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Physical Activity and Cancer Prevention

Pathways and Targets for Intervention

Abstract

The prevalence of obesity, an established epidemiological risk factor for many cancers, has risen steadily for the past several decades in the US and many other countries. Particularly alarming are the increasing rates of obesity among children, portending continuing increases in the rates of obesity and obesity-related cancers for many years to come. Modulation of energy balance, via increased physical activity, has been shown in numerous comprehensive epidemiological reviews to reduce cancer risk. Unfortunately, the effects and mechanistic targets of physical activity interventions on the carcinogenesis process have not been thoroughly characterized.

Studies to date suggest that exercise can exert its cancer-preventive effects at many stages during the process of carcinogenesis, including both tumour initiation and progression. As discussed in this review, exercise may be altering tumour initiation events by modifying carcinogen activation, specifically by enhancing the cytochrome P450 system and by enhancing selective enzymes in the carcinogen detoxification pathway, including, but not limited to, glutathione-S-transferases. Furthermore, exercise may reduce oxidative damage by increasing a variety of anti-oxidant enzymes, enhancing DNA repair systems and improving intracellular protein repair systems.

In addition to altering processes related to tumour initiation, exercise may also exert a cancer-preventive effect by dampening the processes involved in the promotion and progression stages of carcinogenesis, including scavenging reactive oxygen species (ROS); altering cell proliferation, apoptosis and differentiation; decreasing inflammation; enhancing immune function; and suppressing angiogenesis. A paucity of data exists as to whether exercise may be working as an anti-promotion strategy via altering ROS in initiated or preneoplastic models; therefore, no conclusions can be made about this possible mechanism. The studies directly examining cell proliferation and apoptosis have shown that exercise can enhance both processes, which is difficult to interpret in the context of carcinogenesis. Studies examining the relationship between exercise and chronic inflammation suggest that exercise may reduce pro-inflammatory mediators and reduce the state of low-grade, chronic inflammation. Additionally, exercise has been shown to enhance components of the innate immune response (i.e. macrophage and natural killer cell function). Finally, only a limited number of studies have explored the relationship between exercise and angiogenesis; therefore, no conclusions can be made currently about the role of exercise in the angiogenesis process as it relates to tumour progression.

In summary, exercise can alter biological processes that contribute to both antiinitiation and anti-progression events in the carcinogenesis process. However, more sophisticated, detailed studies are needed to examine each of the potential mechanisms contributing to an exercise-induced decrease in carcinogenesis in order to determine the minimum dose, duration and frequency of exercise needed to yield significant cancer-preventive effects, and whether exercise can be used prescriptively to reverse the obesity-induced physiological changes that increase cancer risk.

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References

  1. Doll R, Peto R. The causes of cancer: quantitative estimates of avoidable risks of cancer in the United States today. J Natl Cancer Inst 1981 Jun; 66 (6): 1191–308

    Google Scholar 

  2. Calle EE, Rodriguez C, Walker-Thurmond K, et al. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U.S. adults. N Engl J Med 2003 Apr 24; 348 (17): 1625–38

    Google Scholar 

  3. Rice-Wray E. Cigarette smoking and health. Am J Public Health Nations Health 1964 Feb; 54: 322–4

    Google Scholar 

  4. Weir HK, Thun MJ, Hankey BF, et al. Annual report to the nation on the status of cancer, 1975—2000, featuring the uses of surveillance data for cancer prevention and control. J Natl Cancer Inst 2003 Sep 3; 95 (17): 1276–99

    Google Scholar 

  5. Vainio H, Bianchini F, editors. Weight control and physical activity. Lyon: IARC Press, 2002

    Google Scholar 

  6. Friedenreich CM, Orenstein MR. Physical activity and cancer prevention: etiologic evidence and biological mechanisms. J Nutr 2002 Nov; 132 (11 Suppl.): 3456–64S

    Google Scholar 

  7. Willer A. Cancer risk reduction by physical exercise. World Rev Nutr Diet 2005; 94: 176–88

    PubMed  Google Scholar 

  8. Trojian TH, Mody K, Chain P. Exercise and colon cancer: primary and secondary prevention. Curr Sports Med Rep 2007 Apr; 6 (2): 120–4

    Google Scholar 

  9. Monninkhof EM, Elias SG, Vlems FA, et al. Physical activity and breast cancer: a systematic review. Epidemiology 2007 Jan; 18 (1): 137–57

    Google Scholar 

  10. Hursting S, Cantwell M, Sansbury L, et al. Primary prevention by nutrition intervention in infancy and childhood. Nestlé Nutr Workshop Ser Pediatr Program 2006; 57: 153–202

    CAS  PubMed  Google Scholar 

  11. Hursting SD, Slaga TJ, Fischer SM, et al. Mechanism—based cancer prevention approaches: targets, examples, and the use of transgenic mice. J Natl Cancer Inst 1999 Feb 3; 91 (3): 215–25

    Google Scholar 

  12. Hursting SD, Lavigne JA, Berrigan D, et al. Calorie restriction, aging, and cancer prevention: mechanisms of action and applicability to humans. Annu Rev Med 2003; 54: 131–52

    CAS  PubMed  Google Scholar 

  13. Hursting SD, Nunez NP, Patel AC, et al. The utility of genetically altered mouse models for nutrition and cancer chemoprevention research. Mutat Res 2005 Aug 25; 576 (1-2): 80–92

    Google Scholar 

  14. Yuspa SH, Shields PG. Etiology of cancer: chemical factors. In: Devita VT, Hellman SH, Rosenberg SA, editors. Cancer: principles and practices of oncology. Philadelphia (PA): Lippincott—Raven, 1997: 185–202

    Google Scholar 

  15. Slaga TJ. Mechanisms involved in two—stage carcinogenesis in mouse skin. In: Slaga TJ, editor. Mechanisms of tumor promotion. Boca Raton (FL): CRC Press, 1984: 1–93

    Google Scholar 

  16. Yuspa SH, Poirier MC. Chemical carcinogenesis: from animal models to molecular models in one decade. Adv Cancer Res 1988; 50: 25–70

    CAS  PubMed  Google Scholar 

  17. Pitot HC. Progression: the terminal stage in carcinogenesis. Jpn J Cancer Res 1989 Jul; 80 (7): 599–607

    Google Scholar 

  18. Fearon ER, Vogelstein B. A genetic model for colorectal tumorigenesis. Cell 1990 Jun 1; 61 (5): 759–67

    Google Scholar 

  19. Spitz MR, Bondy ML. Genetic susceptibility to cancer. Cancer 1993 Aug 1; 72 (3 Suppl.): 991–5

    Google Scholar 

  20. Sugimura T. Multistep carcinogenesis: a 1992 perspective. Science 1992 Oct 23; 258 (5082): 603–7

    Google Scholar 

  21. Sporn MB. Approaches to prevention of epithelial cancer during the preneoplastic period. Cancer Res 1976 Jul; 36 (7 Pt 2): 2699–702

    Google Scholar 

  22. Forman MR, Hursting SD, Umar A, et al. Nutrition and cancer prevention: a multidisciplinary perspective on human trials. Annu Rev Nutr 2004; 24: 223–54

    CAS  PubMed  Google Scholar 

  23. Hoffman-Goetz L. Physical activity and cancer prevention: animal—tumor models. Med Sci Sports Exerc 2003 Nov; 35 (11): 1828–33

    PubMed  Google Scholar 

  24. Thompson HJ. Pre—clinical investigations of physical activity and cancer: a brief review and analysis. Carcinogenesis 2006 Oct; 27 (10): 1946–9

