A weighty problem: metabolic perturbations and the obesity-cancer link

References

1. Flegal KM, Carroll MD, Kit BK, Ogden CL. Prevalence of obesity and trends in the distribution of body mass index among US adults, 1999–2010. J Am Med Assoc 2012;307:491–7.10.1001/jama.2012.39Search in Google Scholar

2. Ng M, Fleming T, Robinson M, Thomson B, Graetz N, Margono C, Mullany EC, Biryukov S, Abbafati C, Abera SF, Abraham JP, Abu-Rmeileh NM, Achoki T, AlBuhairan FS, Alemu ZA, Alfonso R, Ali MK, Ali R, Guzman NA, Ammar W, Anwari P, Banerjee A, Barquera S, Basu S, Bennett DA, Bhutta Z, Blore J, Cabral N, Nonato IC, Chang JC, Chowdhury R, Courville KJ, Criqui MH, Cundiff DK, Dabhadkar KC, Dandona L, Davis A, Dayama A, Dharmaratne SD, Ding EL, Durrani AM, Esteghamati A, Farzadfar F, Fay DF, Feigin VL, Flaxman A, Forouzanfar MH, Goto A, Green MA, Gupta R, Hafezi-Nejad N, Hankey GJ, Harewood HC, Havmoeller R, Hay S, Hernandez L, Husseini A, Idrisov BT, Ikeda N, Islami F, Jahangir E, Jassal SK, Jee SH, Jeffreys M, Jonas JB, Kabagambe EK, Khalifa SE, Kengne AP, Khader YS, Khang YH, Kim D, Kimokoti RW, Kinge JM, Kokubo Y, Kosen S, Kwan G, Lai T, Leinsalu M, Li Y, Liang X, Liu S, Logroscino G, Lotufo PA, Lu Y, Ma J, Mainoo NK, Mensah GA, TR Merriman, Mokdad AH, Moschandreas J, Naghavi M, Naheed A, Nand D, Narayan KM, Nelson EL, Neuhouser ML, Nisar MI, Ohkubo T, Oti SO, Pedroza A, Prabhakaran D, Roy N, Sampson U, Seo H, Sepanlou SG, Shibuya K, Shiri R, Shiue I, Singh GM, Singh JA, Skirbekk V, Stapelberg NJ, Sturua L, Sykes BL, Tobias M, Tran BX, Trasande L, Toyoshima H, van de Vijver S, TJ Vasankari, Veerman JL, Velasquez-Melendez G, Vlassov VV, Vollset SE, Vos T, Wang C, Wang X, Weiderpass E, Werdecker A, Wright JL, Yang YC, Yatsuya H, Yoon J, Yoon SJ, Zhao Y, Zhou M, Zhu S, Lopez AD, Murray CJ, Gakidou E. Global, regional, and national prevalence of overweight and obesity in children and adults during 1980–2013: a systematic analysis for the global burden of disease study 2013. Lancet 2014;384:766–81.10.1016/S0140-6736(14)60460-8Search in Google Scholar

3. Khaodhiar L, McCowen KC, Blackburn GL. Obesity and its comorbid conditions. Clin Cornerstone 1999;2:17–31.10.1016/S1098-3597(99)90002-9Search in Google Scholar

4. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes 2013;2013:291546.10.1155/2013/291546Search in Google Scholar PubMed PubMed Central

5. Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of US adults. N Engl J Med 2003;348:1625–38.10.1056/NEJMoa021423Search in Google Scholar PubMed

6. Sinicrope FA, Dannenberg AJ. Obesity and breast cancer prognosis: weight of the evidence. J Clin Oncol 2011;29:4–7.10.1200/JCO.2010.32.1752Search in Google Scholar PubMed

7. Hursting SD, Berger NA. Energy balance, host-related factors, and cancer progression. J Clin Oncol 2010;28:4058–65.10.1200/JCO.2010.27.9935Search in Google Scholar PubMed PubMed Central

8. Bonomini F, Rodella LF, Rezzani R. Metabolic syndrome, aging and involvement of oxidative stress. Aging Dis 2015;6:109–20.10.14336/AD.2014.0305Search in Google Scholar PubMed PubMed Central

9. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell 2011;144:646–74.10.1016/j.cell.2011.02.013Search in Google Scholar PubMed

10. Chen X, Qian Y, Wu S. The Warburg effect: evolving interpretations of an established concept. Free Radic Biol Med 2015;79:253–63.10.1016/j.freeradbiomed.2014.08.027Search in Google Scholar PubMed PubMed Central

11. Ward PS, Thompson CB. Metabolic reprogramming: a cancer hallmark even warburg did not anticipate. Cancer Cell 2012;21:297–308.10.1016/j.ccr.2012.02.014Search in Google Scholar PubMed PubMed Central

12. Ganapathy-Kanniappan S, Geschwind JF. Tumor glycolysis as a target for cancer therapy: progress and prospects. Mol Cancer 2013;12:152.10.1186/1476-4598-12-152Search in Google Scholar PubMed PubMed Central

