see any advantage in alcohol consumption: recommendation of max 10 units/week, spread over several days

Damaging effects of ethanol on eukaryote cells

In microsomes and peroxisomes of liver cells there are also alternative pathways to convert ethanol into acetaldehyde (catalase or CYP2E1), this pathways involve the production of reactive oxygen species (H2O2, OH-, O2-)

Ethanol enhances cellular ROS levels, ROS can:

• result in direct oxidation of DNA base pairs

• result in DNA-DNA crosslinks

• result in GC → TA transversions

• result in lipid peroxidation, producing malondealdehyde which can form DNA adducts that can induce base-pair substitions (cell membranes consist of lipids)

Reaching dose of acetaldehyde in saliva: 140 µM while the carcinogenic treshold is 50-100 µM

Formation of DNA adducts

Acetaldehyde can directly interact with DNA base pairs resulting in DNA adducts, this leads to problems in DNA replication such as:

• Block replicative DNA polymerase, frameshift mutations

• Ring closed confirmation blocks replication, ring-closed state leads to interstrand crosslinks

• Block replicative DNA polymerase, double-strand breaks

This leads to uncontrolled cell division

Effect of alcohol on the epigenome

Methylation blocks certain genes from being expressed → no transcription

Ethanol leads to DNA hypomethylation: ethanol decreases SAM levels which results in upregulation of oncogenes (inihibition of apoptosis → tumor progression)

Ethanol can lead to hypermethylation of silence tumor suppressor genes which promotes carcinogenesis

Histone modification in the presence of ethanol

Histone hypomethylation

Acetate coming from ethanol can lead to acetylation in the brain of mice

Can alter gene expression by activating oncogenes → tumorigenesis

Ethanol induces proteotoxic stress

Acetaldehyde interacts with lysine, this inhibits the function of the protein: DNA repair enzyems are targeted (GSH, CYP2E1)

Products of lipid peroxidation can bind the protein: formation of malondialdehyde-acetaldehyde protein adducts → certain protein activities are reduced

Ethanol can react with OH. and form a racial

Protein adducts induce an immune response, Ig target cells with protein adducts destroy them: antibody-dependent cell-mediated cytotoxicity

Ethanol increases membrane permeability

Minor compositions in the protein structure of the membrane proteins:

• Increases the fluidity of the membranes

• Compromises its barrier function

• Impaires receptor function and signalling pathways

Similar effects due to lipid peroxidation of the lipid bilayer

Also the membranes of organelles are harmed: leakage of Cyt c into the cytoplasma induces apoptosis