    Google Scholar 

  25. Shephard RJ, Futcher R. Physical activity and cancer: how may protection be maximized? Crit Rev Oncog 1997; 8 (2-3): 219–72

    CAS  PubMed  Google Scholar 

  26. Woods JA. Exercise and resistance to neoplasia. Can J Physiol Pharmacol 1998 May; 76 (5): 581–8

    Google Scholar 

  27. Campbell KL, Mc Tiernan A. Exercise and biomarkers for cancer prevention studies. J Nutr 2007 Jan; 137 (1 Suppl.): 161–9S

    Google Scholar 

  28. Gonzalez FJ. Genetic polymorphism and cancer susceptibility: fourteenth Sapporo Cancer Seminar. Cancer Res 1995 Feb 1; 55 (3): 710–5

    Google Scholar 

  29. Drinkwater NR, Bennett LM. Genetic control of carcinogenesis in experimental animals. Prog Exp Tumor Res 1991; 33: 1–20

    CAS  PubMed  Google Scholar 

  30. Stanley LA. Molecular aspects of chemical carcinogenesis: the roles of oncogenes and tumour suppressor genes. Toxicology 1995 Feb 27; 96 (3): 173–94

    Google Scholar 

  31. Nebert DW, Nelson DR, Coon MJ, et al. The P450 superfamily: update on new sequences, gene mapping, and recommended nomenclature. DNA Cell Biol 1991 Jan-Feb; 10 (1): 1–14

    Google Scholar 

  32. Guengerich FP. Metabolic activation of carcinogens. Pharmacol Ther 1992; 54 (1): 17–61

    CAS  PubMed  Google Scholar 

  33. Eling TE, Thompson DC, Foureman GL, et al. Prostaglandin H synthase and xenobiotic oxidation. Annu Rev Pharmacol Toxicol 1990; 30: 1–45

    CAS  PubMed  Google Scholar 

  34. Mac Leod MC, Slaga TJ. Multiple strategies for the inhibition of cancer induction. Cancer Bull 1995; 47: 492–8

    Google Scholar 

  35. Miller EC, Miller JA. Searches for ultimate chemical carcinogens and their reactions with cellular macromolecules. Cancer 1981 May 15; 47 (10): 2327–45

    Google Scholar 

  36. Perchellet JP, Perchellet EM, Gali HU, et al. Oxidant stress and multistage carcinogenesis. In: Mukhtar H, editor. Skin cancer: mechanisms and human relevance. Boca Raton (FL): CRC Press, 1995: 145–80

    Google Scholar 

  37. Mantle TJ, Pickett CB, Hayes JD. Glutathione S—transferases and carcinogenesis. Philadelphia (PA): Taylor and Francis, 1987: 1–121

    Google Scholar 

  38. Ketterer B. Protective role of glutathione and glutathione transferases in mutagenesis and carcinogenesis. Mutat Res 1988 Dec; 202 (2): 343–61

    Google Scholar 

  39. Oesch F, Doehmer J, Friedberg T, et al. Control of ultimate mutagenic species by diverse enzymes. Prog Clin Biol Res 1990; 340B: 49–65

    CAS  PubMed  Google Scholar 

  40. James MO, Schell JD, Boyle SM, et al. Southern flounder hepatic and intestinal metabolism and DNA binding of benzo[a]pyrene (BaP) metabolites following dietary administration of low doses of BaP, BaP−7,8−dihydrodiol or a BaP metabolite mixture. Chem Biol Interact 1991; 79 (3): 305–21

    CAS  PubMed  Google Scholar 

  41. Mitchell DL, Adair GM, Mac Leod MC, et al. DNA damage and repair in the initiation phase of carcinogenesis. Cancer Bull 1995; 47: 449–55

    Google Scholar 

  42. Friedberg EC, Walker GC, Siede W, et al. DNA repair and mutagenesis. Washington, DC: ASM Press, 2005: 1–97

    Google Scholar 

  43. Sancar A. Mechanisms of DNA excision repair. Science 1995; 266 (5193): 1954–6

    Google Scholar 

  44. Sancar A, Tang MS. Nucleotide excision repair. Photochem Photobiol 1993 May; 57 (5): 905–21

    Google Scholar 

  45. Modrich P. Mismatch repair, genetic stability and tumour avoidance. Philos Trans R Soc Lond B Biol Sci 1995 Jan 30; 347 (1319): 89–95

    Google Scholar 

  46. Frenkl R, Gyore A, Szeberenyi S. The effect of muscular exercise on the microsomal enzyme system of the rat liver. Eur J Appl Physiol Occup Physiol 1980; 44 (2): 135–40

    CAS  PubMed  Google Scholar 

  47. Kim HJ, Lee AK, Kim YG, et al. Influence of 4−week and 8−week exercise training on the pharmacokinetics and pharmacodynamics of intravenous and oral azosemide in rats. Life Sci 2002 Mar 29; 70 (19): 2299–319

    Google Scholar 

  48. Piatkowski TS, Day WW, Weiner M. Increased renal drug metabolism in treadmill—exercised Fischer−344 male rats. Drug Metab Dispos 1993 May-Jun; 21 (3): 474–9

    Google Scholar 

  49. Vistisen K, Loft S, Poulsen HE. Cytochrome P450 IA2 activity in man measured by caffeine metabolism: effect of smoking, broccoli and exercise. Adv Exp Med Biol 1991; 283: 407–11

    CAS  PubMed  Google Scholar 

  50. Day WW, Weiner M. Inhibition of hepatic drug metabolism and carbon tetrachloride toxicity in Fischer−344 rats by exercise. Biochem Pharmacol 1991 Jun 21; 42 (1): 181–4

    Google Scholar 

  51. Reddy KV, Anuradha D, Kumar TC, et al. Induction of Ya1 subunit of rat hepatic glutathione S—transferases by exercise induced oxidative stress. Arch Biochem Biophys 1995 Oct 20; 323 (1): 6–10

    Google Scholar 

  52. Yiamouyiannis CA, Sanders RA, Watkins III JB, et al. Chronic physical activity: hepatic hypertrophy and increased total biotransformation enzyme activity. Biochem Pharmacol 1992 Jul 7; 44 (1): 121–7

    Google Scholar 

  53. Roth RA, Wiersma DA. Role of the lung in total body clearance of circulating drugs. Clin Pharmacokinet 1979 Sep-Oct; 4 (5): 355–67

    Google Scholar 

  54. Trush MA, Kensler TW. An overview of the relationship between oxidative stress and chemical carcinogenesis. Free Radic Biol Med 1991; 10 (3-4): 201–9

    CAS  PubMed  Google Scholar 

  55. Valko M, Izakovic M, Mazur M, et al. Role of oxygen radicals in DNA damage and cancer incidence. Mol Cell Biochem 2004 Nov; 266 (1-2): 37–56

    Google Scholar 

  56. Davies KJ, Quintanilha AT, Brooks GA, et al. Free radicals and tissue damage produced by exercise. Biochem Biophys Res Commun 1982 Aug 31; 107 (4): 1198–205

    Google Scholar 

  57. Ji LL. Antioxidants and oxidative stress in exercise. Proc Soc Exp Biol Med 1999 Dec; 222 (3): 283–92

    Google Scholar 

  58. Marnett LJ. Oxyradicals and DNA damage. Carcinogenesis 2000 Mar; 21 (3): 361–70

    Google Scholar 

  59. Mc Ardle A, Dillmann WH, Mestril R, et al. Overexpression of HSP70 in mouse skeletal muscle protects against muscle damage and age—related muscle dysfunction. FASEB J 2004 Feb; 18 (2): 355–7