13. Pizzuti L, Vici P, Di Lauro L, Sergi D, Della Giulia M, Marchetti P, Maugeri-Sacca M, Giordano A, Barba M. Metformin and breast cancer: basic knowledge in clinical context. Cancer Treat Rev 2015;41:441–7.10.1016/j.ctrv.2015.03.002Search in Google Scholar PubMed

14. Cifarelli V, Lashinger LM, Devlin KL, Dunlap SM, Huang J, Kaaks R, Pollak MN, Hursting SD. Metformin and rapamycin reduce pancreatic cancer growth in obese prediabetic mice by distinct microRNA-regulated mechanisms. Diabetes 2015;64:1632–42.10.2337/db14-1132Search in Google Scholar PubMed PubMed Central

15. Mohammed A, Janakiram NB, Brewer M, Ritchie RL, Marya A, Lightfoot S, Steele VE, Rao CV. Antidiabetic drug metformin prevents progression of pancreatic cancer by targeting in part cancer stem cells and mTOR signaling. Transl Oncol 2013;6:649–59.10.1593/tlo.13556Search in Google Scholar PubMed PubMed Central

16. Al-Wahab Z, Mert I, Tebbe C, Chhina J, Hijaz M, Morris RT, Ali-Fehmi R, Giri S, Munkarah AR, Rattan R. Metformin prevents aggressive ovarian cancer growth driven by high-energy diet: similarity with calorie restriction. Oncotarget 2015;6:10908–23.10.18632/oncotarget.3434Search in Google Scholar PubMed PubMed Central

17. Bluher M. The distinction of metabolically ‘healthy’ from ‘unhealthy’ obese individuals. Curr Opin Lipidol 2010;21:38–43.10.1097/MOL.0b013e3283346cccSearch in Google Scholar PubMed

18. Madeira FB, Silva AA, Veloso HF, Goldani MZ, Kac G, Cardoso VC, Bettiol H, Barbieri MA. Normal weight obesity is associated with metabolic syndrome and insulin resistance in young adults from a middle-income country. PloS One 2013;8:e60673.10.1371/journal.pone.0060673Search in Google Scholar PubMed PubMed Central

19. Saely CH, Geiger K, Drexel H. Brown versus white adipose tissue: a mini-review. Gerontology 2012;58:15–23.10.1159/000321319Search in Google Scholar PubMed

20. Eto H, Suga H, Matsumoto D, Inoue K, Aoi N, Kato H, Araki J, Yoshimura K. Characterization of structure and cellular components of aspirated and excised adipose tissue. Plast Reconstr Surg 2009;124:1087–97.10.1097/PRS.0b013e3181b5a3f1Search in Google Scholar PubMed

21. Coelho M, Oliveira T, Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci 2013;9:191–200.10.5114/aoms.2013.33181Search in Google Scholar PubMed PubMed Central

22. Adamczak M, Wiecek A. The adipose tissue as an endocrine organ. Semin Nephrol 2013;33:2–13.10.1016/j.semnephrol.2012.12.008Search in Google Scholar PubMed

23. Duncan RE, Ahmadian M, Jaworski K, Sarkadi-Nagy E, Sul HS. Regulation of lipolysis in adipocytes. Ann Rev Nutr 2007;27: 79–101.10.1146/annurev.nutr.27.061406.093734Search in Google Scholar PubMed PubMed Central

24. Jung UJ, Choi MS. Obesity and its metabolic complications: the role of adipokines and the relationship between obesity, inflammation, insulin resistance, dyslipidemia and non-alcoholic fatty liver disease. Int J Mol Sci 2014;15:6184–223.10.3390/ijms15046184Search in Google Scholar PubMed PubMed Central

25. Balaban S, Lee LS, Schreuder M, Hoy AJ. Obesity and cancer progression: is there a role of fatty acid metabolism? BioMed Res Int 2015;2015:274585.10.1155/2015/274585Search in Google Scholar PubMed PubMed Central

26. Gottschling-Zeller H, Birgel M, Scriba D, Blum WF, Hauner H. Depot-specific release of leptin from subcutaneous and omental adipocytes in suspension culture: effect of tumor necrosis factor-alpha and transforming growth factor-beta1. Eur J Endocrinol 1999;141:436–42.10.1530/eje.0.1410436Search in Google Scholar PubMed

27. Pellegrinelli V, Rouault C, Rodriguez-Cuenca S, Albert V, Edom-Vovard F, Vidal-Puig A, Clement K, Butler-Browne G, Lacasa D. Human adipocytes induce inflammation and atrophy in muscle cells during obesity. Diabetes 2015. DOI: 10.2337/db14-0796.10.2337/db14-0796Search in Google Scholar PubMed

28. Bjorndal B, Burri L, Staalesen V, Skorve J, Berge RK. Different adipose depots: their role in the development of metabolic syndrome and mitochondrial response to hypolipidemic agents. J Obesity 2011;2011:490650.10.1155/2011/490650Search in Google Scholar PubMed PubMed Central

