Effect of Underfeeding on Carcinogenesis

3. Effect of Underfeeding on Carcinogenesis Mouse strain Carcinogen Site Full fed Underfed DBA Spontaneous Breast 13 3 DBA Spontaneous Breast 20 1 ABC BP Skin 22 7 Swiss BP Skin 24 6 C57 BP Subq. 36 22 No. of tumors

4. Influence of Fat and Calories on Methylcholanthrene -Induced Skin Tumorsin Mice Fat Calories Tumor incidence (%) Low Low 0 High Low 28 Low High 54 High High 66 Regimen

5. Influence of 40% Energy Restriction and Fat on DMBA-induced Mammary Tumors in Rats Fat type Amount (%) Regimen Tumor incidence Coconut oil 4.0 Ad lib 14/24 (58%) Coconut oil 7.9 Restricted 0/23 (0%) Corn oil 4.0 Ad lib 16/20 (80%) Corn oil 7.9 Restricted 4/20 (20%)

6. Degree of Energy Restriction and DMBA-Induced Mammary Tumorigenesis in Rats Group Incidence (%) Multiplicity Tumor burden (g) Ad lib 60 4.7 ±1.3 10.1 ± 3.3 10% Restricted 60 3.0 ±0.8 5.4 ± 3.0 20% Restricted 40 2.8 ±0.7 4.7 ± 1.9 30% Restricted 35 1.3 ±0.3 0.9 ± 0.8 40% Restricted 5 1.0 - p<0.005 p<0.05

7. Influence of Energy Restriction on DMBA-induced Mammary Tumorigenesis in Rats Fed High-Fat Diets Group Incidence (%) Multiplicity Tumor burden Ad lib 5 % Corn oil 65 1.9 ± 0.3 4.2 ± 1.9 15 % Corn oil 85 3.0 ± 0.6 6.6 ± 2.7 20 % Corn oil 80 4.1 ± 0.6 11.8 ± 3.2 25 % Restricted 20 % Corn oil 60 1.9 ± 0.4 1.5 ± 0.5 26.7 % Corn oil 30 1.5 ± 0.3 2.3 ± 1.6 p<0.005 p<0.0001 p<0.0001

8. Plasma Insulin Levels (µU/ml) in Ad libitum Fed or Energy restricted Rats Regimenn % Fat Insulin Ad libitum 5 122 ± 16 10% Restricted 5 191 ±10 20% Restricted 5 109 ±137 30% Restricted 5 42 ±5 40% Restricted 5 41 ± 8 Ad libitum 5 143 ± 16 Ad libitum 15 164 ± 15 Ad libitum 20 158 ± 11 30% Restricted 20 100 ± 2 30% Restricted 26.7 117 ± 13

9. Papilloma Development (TPA-induced) in Adrenalectomized, Food Restricted Mice Group Regimen Papillomas/mouse Sham operated AL 5.4 Adrenalectomized AL 7.7 Sham operated FR 1.0 Adrenalectomized FR 6.2

13. Connection Between Energy Intake and Cancer: Possible Mechanisms • Insulin, IGF-I • Estrogen-level • Estrogen binding capacity (SHBG) • Glucocorticoid-concentration (better stress-reaction) • Adipokines (e.g. leptin) • Inflammatory molecules, cytokines (e.g. IL-6) • Oxidative stress • DNS-repair-capacity • Apoptotic pathways

14. Obesity and Cell Proliferation Excess body weight Insulin IR Cellproliferation Apoptosis IGFBP-1 IGFBP-2 Total IGF-I IGFBP-3 Target cell IGF-IR Free IGF-I

15. Possible role ofenergy imbalance in prostate carcinogenesis. Energy imbalance likely increases the production of IGF-I, which through the type 1 insulin-like growth factor receptor (IGF-1R) in turn may promote proliferation and inhibit apoptosis in a forming prostate tumor. Energy imbalance may also enhance the production of VEGF, possibly through the increased production of IGF-1. VEGF promotes the generation of new blood vessels in the growing prostate tumor, contributing to tumor survival and ability to metastasize. Consistent with these hypotheses, energy restriction appears to act late in several mouse and rat models of carcinogenesis

17. Types of lipids • Lipids with fatty acids Waxes Fats and oils (trigycerides) Phospholipids Sphingolipids • Lipids without fatty acids Steroids

18. Triglycerides • Neutral fats: glycerine, fatty acids • Fatty acids: Long-chain carboxylic acids, insoluble in water • TG: 1,3: saturated, 2: unsaturated • cis-trans isomers • Digestion, absorption, metabolism • MCT • Functions: membrane component, energy (heat production, brown adipose tissue), protection, synthesis of bioactive compounds • Fatty acids (examples): linoleic acid (18:2), butyric acid (4:0), alpha-linolenic acid (18:3), palmitic acid (16:0), stearic acid (18:0) oleic acid (18:1), arachidonic acid (20:3), eicosapentaenoic acid (20:5), docosahexaenoic acid (22:6)

19. Fatty acids

20. Occurrence • Red meats 40-75 E% • White meats 25-50 E% • Egg 65 E% • Milk 50 E% • Fish 5-60 E% • Nuts 80-90 E%

21. Saturated fats • Milk 65% • Meat, butter, lard, coconut oil, hard margarines 45-50% • Palm oil 80% • Egg, poultry 30-35% • Vegetable oil 10-20% • Soft margarines 20-30% • Fish 10-25%