    Google Scholar 

  60. Mc Ardle A, Jackson MJ. Exercise, oxidative stress and ageing. J Anat 2000 Nov; 197 Pt 4: 539–41

    Google Scholar 

  61. Radak Z, Kaneko T, Tahara S, et al. The effect of exercise training on oxidative damage of lipids, proteins, and DNA in rat skeletal muscle: evidence for beneficial outcomes. Free Radic Biol Med 1999 Jul; 27 (1-2): 69–74

    Google Scholar 

  62. Radak Z, Taylor AW, Ohno H, et al. Adaptation to exercise induced oxidative stress: from muscle to brain. Exerc Immunol Rev 2001; 7: 90–107

    CAS  PubMed  Google Scholar 

  63. Fehrenbach E, Northoff H. Free radicals, exercise, apoptosis, and heat shock proteins. Exerc Immunol Rev 2001; 7: 66–89

    CAS  PubMed  Google Scholar 

  64. Wittwer M, Billeter R, Hoppeler H, et al. Regulatory gene expression in skeletal muscle of highly endurance—trained humans. Acta Physiol Scand 2004 Feb; 180 (2): 217–27

    Google Scholar 

  65. Ames BN, Gold LS, Willett WC. The causes and prevention of cancer. Proc Natl Acad Sci U S A 1995 Jun 6; 92 (12): 5258–65

    Google Scholar 

  66. Clayson DB, Mehta R, Iverson F. International commission for protection against environmental mutagens and carcinogens: oxidative DNA damage: the effects of certain genotoxic and operationally non—genotoxic carcinogens. Mutat Res 1994 Feb; 317 (1): 25–42

    Google Scholar 

  67. Feig DI, Reid TM, Loeb LA. Reactive oxygen species in tumorigenesis. Cancer Res 1994 Apr 1; 54 (7 Suppl.): 1890–4s

    Google Scholar 

  68. Kasai H, Nishimura S. Hydroxylation of deoxyguanosine at the C−8 position by ascorbic acid and other reducing agents. Nucleic Acids Res 1984 Feb 24; 12 (4): 2137–45

    Google Scholar 

  69. Asami S, Hirano T, Yamaguchi R, et al. Reduction of 8−hydroxyguanine in human leukocyte DNA by physical exercise. Free Radic Res 1998 Dec; 29 (6): 581–4

    Google Scholar 

  70. Sato Y, Nanri H, Ohta M, et al. Increase of human MTH1 and decrease of 8−hydroxydeoxyguanosine in leukocyte DNA by acute and chronic exercise in healthy male subjects. Biochem Biophys Res Commun 2003 May 30; 305 (2): 333–8

    Google Scholar 

  71. Ogonovszky H, Sasvari M, Dosek A, et al. The effects of moderate, strenuous, and overtraining on oxidative stress markers and DNA repair in rat liver. Can J Appl Physiol 2005 Apr; 30 (2): 186–95

    Google Scholar 

  72. Ennezat PV, Malendowicz SL, Testa M, et al. Physical training in patients with chronic heart failure enhances the expression of genes encoding antioxidative enzymes. J Am Coll Cardiol 2001 Jul; 38 (1): 194–8

    Google Scholar 

  73. Radak Z, Naito H, Kaneko T, et al. Exercise training decreases DNA damage and increases DNA repair and resistance against oxidative stress of proteins in aged rat skeletal muscle. Pflugers Arch 2002 Nov; 445 (2): 273–8

    Google Scholar 

  74. Nakatani K, Komatsu M, Kato T, et al. Habitual exercise induced resistance to oxidative stress. Free Radic Res 2005 Sep; 39 (9): 905–11

    Google Scholar 

  75. Duncan K, Harris S, Ardies CM. Running exercise may reduce risk for lung and liver cancer by inducing activity of antioxidant and phase II enzymes. Cancer Lett 1997 Jun 24; 116 (2): 151–8

    Google Scholar 

  76. Beyer RE, Segura-Aguilar J, Di Bernardo S, et al. The role of DT—diaphorase in the maintenance of the reduced antioxidant form of coenzyme Q in membrane systems. Proc Natl Acad Sci U S A 1996 Mar 19; 93 (6): 2528–32

    Google Scholar 

  77. Radak Z, Gaal D, Taylor AW, et al. Attenuation of the development of murine solid leukemia tumor by physical exercise. Antioxid Redox Signal 2002 Feb; 4 (1): 213–9

    Google Scholar 

  78. Sakumi K, Furuichi M, Tsuzuki T, et al. Cloning and expression of cDNA for a human enzyme that hydrolyzes 8−oxo—dGTP, a mutagenic substrate for DNA synthesis. J Biol Chem 1993 Nov 5; 268 (31): 23524–30

    Google Scholar 

  79. Kang JJ, Yokoi TJ, Holland MJ. Binding sites for abundant nuclear factors modulate RNA polymerase I—dependent enhancer function in Saccharomyces cerevisiae. J Biol Chem 1995 Dec 1; 270 (48): 28723–32

    Google Scholar 

  80. Goto S, Takahashi R, Kumiyama AA, et al. Implications of protein degradation in aging. Ann N Y Acad Sci 2001 Apr; 928: 54–64

    Google Scholar 

  81. Thompson HJ, Strange R, Schedin PJ. Apoptosis in the genesis and prevention of cancer. Cancer Epidemiol Biomarkers Prev 1992 Nov-Dec; 1 (7): 597–602

    Google Scholar 

  82. Slaga TJ, Klein-Szanto AJ, Fischer SM, et al. Studies on mechanism of action of anti—tumor—promoting agents: their specificity in two—stage promotion. Proc Natl Acad Sci U S A 1980 Apr; 77 (4): 2251–4

    Google Scholar 

  83. Blumberg PM. Protein kinase C as the receptor for the phorbolester tumor promoters. Cancer Res 1988; 48: 1–8

    CAS  PubMed  Google Scholar 

  84. Fischer SM, DiGiovanni J. Mechanisms of tumor promotion: epigenetic changes in cell signaling. Cancer Bull 1995; 47: 456–63

    Google Scholar 

  85. DiGiovanni J. Multistage carcinogenesis in mouse skin. Pharmacol Ther 1992; 54 (1): 63–128

    Google Scholar 

  86. Furstenberger G, Marks F. Prostaglandins, epidermal hyperplasia and skin tumor promotion. In: Honn KV, Martin LJ, editors. Prostaglandins, leukotrienes and cancer. Boston (MA): Marinus Nijhoff Publishers, 1985: 22–37

    Google Scholar 

  87. Sigal E. The molecular biology of mammalian arachidonic acid metabolism. Am J Physiol 1991 Feb; 260 (2 Pt 1): L13–28

    Google Scholar 

  88. Simonson MS, Wolfe JA, Dunn MJ. Regulation of prostaglandin synthesis by differential expression of the gene encoding prostaglandin endoperoxide synthase. In: Sammuelsson B, editor. Advances in prostaglandin, thromboxane and leukotriene research. Vol. 21. New York: Raven Press, 1990

    Google Scholar 

  89. Harris CC. p53: at the crossroads of molecular carcinogenesis and risk assessment. Science 1993 Dec 24; 262 (5142): 1980–1

    Google Scholar 

  90. Smith ML, Chen IT, Zhan Q, et al. Involvement of the p53 tumor suppressor in repair of u.v.—type DNA damage. Oncogene 1995 Mar 16; 10 (6): 1053–9