29. Huffman DM, Barzilai N. Role of visceral adipose tissue in aging. Biochim Biophys Acta 2009;1790:1117–23.10.1016/j.bbagen.2009.01.008Search in Google Scholar PubMed PubMed Central

30. Henry SL, Bensley JG, Wood-Bradley RJ, Cullen-McEwen LA, Bertram JF, Armitage JA. White adipocytes: more than just fat depots. Int J Biochem Cell Biol 2012;44:435–40.10.1016/j.biocel.2011.12.011Search in Google Scholar PubMed

31. Suganami T, Tanaka M, Ogawa Y. Adipose tissue inflammation and ectopic lipid accumulation. Endocr J 2012;59:849–57.10.1507/endocrj.EJ12-0271Search in Google Scholar

32. Smits MM, van Geenen EJ. The clinical significance of pancreatic steatosis. Nat Rev Gastroenterol Hepatol 2011;8:169–77.10.1038/nrgastro.2011.4Search in Google Scholar PubMed

33. van Geenen EJ, Smits MM, Schreuder TC, van der Peet DL, Bloemena E, Mulder CJ. Non-alcoholic fatty liver disease is related to non-alcoholic fatty pancreas disease. Pancreas 2010;39:1185–90.10.1097/MPA.0b013e3181f6fce2Search in Google Scholar PubMed

34. Rebours V, Gaujoux S, d’Assignies G, Sauvanet A, Ruszniewski P, Levy P, Bedossa P, Paradis V, Couvelard A. Obesity and fatty pancreatic infiltration are risk factors for pancreatic precancerous lesions (PanIN). Clin Cancer Res 2015. DOI: 10.1158/1078-0432.CCR-14-2385.10.1158/1078-0432.CCR-14-2385Search in Google Scholar PubMed

35. Braun S, Bitton-Worms K, LeRoith D. The link between the metabolic syndrome and cancer. Int J Biol Sciences 2011;7:1003–15.10.7150/ijbs.7.1003Search in Google Scholar PubMed PubMed Central

36. Agrogiannis GD, Sifakis S, Patsouris ES, Konstantinidou AE. Insulin-like growth factors in embryonic and fetal growth and skeletal development (Review). Mol Med Rep 2014;10:579–84.10.3892/mmr.2014.2258Search in Google Scholar PubMed PubMed Central

37. Pollak M. The insulin and insulin-like growth factor receptor family in neoplasia: an update. Nat Rev Cancer 2012;12:159–69.10.1038/nrc3215Search in Google Scholar PubMed

38. Wong KK, Engelman JA, Cantley LC. Targeting the PI3K signaling pathway in cancer. Curr Opin Genet Dev 2010;20:87–90.10.1016/j.gde.2009.11.002Search in Google Scholar PubMed PubMed Central

39. Memmott RM, Dennis PA. Akt-dependent and -independent mechanisms of mTOR regulation in cancer. Cell Signal 2009;21:656–64.10.1016/j.cellsig.2009.01.004Search in Google Scholar PubMed PubMed Central

40. Hardie DG, Ross FA, Hawley SA. AMPK: a nutrient and energy sensor that maintains energy homeostasis. Nat Rev Mol Cell Bio 2012;13:251–62.10.1038/nrm3311Search in Google Scholar PubMed PubMed Central

41. Moore T, Beltran L, Carbajal S, Strom S, Traag J, Hursting SD, DiGiovanni J. Dietary energy balance modulates signaling through the Akt/mammalian target of rapamycin pathways in multiple epithelial tissues. Cancer Prev Res (Phila) 2008;1:65–76.10.1158/1940-6207.CAPR-08-0022Search in Google Scholar PubMed

42. De Angel RE, Conti CJ, Wheatley KE, Brenner AJ, Otto G, Degraffenried LA, Hursting SD. The enhancing effects of obesity on mammary tumor growth and Akt/mTOR pathway activation persist after weight loss and are reversed by RAD001. Mol Carcinog 2013;52:446–58.10.1002/mc.21878Search in Google Scholar PubMed

43. Nogueira LM, Dunlap SM, Ford NA, Hursting SD. Calorie restriction and rapamycin inhibit MMTV-Wnt-1 mammary tumor growth in a mouse model of postmenopausal obesity. Endocr Relat Cancer 2012;19:57–68.10.1530/ERC-11-0213Search in Google Scholar PubMed

44. Athar M, Kopelovich L. Rapamycin and mTORC1 inhibition in the mouse: skin cancer prevention. Cancer Prev Res (Phila) 2011;4:957–61.10.1158/1940-6207.CAPR-11-0266Search in Google Scholar PubMed PubMed Central

45. Back JH, Rezvani HR, Zhu Y, Guyonnet-Duperat V, Athar M, Ratner D, Kim AL. Cancer cell survival following DNA damage-mediated premature senescence is regulated by mammalian target of rapamycin (mTOR)-dependent Inhibition of sirtuin 1. J Biol Chem 2011;286:19100–8.10.1074/jbc.M111.240598Search in Google Scholar PubMed PubMed Central