22. Monounsaturated • Olive oil 70-90% • Avocado 60-70% • Meat, poultry, milk, egg, butter, vegetable oil, etc 10-50% Polyunsaturated • Vegetable oil 50-75% • Margarines 15-40% • Fish (-3)

23. Trans-fatty acids • Margarines, cakes 30-40% Essential fatty acids • Linoleic acid, linolenic acid • Capability for elongation and production of further double bounds

24. Major Food Sources of Trans Fat for American Adults

25. Fats and Cancer: Possible Mechanisms • Energy intake (high energy-density) • Lipid soluble carcinogens • Lipid-peroxidation • Temperature, rancid fats • Membrane-composition • Species and tissue specificity, but it can be influenced • Prostaglandin/prostacycline synthesis • Immune system • Direct cytotoxic effect • Metabolizing enzymes • DAG properties • Secondary bile acids

26. Relationship between the oleic acid:linoleic acid (OA:LA) ratio in the diet and spleen lymphocyte proliferation in rats.

27. Omega-3 family Omega-6 family pge, pgf10, txa1, blocks lt4 pgd3, pge3, pgf3a pgi3, txa3, lta5, ltb5, ltc5, ltd5 pgd2, pge2, pgf2a pgi2, txa2, lta4, ltb4, ltc4, ltd4, lte4 arachidonic acid AA 20:4 ɷ-6 docosahexaenoic acid DHA 22:6 ɷ-3 docosapentaenoic acid 22:5 ɷ-6 docosapentaenoic acid DPA 22:5 ɷ-3 eicosatetraenoic acid 20:4 ɷ-3 docosatetraenoic acid 22:4 ɷ-6 dihomo ɤ-linolenic acid DGLA 20:3 ɷ-6 eicosapentaenoic acid EPA 20:5 ɷ-3 stearidonic acid 18:4 ɷ-3 ɤ-linolenic acid GLA 18:3 ɷ-6 ɑ-linolenic acid 18:3 ɷ-3 linoleic acid 18:2 ɷ-6

28. Effect of Different Fatty Acids on Cancer Risk • Saturated increase • Monounsaturated decrease • Polyunsaturated • -6 serie increase • -3 serie • Long-chain (EPA, DHA) chemopreventive • Linolenic acid chemopreventive? • Trans-fatty acids increase • Conjugated linoleic acid (CLA ) promising • Branched-chain fatty acids (BCFA) promising

29. Conjugated Linoleic Acids • Mixture of fatty acids containing conjugated double bounds (octadecadienoic acids e.g.:c9t11, t10c12) • -C=C—C—C=C- linoleic acid-C=C—C=C- CLA • Occurence: grilled beef (hamburger!), milk (food of cow is important), meat of ruminants • Effects: anticarcinogenic (even at 0.5% cc), antiatherogenic, antioxidant (?), etc. • Possible mode of action of anticarcinogenic effects: • antioxidant • fat metabolism • immune system • cytotoxicity • PG-prostacycline synthesis • Future: • foods with high CLA content • supplementation (?) • human prospective studies !! • prevention of side effects (egg, monounsaturated/saturated, olive oil)

30. Type of Oil or Fat Saturated Monounsaturated Polyunsaturated Mustard Oil 1% 76% 23% Canola Oil    6% 62% 32% Almond Oil 8% 73% 19% Hazelnut Oil 10% 76% 14% Safflower Oil 10% 13% 77% Sunflower Oil    11% 20% 69% Grape Seed Oil 12% 17% 71% Corn Oil 13% 25% 62% Olive Oil 14% 77% 9% Sesame Oil 14% 40% 46% Walnut Oil 14% 19% 67% Soybean Oil 15% 24% 61% Fat Composition of Various Oils and Fats(Percentages in bold indicate that an oil contains either the highest or lowest level among edible oils for a particular fat component.)

31. Fat Composition of Various Oils and Fats(Percentages in bold indicate that an oil contains either the highest or lowest level among edible oils for a particular fat component.) Type of Oil or Fat Saturated Monounsaturated Polyunsaturated Peanut Oil 18% 49% 33% Avocado Oil 20% 70% 10% Margarine (Soft) 20% 47% 33% Wheat Germ Oil 20% 30% 50% Cottonseed Oil 24% 26% 50% Lard 41% 47% 12% Palm Oil 52% 38% 10% Cocoa Butter 62% 35% 3% Butter 66% 30% 4% Margarine (Hard) 80% 14% 16% Palm Kernel Oil 86% 12% 2% Coconut Oil 92% 6% 2%

35. MeatConsumption and Colon CancerIncidence Colon cancerincidence / 100.000 women Armstrong and Doll, Int. J. Cancer, 1975: 15: 617-31 Meat consumption g/day

36. Interaction Between Meat Consumption and Dietary Fiber Intake in Colorectal Carcinogenesis Fiber Red meat Norat , 2005

41. ChangeinFaecalN-nitrosoCompoundLevelsinHealthyVolunteerswithChangein Red MeatLevels µg/100 g µg/d ATNC (apparent total N-nitrosocompounds) Grams of red meat per day

42. Stop here immediately!!!