    Google Scholar 

  91. Livingstone LR, White A, Sprouse J, et al. Altered cell cycle arrest and gene amplification potential accompany loss of wild—type p53. Cell 1992 Sep 18; 70 (6): 923–35

    Google Scholar 

  92. Guinn BA, Mills KI. p53 mutations, methylation and genomic instability in the progression of chronic myeloid leukaemia. Leuk Lymphoma 1997 Jul; 26 (3-4): 211–26

    Google Scholar 

  93. Albanes D, Winick M. Are cell number and cell proliferation risk factors for cancer? J Natl Cancer Inst 1988 Jul 20; 80 (10): 772–4

    Google Scholar 

  94. Boyd NF, Martin LJ, Stone J, et al. Mammographic densities as a marker of human breast cancer risk and their use in chemoprevention. Curr Oncol Rep 2001 Jul; 3 (4): 314–21

    Google Scholar 

  95. Westerlind KC, Mc Carty HL, Gibson KJ, et al. Effect of exercise on the rat mammary gland: implications for carcinogenesis. Acta Physiol Scand 2002 Jun; 175 (2): 147–56

    Google Scholar 

  96. Russo J, Russo IH. Biological and molecular bases of mammary carcinogenesis. Lab Invest 1987 Aug; 57 (2): 112–37

    Google Scholar 

  97. Whittal KS, Parkhouse WS. Exercise during adolescence and its effects on mammary gland development, proliferation, and nitrosomethylurea (NMU) induced tumorigenesis in rats. Breast Cancer Res Treat 1996; 37 (1): 21–7

    CAS  PubMed  Google Scholar 

  98. Whittal-Strange KS, Chadan S, Parkhouse WS. Exercise during puberty and NMU induced mammary tumorigenesis in rats. Breast Cancer Res Treat 1998 Jan; 47 (1): 1–8

    Google Scholar 

  99. Michna L, Wagner GC, Lou YR, et al. Inhibitory effects of voluntary running wheel exercise on UVB—induced skin carcinogenesis in SKH−1 mice. Carcinogenesis 2006 Oct; 27 (10): 2108–15

    Google Scholar 

  100. Lu YP, Lou YR, Nolan B, et al. Stimulatory effect of voluntary exercise or fat removal (partial lipectomy) on apoptosis in the skin of UVB light—irradiated mice. Proc Natl Acad Sci U S A 2006 Oct 31; 103 (44): 16301–6

    Google Scholar 

  101. Leung PS, Aronson WJ, Ngo TH, et al. Exercise alters the IGF axis in vivo and increases p53 protein in prostate tumor cells in vitro. J Appl Physiol 2004 Feb; 96 (2): 450–4

    Google Scholar 

  102. Weindruch R, Walford RL. The retardation of aging and disease by dietary restriction. Springfield (IL): Charles C. Thomas, 1988: 1–291

    Google Scholar 

  103. Cohen LA, Choi KW, Wang CX. Influence of dietary fat, caloric restriction, and voluntary exercise on N—nitrosomethylurea—induced mammary tumorigenesis in rats. Cancer Res 1988 Aug 1; 48 (15): 4276–83

    Google Scholar 

  104. Cohen LA, Choi K, Backlund JY, et al. Modulation of N—nitrosomethylurea induced mammary tumorigenesis by dietary fat and voluntary exercise. In Vivo 1991 Jul-Aug; 5 (4): 333–44

    Google Scholar 

  105. Cohen LA, Kendall ME, Meschter C, et al. Inhibition of rat mammary tumorigenesis by voluntary exercise. In Vivo 1993 Mar-Apr; 7 (2): 151–8

    Google Scholar 

  106. Thompson HJ, Ronan AM, Ritacco KA, et al. Effect of exercise on the induction of mammary carcinogenesis. Cancer Res 1988 May 15; 48 (10): 2720–3

    Google Scholar 

  107. Thompson HJ, Ronan AM, Ritacco KA, et al. Effect of type and amount of dietary fat on the enhancement of rat mammary tumorigenesis by exercise. Cancer Res 1989 Apr 15; 49 (8): 1904–8

    Google Scholar 

  108. Thompson HJ, Westerlind KC, Snedden J, et al. Exercise intensity dependent inhibition of 1−methyl−1−nitrosourea induced mammary carcinogenesis in female F−344 rats. Carcinogenesis 1995 Aug; 16 (8): 1783–6

    Google Scholar 

  109. Gillette CA, Zhu Z, Westerlind KC, et al. Energy availability and mammary carcinogenesis: effects of calorie restriction and exercise. Carcinogenesis 1997 Jun; 18 (6): 1183–8

    Google Scholar 

  110. Westerlind KC, Mc Carty HL, Schultheiss PC, et al. Moderate exercise training slows mammary tumour growth in adolescent rats. Eur J Cancer Prev 2003 Aug; 12 (4): 281–7

    Google Scholar 

  111. Thorling EB, Jacobsen NO, Overvad K. Effect of exercise on intestinal tumour development in the male Fischer rat after exposure to azoxymethane. Eur J Cancer Prev 1993 Jan; 2 (1): 77–82

    Google Scholar 

  112. Reddy BS, Sugie S, Lowenfels A. Effect of voluntary exercise on azoxymethane—induced colon carcinogenesis in male F344 rats. Cancer Res 1988 Dec 15; 48 (24 Pt 1): 7079–81

    Google Scholar 

  113. Moser AR, Pitot HC, Dove WF. A dominant mutation that predisposes to multiple intestinal neoplasia in the mouse. Science 1990 Jan 19; 247 (4940): 322–4

    Google Scholar 

  114. Colbert LH, Davis JM, Essig DA, et al. Exercise and tumor development in a mouse predisposed to multiple intestinal adenomas. Med Sci Sports Exerc 2000 Oct; 32 (10): 1704–8

    Google Scholar 

  115. Colbert LH, Mai V, Perkins SN, et al. Exercise and intestinal polyp development in APCMin mice. Med Sci Sports Exerc 2003 Oct; 35 (10): 1662–9

    Google Scholar 

  116. Colbert LH, Mai V, Tooze JA, et al. Negative energy balance induced by voluntary wheel running inhibits polyp development in APCMin mice. Carcinogenesis 2006 Oct; 27 (10): 2103–7

    Google Scholar 

  117. Roebuck BD, Mc Caffrey J, Baumgartner KJ. Protective effects of voluntary exercise during the postinitiation phase of pancreatic carcinogenesis in the rat. Cancer Res 1990 Nov 1; 50 (21): 6811–6

    Google Scholar 

  118. Giles TC, Roebuck BD. Effects of voluntary exercise and/or food restriction on pancreatic tumorigenesis in male rats. Adv Exp Med Biol 1992; 322: 17–27

    CAS  PubMed  Google Scholar 

  119. Kazakoff K, Cardesa T, Liu J, et al. Effects of voluntary physical exercise on high—fat diet—promoted pancreatic carcinogenesis in the hamster model. Nutr Cancer 1996; 26 (3): 265–79

    CAS  PubMed  Google Scholar 

  120. Baracos VE. Exercise inhibits progressive growth of the Morris hepatoma 7777 in male and female rats. Can J Physiol Pharmacol 1989 Aug; 67 (8): 864–70

    Google Scholar 

  121. Sugie S, Reddy BS, Lowenfels A, et al. Effect of voluntary exercise on azoxymethane-induced hepatocarcinogenesis in male F344 rats. Cancer Lett 1992 Mar 31; 63 (1): 67–72