46. Anisimov VN, Zabezhinski MA, Popovich IG, Piskunova TS, Semenchenko AV, Tyndyk ML, Yurova MN, Antoch MP, Blagosklonny MV. Rapamycin extends maximal lifespan in cancer-prone mice. Am J Pathol 2010;176:2092–7.10.2353/ajpath.2010.091050Search in Google Scholar PubMed PubMed Central

47. Tomimoto A, Endo H, Sugiyama M, Fujisawa T, Hosono K, Takahashi H, Nakajima N, Nagashima Y, Wada K, Nakagama H, Nakajima A. Metformin suppresses intestinal polyp growth in ApcMin/+ mice. Cancer Sci 2008;99:2136–41.10.1111/j.1349-7006.2008.00933.xSearch in Google Scholar PubMed

48. Chaudhary SC, Kurundkar D, Elmets CA, Kopelovich L, Athar M. Metformin, an antidiabetic agent reduces growth of cutaneous squamous cell carcinoma by targeting mTOR signaling pathway. Photochem Photobiol 2012;88:1149–56.10.1111/j.1751-1097.2012.01165.xSearch in Google Scholar PubMed PubMed Central

49. Checkley LA, Rho O, Moore T, Hursting S, DiGiovanni J. Rapamycin is a potent inhibitor of skin tumor promotion by 12-O-tetradecanoylphorbol-13-acetate. Cancer Prev Res (Phila) 2011;4:1011–20.10.1158/1940-6207.CAPR-10-0375Search in Google Scholar PubMed PubMed Central

50. Friedman JM. CS Mantzoros 20 years of leptin: from the discovery of the leptin gene to leptin in our therapeutic armamentarium. Metab Clin Exp 2015;64:1–4.10.1016/j.metabol.2014.10.023Search in Google Scholar PubMed

51. Gautron L, Elmquist JK. Sixteen years and counting: an update on leptin in energy balance. J Clin Invest 2011;121:2087–93.10.1172/JCI45888Search in Google Scholar PubMed PubMed Central

52. Yu H, Lee H, Herrmann A, Buettner R, Jove R. Revisiting STAT3 signalling in cancer: new and unexpected biological functions. Nat Rev Cancer 2014;14:736–46.10.1038/nrc3818Search in Google Scholar PubMed

53. Vaiopoulos AG, Marinou K, Christodoulides C, Koutsilieris M. The role of adiponectin in human vascular physiology. Int J Cardiol 2012;155:188–93.10.1016/j.ijcard.2011.07.047Search in Google Scholar PubMed

54. Fantuzzi G. Adiponectin in inflammatory and immune-mediated diseases. Cytokine 2013;64:1–10.10.1016/j.cyto.2013.06.317Search in Google Scholar PubMed PubMed Central

55. Otvos Jr L, Haspinger E, La Russa F, Maspero F, Graziano P, Kovalszky I, Lovas S, Nama K, Hoffmann R, Knappe D, Cassone M, Wade J, Surmacz E. Design and development of a peptide-based adiponectin receptor agonist for cancer treatment. BMC Biotechn 2011;11:90.10.1186/1472-6750-11-90Search in Google Scholar PubMed PubMed Central

56. Grossmann ME, Cleary MP. The balance between leptin and adiponectin in the control of carcinogenesis – focus on mammary tumorigenesis. Biochimie 2012;94:2164–71.10.1016/j.biochi.2012.06.013Search in Google Scholar PubMed PubMed Central

57. Kirschner MA, Schneider G, Ertel NH, Worton E. Obesity, androgens, estrogens, and cancer risk. Cancer Res 1982;42:3281s–5s.Search in Google Scholar

58. Cleary MP, Grossmann ME. Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 2009;150:2537–42.10.1210/en.2009-0070Search in Google Scholar PubMed PubMed Central

59. Meyer MR, Clegg DJ, Prossnitz ER, Barton M. Obesity, insulin resistance and diabetes: sex differences and role of oestrogen receptors. Acta Physiol (Oxf) 2011;203:259–69.10.1111/j.1748-1716.2010.02237.xSearch in Google Scholar PubMed PubMed Central

60. Allan CA, McLachlan RI. Androgens and obesity. Curr Opin Endocrinol Diabetes Obes 2010;17:224–32.10.1097/MED.0b013e3283398ee2Search in Google Scholar PubMed

61. Bernstein L, Ross RK. Endogenous hormones and breast cancer risk. Epidemiol Rev 1993;15:48–65.10.1093/oxfordjournals.epirev.a036116Search in Google Scholar PubMed

62. Ho SM. Estrogen, progesterone and epithelial ovarian cancer. Reprod Biol Endocrinol 2003;1:73.10.1186/1477-7827-1-73Search in Google Scholar