    Google Scholar 

  122. Ikuyama T, Watanabe T, Minegishi Y, et al. Effect of voluntary exercise on 3’−methyl−4−dimethylaminoazobenzene—induced hepatomas in male Jc1:Wistar rats. Proc Soc Exp Biol Med 1993 Nov; 204 (2): 211–5

    Google Scholar 

  123. Holloszy JO. Mortality rate and longevity of food—restricted exercising male rats: a reevaluation. J Appl Physiol 1997 Feb; 82 (2): 399–403

    Google Scholar 

  124. Holloszy JO, Schechtman KB. Interaction between exercise and food restriction: effects on longevity of male rats. J Appl Physiol 1991 Apr; 70 (4): 1529–35

    Google Scholar 

  125. Wang C, Weindruch R, Fernandez JR, et al. Caloric restriction and body weight independently affect longevity in Wistar rats. Int J Obes Relat Metab Disord 2004 Mar; 28 (3): 357–62

    Google Scholar 

  126. Davis BJ, Travlos G, Mc Shane T. Reproductive endocrinology and toxicological pathology over the life span of the female rodent. Toxicol Pathol 2001 Jan-Feb; 29 (1): 77–83

    Google Scholar 

  127. Yu H, Rohan T. Role of the insulin—like growth factor family in cancer development and progression. J Natl Cancer Inst 2000 Sep 20; 92 (18): 1472–89

    Google Scholar 

  128. Kaaks R, Lukanova A. Energy balance and cancer: the role of insulin and insulin—like growth factor—I. Proc Nutr Soc 2001 Feb; 60 (1): 91–106

    Google Scholar 

  129. Wu Y, Yakar S, Zhao L, et al. Circulating insulin—like growth factor—I levels regulate colon cancer growth and metastasis. Cancer Res 2002 Feb 15; 62 (4): 1030–5

    Google Scholar 

  130. Kari FW, Dunn SE, French JE, et al. Roles for insulin—like growth factor−1 in mediating the anti—carcinogenic effects of caloric restriction. J Nutr Health Aging 1999; 3 (2): 92–101

    CAS  PubMed  Google Scholar 

  131. Russell-Jones DL, Umpleby AM, Hennessy TR, et al. Use of a leucine clamp to demonstrate that IGF—I actively stimulates protein synthesis in normal humans. Am J Physiol 1994 Oct; 267 (4 Pt 1): E591–8

    Google Scholar 

  132. Adams GR, Mc Cue SA. Localized infusion of IGF—I results in skeletal muscle hypertrophy in rats. J Appl Physiol 1998 May; 84 (5): 1716–22

    Google Scholar 

  133. Consitt LA, Copeland JL, Tremblay MS. Endogenous anabolic hormone responses to endurance versus resistance exercise and training in women. Sports Med 2002; 32 (1): 1–22

    PubMed  Google Scholar 

  134. Bravenboer N, Engelbregt MJ, Visser NA, et al. The effect of exercise on systemic and bone concentrations of growth factors in rats. J Orthop Res 2001 Sep; 19 (5): 945–9

    Google Scholar 

  135. Caston AL, Farrell PA, Deaver DR. Exercise training—induced changes in anterior pituitary gonadotrope of the female rat. J Appl Physiol 1995 Jul; 79 (1): 194–201

    Google Scholar 

  136. Axelson JF. Forced swimming alters vaginal estrous cycles, body composition, and steroid levels without disrupting lordosis behavior or fertility in rats. Physiol Behav 1987; 41 (5): 471–9

    CAS  PubMed  Google Scholar 

  137. Latour MG, Shinoda M, Lavoie JM. Metabolic effects of physical training in ovariectomized and hyperestrogenic rats. J Appl Physiol 2001 Jan; 90 (1): 235–41

    Google Scholar 

  138. Shinoda M, Latour MG, Lavoie JM. Effects of physical training on body composition and organ weights in ovariectomized and hyperestrogenic rats. Int J Obes Relat Metab Disord 2002 Mar; 26 (3): 335–43

    Google Scholar 

  139. Sakakura Y, Shide N, Tsuruga E, et al. Effects of running exercise on the mandible and tibia of ovariectomized rats. J Bone Miner Metab 2001; 19 (3): 159–67

    CAS  PubMed  Google Scholar 

  140. Hoffman-Goetz L, Fietsch CL, Mc Cutcheon D, et al. Effect of 17beta—estradiol and voluntary exercise on lymphocyte apoptosis in mice. Physiol Behav 2001 Nov-Dec; 74 (4-5): 653–8

    Google Scholar 

  141. Hoffman-Goetz L, Fietsch CL. Lymphocyte apoptosis in ovariectomized mice given progesterone and voluntary exercise. J Sports Med Phys Fitness 2002 Dec; 42 (4): 481–7

    Google Scholar 

  142. Williams NI, Caston-Balderrama AL, Helmreich DL, et al. Longitudinal changes in reproductive hormones and menstrual cyclicity in cynomolgus monkeys during strenuous exercise training: abrupt transition to exercise—induced amenorrhea. Endocrinology 2001 Jun; 142 (6): 2381–9

    Google Scholar 

  143. Loucks AB, Verdun M, Heath EM. Low energy availability, not stress of exercise, alters LH pulsatility in exercising women. J Appl Physiol 1998 Jan; 84 (1): 37–46

    Google Scholar 

  144. Pieper DR, Ali HY, Benson LL, et al. Voluntary exercise increases gonadotropin secretion in male Golden hamsters. Am J Physiol 1995 Jul; 269 (1 Pt 2): R179–85

    Google Scholar 

  145. Pieper DR, Lobocki CA, Lichten EM, et al. Dehydroepiandrosterone and exercise in golden hamsters. Physiol Behav 1999 Oct; 67 (4): 607–10

    Google Scholar 

  146. Hu Y, Asano K, Kim S, et al. Relationship between serum testosterone and activities of testicular enzymes after continuous and intermittent training in male rats. Int J Sports Med 2004 Feb; 25 (2): 99–102

    Google Scholar 

  147. Hu Y, Asano K, Mizuno K, et al. Serum testosterone responses to continuous and intermittent exercise training in male rats. Int J Sports Med 1999 Jan; 20 (1): 12–6

    Google Scholar 

  148. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002 Dec 19-26; 420 (6917): 860–7

    Google Scholar 

  149. Tilg H, Dinarello CA, Mier JW. IL−6 and APPs: anti—inflammatory and immunosuppressive mediators. Immunol Today 1997 Sep; 18 (9): 428–32

    Google Scholar 

  150. Dinarello CA. The role of the interleukin−1−receptor antagonist in blocking inflammation mediated by interleukin−1. N Engl J Med 2000 Sep 7; 343 (10): 732–4

    Google Scholar 

  151. Moore KW, O’Garra A, de Waal Malefyt R, et al. Interleukin−10. Annu Rev Immunol 1993; 11: 165–90

    CAS  PubMed  Google Scholar 

  152. Pretolani M. Interleukin−10: an anti—inflammatory cytokine with therapeutic potential. Clin Exp Allergy 1999 Sep; 29 (9): 1164–71

    Google Scholar 

  153. Coppack SW. Pro—inflammatory cytokines and adipose tissue. Proc Nutr Soc 2001 Aug; 60 (3): 349–56

    Google Scholar 

  154. Dandona P, Aljada A, Bandyopadhyay A. Inflammation: the link between insulin resistance, obesity and diabetes. Trends Immunol 2004 Jan; 25 (1): 4–7

    Google Scholar 

  155. Weisberg SP, Mc Cann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest 2003 Dec; 112 (12): 1796–808

    Google Scholar 

  156. Xu H, Barnes GT, Yang Q, et al. Chronic inflammation in fat plays a crucial role in the development of obesity—related insulin resistance. J Clin Invest 2003 Dec; 112 (12): 1821–30

    Google Scholar 

  157. Bastard JP, Maachi M, Lagathu C, et al. Recent advances in the relationship between obesity, inflammation, and insulin resistance. Eur Cytokine Netw 2006 Mar; 17 (1): 4–12

    Google Scholar 

  158. Hotamisligil GS, Murray DL, Choy LN, et al. Tumor necrosis factor alpha inhibits signaling from the insulin receptor. Proc Natl Acad Sci U S A 1994 May 24; 91 (11): 4854–8

    Google Scholar 

  159. Rotter V, Nagaev I, Smith U. Interleukin−6 (IL−6) induces insulin resistance in 3T3−L1 adipocytes and is, like IL−8 and tumor necrosis factor—alpha, overexpressed in human fat cells from insulin—resistant subjects. J Biol Chem 2003 Nov 14; 278 (46): 45777–84

    Google Scholar 

  160. Ballou SP, Lozanski FB, Hodder S, et al. Quantitative and qualitative alterations of acute—phase proteins in healthy elderly persons. Age Ageing 1996 May; 25 (3): 224–30

    Google Scholar 

  161. Paolisso G, Rizzo MR, Mazziotti G, et al. Advancing age and insulin resistance: role of plasma tumor necrosis factor—alpha. Am J Physiol 1998 Aug; 275 (2 Pt 1): E294–9

    Google Scholar 

  162. Bruunsgaard H, Jensen MS, Schjerling P, et al. Exercise induces recruitment of lymphocytes with an activated phenotype and short telomeres in young and elderly humans. Life Sci 1999; 65 (24): 2623–33

    CAS  PubMed  Google Scholar 

  163. Dobbs RJ, Charlett A, Purkiss AG, et al. Association of circulating TNF—alpha and IL−6 with ageing and parkinsonism. Acta Neurol Scand 1999 Jul; 100 (1): 34–41

    Google Scholar 

  164. Bruunsgaard H, Skinhoj P, Pedersen AN, et al. Ageing, tumour necrosis factor—alpha (TNF—alpha) and atherosclerosis. Clin Exp Immunol 2000 Aug; 121 (2): 255–60

    Google Scholar 

  165. Bruunsgaard H, Christiansen L, Pedersen AN, et al. The IL−6–174G>C polymorphism is associated with cardiovascular diseases and mortality in 80−year—old humans. Exp Gerontol 2004 Feb; 39 (2): 255–61

    Google Scholar 

  166. Vgontzas AN, Papanicolaou DA, Bixler EO, et al. Sleep apnea and daytime sleepiness and fatigue: relation to visceral obesity, insulin resistance, and hypercytokinemia. J Clin Endocrinol Metab 2000 Mar; 85 (3): 1151–8

    Google Scholar 

  167. Feingold KR, Grunfeld C. Role of cytokines in inducing hyperlipidemia. Diabetes 1992 Oct; 41 Suppl. 2: 97–101

    Google Scholar 

  168. Winkler G, Salamon F, Harmos G, et al. Elevated serum tumor necrosis factor—alpha concentrations and bioactivity in type 2 diabetics and patients with android type obesity. Diabetes Res Clin Pract 1998 Dec; 42 (3): 169–74

    Google Scholar 

  169. Mishima Y, Kuyama A, Tada A, et al. Relationship between serum tumor necrosis factor—alpha and insulin resistance in obese men with type 2 diabetes mellitus. Diabetes Res Clin Pract 2001 May; 52 (2): 119–23

    Google Scholar 

  170. Harris TB, Savage PJ, Tell GS, et al. Carrying the burden of cardiovascular risk in old age: associations of weight and weight change with prevalent cardiovascular disease, risk factors, and health status in the Cardiovascular Health Study. Am J Clin Nutr 1997 Oct; 66 (4): 837–44

    Google Scholar 

  171. Bruunsgaard H, Andersen-Ranberg K, Jeune B, et al. A high plasma concentration of TNF—alpha is associated with dementia in centenarians. J Gerontol A Biol Sci Med Sci 1999 Jul; 54 (7): M357–64

    Google Scholar 

  172. Volpato S, Guralnik JM, Ferrucci L, et al. Cardiovascular disease, interleukin−6, and risk of mortality in older women: the women’s health and aging study. Circulation 2001 Feb 20; 103 (7): 947–53

    Google Scholar 

  173. Erlinger TP, Platz EA, Rifai N, et al. C—reactive protein and the risk of incident colorectal cancer. JAMA 2004 Feb 4; 291 (5): 585–90

    Google Scholar 

  174. Lehrer S, Diamond EJ, Mamkine B, et al. C—reactive protein is significantly associated with prostate—specific antigen and metastatic disease in prostate cancer. Br J Urol Int 2005 May; 95 (7): 961–2

    Google Scholar 

  175. Smith JK, Dykes R, Douglas JE, et al. Long—term exercise and atherogenic activity of blood mononuclear cells in persons at risk of developing ischemic heart disease. JAMA 1999 May 12; 281 (18): 1722–7

    Google Scholar 

  176. Mattusch F, Dufaux B, Heine O, et al. Reduction of the plasma concentration of C—reactive protein following nine months of endurance training. Int J Sports Med 2000 Jan; 21 (1): 21–4

    Google Scholar 

  177. Taaffe DR, Harris TB, Ferrucci L, et al. Cross—sectional and prospective relationships of interleukin−6 and C—reactive protein with physical performance in elderly persons: MacArthur studies of successful aging. J Gerontol A Biol Sci Med Sci 2000 Dec; 55 (12): M709–15

    Google Scholar 

  178. Fallon KE, Fallon SK, Boston T. The acute phase response and exercise: court and field sports. Br J Sports Med 2001 Jun; 35 (3): 170–3

    Google Scholar 

  179. Geffken DF, Cushman M, Burke GL, et al. Association between physical activity and markers of inflammation in a healthy elderly population. Am J Epidemiol 2001 Feb 1; 153 (3): 242–50

    Google Scholar 

  180. Abramson JL, Vaccarino V. Relationship between physical activity and inflammation among apparently healthy middle—aged and older US adults. Arch Intern Med 2002 Jun 10; 162 (11): 1286–92

    Google Scholar 

  181. Wannamethee SG, Lowe GD, Whincup PH, et al. Physical activity and hemostatic and inflammatory variables in elderly men. Circulation 2002 Apr 16; 105 (15): 1785–90

    Google Scholar 

  182. King DE, Carek P, Mainous III AG, et al. Inflammatory markers and exercise: differences related to exercise type. Med Sci Sports Exerc 2003 Apr; 35 (4): 575–81

    Google Scholar 

  183. Fischer CP, Berntsen A, Perstrup LB, et al. Plasma levels of interleukin−6 and C—reactive protein are associated with physical inactivity independent of obesity. Scand J Med Sci Sports 2007; 17 (5): 580–7

    CAS  PubMed  Google Scholar 

  184. Starkie R, Ostrowski SR, Jauffred S, et al. Exercise and IL−6 infusion inhibit endotoxin—induced TNF—alpha production in humans. FASEB J 2003 May; 17 (8): 884–6