63. Rizner TL. Estrogen biosynthesis, phase I and phase II metabolism, and action in endometrial cancer. Mol Cell Endocrinol 2013;381:124–39.10.1016/j.mce.2013.07.026Search in Google Scholar

64. Heldring N, Pike A, Andersson S, Matthews J, Cheng G, Hartman J, Tujague M, Strom A, Treuter E, Warner M, Gustafsson JA. Estrogen receptors: how do they signal and what are their targets. Physiol Rev 2007;87:905–31.10.1152/physrev.00026.2006Search in Google Scholar

65. Huang B, Warner M, Gustafsson JA. Estrogen receptors in breast carcinogenesis and endocrine therapy. Mol Cell Endocrinol 2014. DOI: 10.1016/j.mce.2014.11.015.10.1016/j.mce.2014.11.015Search in Google Scholar

66. Althuis MD, Fergenbaum JH, Garcia-Closas M, Brinton LA, Madigan MP, Sherman ME. Etiology of hormone receptor-defined breast cancer: a systematic review of the literature. Cancer Epidemiol Biomark Prev 2004;13:1558–68.10.1158/1055-9965.1558.13.10Search in Google Scholar

67. Goodwin PJ. Obesity and endocrine therapy: host factors and breast cancer outcome. Breast 2013;22(Suppl 2):S44–7.10.1016/j.breast.2013.07.008Search in Google Scholar

68. Fentiman IS, Fourquet A, Hortobagyi GN. Male breast cancer. Lancet 2006;367:595–604.10.1016/S0140-6736(06)68226-3Search in Google Scholar

69. Harvey AE, Lashinger LM, Hursting SD, The growing challenge of obesity and cancer: an inflammatory issue. Ann NY Acad Sci 2011;1229:45–52.10.1111/j.1749-6632.2011.06096.xSearch in Google Scholar

70. Olefsky JM, Glass CK. Macrophages, inflammation, and insulin resistance. Annu Rev Physiol 2010;72:219–46.10.1146/annurev-physiol-021909-135846Search in Google Scholar

71. Subbaramaiah K, Howe LR, Bhardwaj P, Du B, Gravaghi C, Yantiss RK, Zhou XK, Blaho VA, Hla T, Yang P, Kopelovich L, Hudis CA, Dannenberg AJ. Obesity is associated with inflammation and elevated aromatase expression in the mouse mammary gland. Cancer Prev Res (Phila) 2011;4:329–46.10.1158/1940-6207.CAPR-10-0381Search in Google Scholar

72. Fain JN. Release of interleukins and other inflammatory cytokines by human adipose tissue is enhanced in obesity and primarily due to the nonfat cells. Vitam Horm 2006;74: 443–77.10.1016/S0083-6729(06)74018-3Search in Google Scholar

73. Karpe F, Dickmann JR, Frayn KN. Fatty acids, obesity, and insulin resistance: time for a reevaluation. Diabetes 2011;60:2441–9.10.2337/db11-0425Search in Google Scholar PubMed PubMed Central

74. Boden G, Salehi S. Why does obesity increase the risk for cardiovascular disease? Curr Pharm Design 2013;19:5678–83.10.2174/1381612811319320003Search in Google Scholar PubMed

75. O’Rourke RW, Metcalf MD, White AE, Madala A, Winters BR, Maizlin II, Jobe BA, Roberts Jr CT, Slifka MK, Marks DL. Depot-specific differences in inflammatory mediators and a role for NK cells and IFN-gamma in inflammation in human adipose tissue. Int J Obes (Lond) 2009;33:978–90.10.1038/ijo.2009.133Search in Google Scholar PubMed PubMed Central

76. Hoesel B, Schmid JA. The complexity of NF-kappaB signaling in inflammation and cancer. Mol Cancer 2013;12:86.10.1186/1476-4598-12-86Search in Google Scholar PubMed PubMed Central

77. Lee BC, Lee J. Cellular and molecular players in adipose tissue inflammation in the development of obesity-induced insulin resistance. Biochim Biophys Acta 2014;1842:446–62.10.1016/j.bbadis.2013.05.017Search in Google Scholar PubMed PubMed Central

78. Jang PG, Namkoong C, Kang GM, Hur MW, Kim SW, Kim GH, KangY, Jeon MJ, Kim EH, Lee MS, Karin M, Baik JH, Park JY, Lee KU, Kim YB, Kim MS. NF-kappaB activation in hypothalamic pro-opiomelanocortin neurons is essential in illness- and leptin-induced anorexia. J Biol Chem 2010;285:9706–15.10.1074/jbc.M109.070706Search in Google Scholar PubMed PubMed Central

79. Heidland A, Klassen A, Rutkowski P, Bahner U. The contribution of Rudolf Virchow to the concept of inflammation: what is still of importance? J Nephrol 2006;19(Suppl 10):S102–9.Search in Google Scholar