    Google Scholar 

  185. Keller C, Keller P, Giralt M, et al. Exercise normalises over expression of TNF—alpha in knockout mice. Biochem Biophys Res Commun 2004 Aug 13; 321 (1): 179–82

    Google Scholar 

  186. Petersen AM, Pedersen BK. The anti—inflammatory effect of exercise. J Appl Physiol 2005 Apr; 98 (4): 1154–62

    Google Scholar 

  187. Ostrowski K, Rohde T, Asp S, et al. Pro— and anti—inflammatory cytokine balance in strenuous exercise in humans. J Physiol 1999 Feb 15; 515 (Pt 1): 287–91

    Google Scholar 

  188. Ostrowski K, Schjerling P, Pedersen BK. Physical activity and plasma interleukin−6 in humans: effect of intensity of exercise. Eur J Appl Physiol 2000 Dec; 83 (6): 512–5

    Google Scholar 

  189. Pedersen BK, Hoffman-Goetz L. Exercise and the immune system: regulation, integration, and adaptation. Physiol Rev 2000 Jul; 80 (3): 1055–81

    Google Scholar 

  190. Pedersen BK, Steensberg A, Schjerling P. Muscle—derived interleukin−6: possible biological effects. J Physiol 2001 Oct 15; 536 (Pt 2): 329–37

    Google Scholar 

  191. Suzuki K, Nakaji S, Yamada M, et al. Systemic inflammatory response to exhaustive exercise: cytokine kinetics. Exerc Immunol Rev 2002; 8: 6–48

    PubMed  Google Scholar 

  192. Febbraio MA, Hiscock N, Sacchetti M, et al. Interleukin−6 is a novel factor mediating glucose homeostasis during skeletal muscle contraction. Diabetes 2004 Jul; 53 (7): 1643–8

    Google Scholar 

  193. Fischer CP. Interleukin−6 in acute exercise and training: what is the biological relevance? Exerc Immunol Rev 2006; 12: 6–33

    PubMed  Google Scholar 

  194. Pedersen BK, Fischer CP. Physiological roles of muscle—derived interleukin−6 in response to exercise. Curr Opin Clin Nutr Metab Care 2007 May; 10 (3): 265–71

    Google Scholar 

  195. Penkowa M, Keller C, Keller P, et al. Immunohistochemical detection of interleukin−6 in human skeletal muscle fibers following exercise. FASEB J 2003 Nov; 17 (14): 2166–8

    Google Scholar 

  196. Steensberg A, Fischer CP, Keller C, et al. IL−6 enhances plasma IL−1ra, IL−10, and cortisol in humans. Am J Physiol Endocrinol Metab 2003 Aug; 285 (2): E433–7

    Google Scholar 

  197. Hiscock N, Chan MH, Bisucci T, et al. Skeletal myocytes are a source of interleukin−6 mRNA expression and protein release during contraction: evidence of fiber type specificity. FASEB J 2004 Jun; 18 (9): 992–4

    Google Scholar 

  198. Ullum H, Haahr PM, Diamant M, et al. Bicycle exercise enhances plasma IL−6 but does not change IL−1 alpha, IL−1 beta, IL−6, or TNF−alpha pre—mRNA in BMNC. J Appl Physiol 1994 Jul; 77 (1): 93–7

    Google Scholar 

  199. Moldoveanu AI, Shephard RJ, Shek PN. Exercise elevates plasma levels but not gene expression of IL−1beta, IL−6, and TNF—alpha in blood mononuclear cells. J Appl Physiol 2000 Oct; 89 (4): 1499–504

    Google Scholar 

  200. Starkie RL, Rolland J, Angus DJ, et al. Circulating monocytes are not the source of elevations in plasma IL−6 and TNF—alpha levels after prolonged running. Am J Physiol Cell Physiol 2001 Apr; 280 (4): C769–74

    Google Scholar 

  201. Schindler R, Mancilla J, Endres S, et al. Correlations and interactions in the production of interleukin−6 (IL−6), IL−1, and tumor necrosis factor (TNF) in human blood mononuclear cells: IL−6 suppresses IL−1 and TNF. Blood 1990 Jan 1; 75 (1): 40–7

    Google Scholar 

  202. Mizuhara H, O’Neill E, Seki N, et al. T cell activation—associated hepatic injury: mediation by tumor necrosis factors and protection by interleukin 6. J Exp Med 1994 May 1; 179 (5): 1529–37

    Google Scholar 

  203. Matthys P, Mitera T, Heremans H, et al. Anti—gamma interferon and anti—interleukin−6 antibodies affect staphylococcal enterotoxin B—induced weight loss, hypoglycemia, and cytokine release in D—galactosamine—sensitized and unsensitized mice. Infect Immun 1995 Apr; 63 (4): 1158–64

    Google Scholar 

  204. Tilg H, Trehu E, Atkins MB, et al. Interleukin−6 (IL−6) as an anti—inflammatory cytokine: induction of circulating IL−1 receptor antagonist and soluble tumor necrosis factor receptor p55. Blood 1994 Jan 1; 83 (1): 113–8

    Google Scholar 

  205. Steensberg A, Keller C, Starkie RL, et al. IL−6 and TNF—alpha expression in, and release from, contracting human skeletal muscle. Am J Physiol Endocrinol Metab 2002 Dec; 283 (6): E1272–8

    Google Scholar 

  206. Steensberg A, Fischer CP, Sacchetti M, et al. Acute interleukin−6 administration does not impair muscle glucose uptake or whole—body glucose disposal in healthy humans. J Physiol 2003 Apr 15; 548 (Pt 2): 631–8

    Google Scholar 

  207. Ji LL, Gomez-Cabrera MC, Steinhafel N, et al. Acute exercise activates nuclear factor (NF)—kappaB signaling pathway in rat skeletal muscle. FASEB J 2004 Oct; 18 (13): 1499–506

    Google Scholar 

  208. Ho RC, Hirshman MF, Li Y, et al. Regulation of IkappaB kinase and NF—kappaB in contracting adult rat skeletal muscle. Am J Physiol Cell Physiol 2005 Oct; 289 (4): C794–801

    Google Scholar 

  209. Vasilaki A, Mc Ardle F, Iwanejko LM, et al. Adaptive responses of mouse skeletal muscle to contractile activity: the effect of age. Mech Ageing Dev 2006 Nov; 127 (11): 830–9

    Google Scholar 

  210. Hoppeler H, Fluck M. Plasticity of skeletal muscle mitochondria: structure and function. Med Sci Sports Exerc 2003 Jan; 35 (1): 95–104

    Google Scholar 

  211. Durham WJ, Li YP, Gerken E, et al. Fatiguing exercise reduces DNA binding activity of NF—kappaB in skeletal muscle nuclei. J Appl Physiol 2004 Nov; 97 (5): 1740–5

    Google Scholar 

  212. Radak Z, Chung HY, Naito H, et al. Age—associated increase in oxidative stress and nuclear factor kappaB activation are attenuated in rat liver by regular exercise. FASEB J 2004 Apr; 18 (6): 749–50

    Google Scholar 

  213. Bacuau RF, Belmonte MA, Seelaender MC, et al. Effect of a moderate intensity exercise training protocol on the metabolism of macrophages and lymphocytes of tumour—bearing rats. Cell Biochem Funct 2000 Dec; 18 (4): 249–58

    Google Scholar 

  214. Woods JA, Davis JM, Kohut ML, et al. Effects of exercise on the immune response to cancer. Med Sci Sports Exerc 1994 Sep; 26 (9): 1109–15

    Google Scholar 

  215. Shewchuk LD, Baracos VE, Field CJ. Dietary L—glutamine supplementation reduces the growth of the Morris Hepatoma 7777 in exercise—trained and sedentary rats. J Nutr 1997 Jan; 127 (1): 158–66

    Google Scholar 

  216. Zielinski MR, Muenchow M, Wallig MA, et al. Exercise delays allogeneic tumor growth and reduces intratumoral inflammation and vascularization. J Appl Physiol 2004 Jun; 96 (6): 2249–56

    Google Scholar 

  217. Davis JM, Kohut ML, Colbert LH, et al. Exercise, alveolar macrophage function, and susceptibility to respiratory infection. J Appl Physiol 1997 Nov; 83 (5): 1461–6

    Google Scholar 

  218. Murphy EA, Davis JM, Brown AS, et al. Effects of moderate exercise and oat beta—glucan on lung tumor metastases and macrophage antitumor cytotoxicity. J Appl Physiol 2004 Sep; 97 (3): 955–9

    Google Scholar 

  219. Woods JA, Davis JM, Mayer EP, et al. Exercise increases inflammatory macrophage antitumor cytotoxicity. J Appl Physiol 1993 Aug; 75 (2): 879–86

    Google Scholar 

  220. Lu Q, Ceddia MA, Price EA, et al. Chronic exercise increases macrophage—mediated tumor cytolysis in young and old mice. Am J Physiol 1999 Feb; 276 (2 Pt 2): R482–9

    Google Scholar 

  221. Burnet FM. The concept of immunological surveillance. Prog Exp Tumor Res 1970; 13: 1–27

    CAS  PubMed  Google Scholar 

  222. Stutman O. Chemical carcinogenesis in nude mice: comparison between nude mice from homozygous matings and heterozygous matings and effect of age and carcinogen dose. J Natl Cancer Inst 1979 Feb; 62 (2): 353–8

    Google Scholar 

  223. Groopman JE. Neoplasms in the acquired immune deficiency syndrome: the multidisciplinary approach to treatment. Semin Oncol 1987 Jun; 14 (2 Suppl. 3): 1–6

    Google Scholar 

  224. Smyth MJ, Trapani JA. Lymphocyte—mediated immunosurveillance of epithelial cancers? Trends Immunol 2001 Aug; 22 (8): 409–11

    Google Scholar 

  225. Barlozzari T, Leonhardt J, Wiltrout RH, et al. Direct evidence for the role of LGL in the inhibition of experimental tumor metastases. J Immunol 1985 Apr; 134 (4): 2783–9

    Google Scholar 

  226. Cerwenka A, Baron JL, Lanier LL. Ectopic expression of retinoic acid early inducible−1 gene (RAE−1) permits natural killer cell—mediated rejection of a MHC class I—bearing tumor in vivo. Proc Natl Acad Sci U S A 2001 Sep 25; 98 (20): 11521–6

    Google Scholar 

  227. Imai K, Matsuyama S, Miyake S, et al. Natural cytotoxic activity of peripheral—blood lymphocytes and cancer incidence: an 11−year follow—up study of a general population. Lancet 2000 Nov 25; 356 (9244): 1795–9

    Google Scholar 

  228. Kaplan DH, Shankaran V, Dighe AS, et al. Demonstration of an interferon gamma—dependent tumor surveillance system in immunocompetent mice. Proc Natl Acad Sci U S A 1998 Jun 23; 95 (13): 7556–61

    Google Scholar 

  229. Mac Neil B, Hoffman-Goetz L. Chronic exercise enhances in vivo and in vitro cytotoxic mechanisms of natural immunity in mice. J Appl Physiol 1993 Jan; 74 (1): 388–95

    Google Scholar 

  230. Hoffman-Goetz L, May KM, Arumugam Y. Exercise training and mouse mammary tumour metastasis. Anticancer Res 1994 Nov-Dec; 14 (6B): 2627–31

    Google Scholar 

  231. Jadeski L, Hoffman-Goetz L. Exercise and in vivo natural cytotoxicity against tumour cells of varying metastatic capacity. Clin Exp Metastasis 1996 Mar; 14 (2): 138–44

    Google Scholar 

  232. Hoffman-Goetz L, Mac Neil B, Arumugam Y, et al. Differential effects of exercise and housing condition on murine natural killer cell activity and tumor growth. Int J Sports Med 1992 Feb; 13 (2): 167–71

    Google Scholar 

  233. Hirokawa K. Understanding the mechanism of the age—related decline in immune function. Nutr Rev 1992 Dec; 50 (12): 361–6

    Google Scholar 

  234. Miller RA. The aging immune system: primer and prospectus. Science 1996 Jul 5; 273 (5271): 70–4

    Google Scholar 

  235. Miller RA. The aging immune system: subsets, signals, and survival. Aging (Milano) 1997; 9 (4 Suppl.): 23–4

    CAS  Google Scholar 

  236. Pawelec G, Solana R, Remarque E, et al. Impact of aging on innate immunity. J Leukoc Biol 1998 Dec; 64 (6): 703–12

    Google Scholar 

  237. Franceschi C, Bonafe M, Valensin S, et al. Inflamm—aging: an evolutionary perspective on immunosenescence. Ann N Y Acad Sci 2000 Jun; 908: 244–54

    Google Scholar 

  238. Wick G, Jansen-Durr P, Berger P, et al. Diseases of aging. Vaccine 2000 Feb 25; 18 (16): 1567–83

    Google Scholar 

  239. Nasrullah I, Mazzeo RS. Age—related immunosenescence in Fischer 344 rats: influence of exercise training. J Appl Physiol 1992 Nov; 73 (5): 1932–8

    Google Scholar 

  240. Utsuyama M, Ichikawa M, Konno-Shirakawa A, et al. Retardation of the age—associated decline of immune functions in aging rats under dietary restriction and daily physical exercise. Mech Ageing Dev 1996 Nov 13; 91 (3): 219–28

    Google Scholar 

  241. Kohut ML, Boehm GW, Moynihan JA. Moderate exercise is associated with enhanced antigen—specific cytokine, but not IgM antibody production in aged mice. Mech Ageing Dev 2001 Aug; 122 (11): 1135–50

    Google Scholar 

  242. Kohut ML, Thompson JR, Lee W, et al. Exercise training induced adaptations of immune response are mediated by beta adrenergic receptors in aged but not young mice. J Appl Physiol 2004 Apr; 96 (4): 1312–22

    Google Scholar 

  243. Bloor CM. Angiogenesis during exercise and training. Angiogenesis 2005; 8 (3): 263–71

    PubMed  Google Scholar 

  244. Gu JW, Gadonski G, Wang J, et al. Exercise increases endostatin in circulation of healthy volunteers. BMC Physiol 2004 Jan 16; 4: 2

    Google Scholar 

  245. Bailey AP, Shparago M, Gu JW. Exercise increases soluble vascular endothelial growth factor receptor−1 (sFlt−1) in circulation of healthy volunteers. Med Sci Monit 2006 Feb; 12 (2): CR45–50

    Google Scholar 

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Rogers, C.J., Colbert, L.H., Greiner, J.W. et al. Physical Activity and Cancer Prevention. Sports Med 38, 271–296 (2008). https://doi.org/10.2165/00007256-200838040-00002

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Keywords

  • Epidermal Growth Factor Receptor
  • Natural Killer Cell
  • Exercise Training
  • Calorie Restriction
  • Negative Energy Balance