80. Aggarwal BB, Gehlot P. Inflammation and cancer: how friendly is the relationship for cancer patients? Curr Opin Pharmacol 2009;9:351–69.10.1016/j.coph.2009.06.020Search in Google Scholar PubMed PubMed Central

81. Del Prete A, Allavena P, Santoro G, Fumarulo R, Corsi MM, Mantovani A. Molecular pathways in cancer-related inflammation. Biochemia Medica 2011;21:264–75.10.11613/BM.2011.036Search in Google Scholar

82. Ono M. Molecular links between tumor angiogenesis and inflammation: inflammatory stimuli of macrophages and cancer cells as targets for therapeutic strategy. Cancer Science 2008;99:1501–6.10.1111/j.1349-7006.2008.00853.xSearch in Google Scholar PubMed

83. Park YH, Kim N. Review of atrophic gastritis and intestinal metaplasia as a premalignant lesion of gastric cancer. J Cancer Prev 2015;20:25–40.10.15430/JCP.2015.20.1.25Search in Google Scholar PubMed PubMed Central

84. Triantafillidis JK, Nasioulas G, Kosmidis PA. Colorectal cancer and inflammatory bowel disease: epidemiology, risk factors, mechanisms of carcinogenesis and prevention strategies. Anticancer Res 2009;29:2727–37.Search in Google Scholar

85. Hausmann S, Kong B, Michalski C, Erkan M, Friess H. The role of inflammation in pancreatic cancer. Adv Exp Med Biol 2014;816:129–51.10.1007/978-3-0348-0837-8_6Search in Google Scholar PubMed

86. Coussens LM, Werb Z. Inflammation and cancer. Nature 2002;420:860–7.10.1038/nature01322Search in Google Scholar PubMed PubMed Central

87. Singh S, Singh PP, Roberts LR, Sanchez W. Chemopreventive strategies in hepatocellular carcinoma. Nat Rev Gastroenterol Hepatol 2014;11:45–54.10.1038/nrgastro.2013.143Search in Google Scholar PubMed PubMed Central

88. Gao D, Mittal V. Tumor microenvironment regulates epithelial-mesenchymal transitions in metastasis. Expert Rev Anticancer Ther 2012;12:857–9.10.1586/era.12.69Search in Google Scholar PubMed PubMed Central

89. van Kempen LC, Rhee JS, Dehne K, Lee J, Edwards DR, Coussens LM. Epithelial carcinogenesis: dynamic interplay between neoplastic cells and their microenvironment. Differ Res Biol Diver 2002;70:610–23.10.1046/j.1432-0436.2002.700914.xSearch in Google Scholar PubMed

90. Mantovani A. Molecular pathways linking inflammation and cancer. Curr Mol Med 2010;10:369–73.10.2174/156652410791316968Search in Google Scholar PubMed

91. Sobolewski C, Cerella C, Dicato M, Ghibelli L, Diederich M. The role of cyclooxygenase-2 in cell proliferation and cell death in human malignancies. Int J Cell Biol 2010;2010:215158.10.1155/2010/215158Search in Google Scholar PubMed PubMed Central

92. Koki AT, Khan NK, Woerner BM, Seibert K, Harmon JL, Dannenberg AJ, Soslow RA, Masferrer JL. Characterization of cyclooxygenase-2 (COX-2) during tumorigenesis in human epithelial cancers: evidence for potential clinical utility of COX-2 inhibitors in epithelial cancers. Prostagl Leukotr Ess 2002;66:13–8.10.1054/plef.2001.0335Search in Google Scholar PubMed

93. Hsieh PS, Jin JS, Chiang CF, Chan PC, Chen CH, Shih KC. COX-2-mediated inflammation in fat is crucial for obesity-linked insulin resistance and fatty liver. Obesity (Silver Spring) 2009;17:1150–7.10.1038/oby.2008.674Search in Google Scholar PubMed

94. Tian YF, Hsia TL, Hsieh CH, Huang DW, Chen CH, Hsieh PS. The importance of cyclooxygenase 2-mediated oxidative stress in obesity-induced muscular insulin resistance in high-fat-fed rats. Life Sciences 2011;89:107–14.10.1016/j.lfs.2011.05.006Search in Google Scholar PubMed

95. Coffelt SB, de Visser KE. Cancer: inflammation lights the way to metastasis. Nature 2014;507:48–9.10.1038/nature13062Search in Google Scholar PubMed

96. Papandreou D, Andreou E. Role of diet on non-alcoholic fatty liver disease: an updated narrative review. World J Hepatol 2015;7:575–82.10.4254/wjh.v7.i3.575Search in Google Scholar PubMed PubMed Central

97. Hui JM, Kench JG, Chitturi S, Sud A, Farrell GC, Byth K, Hall P, Khan M, George J. Long-term outcomes of cirrhosis in non-alcoholic steatohepatitis compared with hepatitis C. Hepatology 2003;38:420–7.10.1053/jhep.2003.50320Search in Google Scholar PubMed

98. Vanni E, Bugianesi E, Kotronen A, De Minicis S, Yki-Jarvinen H, Svegliati-Baroni G. From the metabolic syndrome to NAFLD or vice versa? Digest Liver Dis 2010;42:320–30.10.1016/j.dld.2010.01.016Search in Google Scholar PubMed

99. White DL, Kanwal F, El-Serag HB. Association between non-alcoholic fatty liver disease and risk for hepatocellular cancer, based on systematic review. Clin Gastroenterol Hepatol 2012;10:1342–59 e1342.10.1016/j.cgh.2012.10.001Search in Google Scholar PubMed PubMed Central

100. Browning JD, Szczepaniak LS, Dobbins R, Nuremberg P, Horton JD, Cohen JC, Grundy SM, Hobbs HH. Prevalence of hepatic steatosis in an urban population in the United States: impact of ethnicity. Hepatology 2004;40:1387–95.10.1002/hep.20466Search in Google Scholar PubMed

101. Bellentani S, Scaglioni F, Marino M, Bedogni G. Epidemiology of non-alcoholic fatty liver disease. Dig Dis 2010;28:155–61.10.1159/000282080Search in Google Scholar PubMed

102. Berardis S, Sokal E. Pediatric non-alcoholic fatty liver disease: an increasing public health issue. Eur J Pediatr 2014;173:131–9.10.1007/s00431-013-2157-6Search in Google Scholar PubMed PubMed Central

103. Anderson N, Borlak J. Molecular mechanisms and therapeutic targets in steatosis and steatohepatitis. Pharmacol Rev 2008;60:311–57.10.1124/pr.108.00001Search in Google Scholar PubMed

104. Tolman KG, Dalpiaz AS. Treatment of non-alcoholic fatty liver disease. Therapeut Clin Risk Manage 2007;3:1153–63.Search in Google Scholar

105. Farese Jr RV, Zechner R, Newgard CB, Walther TC. The problem of establishing relationships between hepatic steatosis and hepatic insulin resistance. Cell Metab 2012;15:570–3.10.1016/j.cmet.2012.03.004Search in Google Scholar PubMed PubMed Central

106. Ahmadian M, Suh JM, Hah N, Liddle C, Atkins AR, Downes M, Evans RM. PPARgamma signaling and metabolism: the good, the bad and the future. Nat Med 2013;19:557–66.10.1038/nm.3159Search in Google Scholar PubMed PubMed Central

107. Hijona E, Hijona L, Arenas JI, Bujanda L. Inflammatory mediators of hepatic steatosis. Mediat Inflam 2010;2010:837419.10.1155/2010/837419Search in Google Scholar PubMed PubMed Central

108. Byrne AM, Bouchier-Hayes DJ, Harmey JH. Angiogenic and cell survival functions of vascular endothelial growth factor (VEGF). J Cell Mol Med 2005;9:777–94.10.1111/j.1582-4934.2005.tb00379.xSearch in Google Scholar PubMed PubMed Central

109. Cottam D, Fisher B, Ziemba A, Atkinson J, Grace B, Ward DC, Pizzorno G. Tumor growth factor expression in obesity and changes in expression with weight loss: another cause of increased virulence and incidence of cancer in obesity. Surg Obes Relat Dis 2010;6:538–41.10.1016/j.soard.2010.04.011Search in Google Scholar PubMed

110. Slaughter KN, Thai T, Penaroza S, Benbrook DM, Thavathiru E, Ding K, Nelson T, McMeekin DS, Moore KN. Measurements of adiposity as clinical biomarkers for first-line bevacizumab-based chemotherapy in epithelial ovarian cancer. Gynecol Oncol 2014;133:11–5.10.1016/j.ygyno.2014.01.031Search in Google Scholar PubMed

111. Iwaki T, Urano T, Umemura K. PAI-1, progress in understanding the clinical problem and its aetiology. Br J Haematol 2012;157:291–8.10.1111/j.1365-2141.2012.09074.xSearch in Google Scholar PubMed

112. Bauman KA, Wettlaufer SH, Okunishi K, Vannella KM, Stoolman JS, Huang SK, Courey AJ, White ES, Hogaboam CM, Simon RH, Toews GB, Sisson TH, Moore BB, Peters-Golden M. The antifibrotic effects of plasminogen activation occur via prostaglandin E2 synthesis in humans and mice. J Clin Invest 2010;120:1950–60.10.1172/JCI38369Search in Google Scholar PubMed PubMed Central

113. Malik R, Lelkes PI, Cukierman E. Biomechanical and biochemical remodeling of stromal extracellular matrix in cancer. Trends Biotechnol 2015;33:230–6.10.1016/j.tibtech.2015.01.004Search in Google Scholar PubMed PubMed Central

114. Eckburg PB, Bik EM, Bernstein CN, Purdom E, Dethlefsen L, Sargent M, Gill SR, Nelson KE, Relman DA. Diversity of the human intestinal microbial flora. Science 2005;308:1635–8.10.1126/science.1110591Search in Google Scholar PubMed PubMed Central

115. Turnbaugh PJ, Ley RE, Mahowald MA, Magrini V, Mardis ER, Gordon JI. An obesity-associated gut microbiome with increased capacity for energy harvest. Nature 2006;444:1027–31.10.1038/nature05414Search in Google Scholar PubMed

116. Turnbaugh PJ, Hamady M, Yatsunenko T, Cantarel BL, Duncan A, Ley RE, Sogin ML, Jones WJ, Roe BA, Affourtit JP, Egholm M, Henrissat B, Heath AC, Knight R, Gordon JI. A core gut microbiome in obese and lean twins. Nature 2009;457:480–4.10.1038/nature07540Search in Google Scholar PubMed PubMed Central

117. Le Chatelier E, Nielsen T, Qin J, Prifti E, Hildebrand F, Falony G, Almeida M, Arumugam M, Batto JM, Kennedy S, Leonard P, Li J, Burgdorf K, Grarup N, Jorgensen T, Brandslund I, Nielsen HB, Juncker AS, Bertalan M, Levenez F, Pons N, Rasmussen S, Sunagawa S, Tap J, Tims S, Zoetendal EG, Brunak S, Clement K, Dore J, Kleerebezem M, Kristiansen K, Renault P, Sicheritz-Ponten T, de Vos WM, Zucker JD, Raes J, Hansen T, Bork P, Wang J, Ehrlich SD, Pedersen O. Richness of human gut microbiome correlates with metabolic markers. Nature 2013;500:541–6.10.1038/nature12506Search in Google Scholar PubMed

118. Cotillard A, Kennedy SP, Kong LC, Prifti E, Pons N, Le Chatelier E, Almeida M, Quinquis B, Levenez F, Galleron N, Gougis S, Rizkalla S, Batto JM, Renault P, Dore J, Zucker JD, Clement K, Ehrlich SD. Dietary intervention impact on gut microbial gene richness. Nature 2013;500:585–8.10.1038/nature12480Search in Google Scholar PubMed

119. Cani PD, Bibiloni R, Knauf C, Waget A, Neyrinck AM, Delzenne NM, Burcelin R. Changes in gut microbiota control metabolic endotoxemia-induced inflammation in high-fat diet-induced obesity and diabetes in mice. Diabetes 2008;57:1470–81.10.2337/db07-1403Search in Google Scholar PubMed

120. Cani PD, Amar J, Iglesias MA, Poggi M, Knauf C, Bastelica D, Neyrinck AM, Fava F, Tuohy KM, Chabo C, Waget A, Delmee E, Cousin B, Sulpice T, Chamontin B, Ferrieres J, Tanti JF, Gibson GR, Casteilla L, Delzenne NM, Alessi MC, Burcelin R. Metabolic endotoxemia initiates obesity and insulin resistance. Diabetes 2007;56:1761–72.10.2337/db06-1491Search in Google Scholar PubMed

121. Lashinger LM, Ford NA, Hursting SD. Interacting inflammatory and growth factor signals underlie the obesity-cancer link. J Nutr 2014;144:109–13.10.3945/jn.113.178533Search in Google Scholar PubMed PubMed Central

122. Schwartz K, Chang HT, Nikolai M, Pernicone J, Rhee S, Olson K, Kurniali PC, Hord NG, Noel M. Treatment of glioma patients with ketogenic diets: report of two cases treated with an IRB-approved energy-restricted ketogenic diet protocol and review of the literature. Cancer Met 2015;3:3.10.1186/s40170-015-0129-1Search in Google Scholar PubMed PubMed Central

123. Scheck AC, Abdelwahab MG, Fenton KE, Stafford P. The ketogenic diet for the treatment of glioma: insights from genetic profiling. Epilepsy Res 2012;100:327–37.10.1016/j.eplepsyres.2011.09.022Search in Google Scholar PubMed

124. Abdelwahab MG, Fenton KE, Preul MC, Rho JM, Lynch A, Stafford P, Scheck AC. The ketogenic diet is an effective adjuvant to radiation therapy for the treatment of malignant glioma. PloS One 2012;7:e36197.10.1371/journal.pone.0036197Search in Google Scholar PubMed PubMed Central

125. Westman EC, Yancy Jr WS, Mavropoulos JC, Marquart M, McDuffie JR. The effect of a low-carbohydrate, ketogenic diet versus a low-glycemic index diet on glycemic control in type 2 diabetes mellitus. Nutr Metab 2008;5:36.10.1186/1743-7075-5-36Search in Google Scholar PubMed PubMed Central

126. Otto C, Kaemmerer U, Illert B, Muehling B, Pfetzer N, Wittig R, Voelker HU, Thiede A, Coy JF. Growth of human gastric cancer cells in nude mice is delayed by a ketogenic diet supplemented with omega-3 fatty acids and medium-chain triglycerides. BMC Cancer 2008;8:122.10.1186/1471-2407-8-122Search in Google Scholar PubMed PubMed Central