Rund und gesund? − Der Beitrag von Übergewicht zur Krebsentstehung und Implikationen für die Therapie

Zusammenfassung

Die Prävalenz von Übergewicht und Adipositas hat in den letzten Jahrzehnten stark zugenommen und betrifft heute weltweit mehr als 1,5 Milliarden Menschen [23]. Ein erhöhter Body Mass Index (BMI) ist seit Langem als Risikofaktor für die Entstehung kardiovaskulärer Erkrankungen und Typ-2-Diabetes anerkannt. Innerhalb der letzten zehn Jahre wurde jedoch auch zunehmend ein Zusammenhang zwischen Übergewicht und Krebsentstehung sowie einer schlechteren Prognose im Verlauf einer Krebserkrankung bei Übergewicht festgestellt. Im Folgenden werden epidemiologische Nachweise dieses Zusammenhangs sowie mögliche Mechanismen des Zusammenspiels von Adipositas und Krebsentstehung dargestellt. Darüber hinaus gibt dieser Artikel einen Überblick über Therapie- und Präventionsstrategien, welche die metabolischen Ursachen von Krebserkrankungen adressieren.

Summary

Obesity is now affecting more than 1.5 billion people worldwide and is known to represent a major health threat due to the development of cardiovascular disease, diabetes and the metabolic syndrome. In the last decade, evidence is increasing that obesity is also involved in the development of cancer. In this review we discuss the existing interlinks and potential implications for cancer therapy. Hyperinsulinemia, hyperglycemia, lipotoxicity and metaflammation are known consequences of obesity and have also been shown to promote tumor growth by common pathways. The most convincing evidence exists for the association between obesity and postmenopausal breast cancer, colon and rectal cancer, esophagus cancer, kidney cancer, endometrial cancer and pancreatic cancer. Diabetes may be an independent risk factor. In addition, obesity also increases the cancer mortality. Maintaining a healthy body weight throughout the whole life, regular exercise and a healthy diet therefore reduce the risk of cancer incidence and progression. Novel treatment strategies targeting the interaction sites between metabolic disease and cancer may include the use of chemoprotective phytochemicals, non-steroidal anti- inflammatory drugs or glucose lowering agents such as metformin.

Schlüsselwörter

Übergewicht - Adipositas - Diabetes - Metaflammation - Krebs

Keywords

Overweight - Obesity - Diabetes - Metaflammation - Cancer

• Literatur

• 1 Algire C, Amrein L, Zakikhani M, Panasci L, Pollak M. Metformin blocks the stimulative effect of a high-energy diet on colon carcinoma growth in vivo and is associated with reduced expression of fatty acid synthase. Endocr Relat Cancer 2010; 17: 351-360
• 2 Alli PM, Pinn ML, Jaffee EM, McFadden JM, Kuhajda FP. Fatty acid synthase inhibitors are chemopreventive for mammary cancer in neu-N transgenic mice. Oncogene 2005; 24: 39-46
• 3 American Cancer Society. Cancer Facts & Figures 2013. Atlanta: American Cancer Society; 2013
• 4 Barone BB, Yeh HC, Snyder CF et al Long-term all-cause mortality in cancer patients with preexisting diabetes mellitus: a systematic review and meta-analysis. JAMA 2008; 300: 2754-2764
• 5 Bortoluzzi S, Scannapieco P, Cestaro A, Danieli GA, Schiaffino S. Computational reconstruction of the human skeletal muscle secretome. Proteins 2006; 62: 776-792
• 6 Brown MV, Compton SA, Milburn MV, Lawton KA, Cheatham B. Metabolomic signatures in lipid-loaded HepaRGs reveal pathways involved in steatotic progression. Obesity (Silver Spring) 2013; 21 E561−570
• 7 Bugianesi E, Leone N, Vanni E et al Expanding the natural history of nonalcoholic steatohepatitis: from cryptogenic cirrhosis to hepatocellular carcinoma. Gastroenterology 2002; 123: 134-140
• 8 Calle EE, Kaaks R. Overweight, obesity and cancer: epidemiological evidence and proposed mechanisms. Nat Rev Cancer 2004; 4: 579-591
• 9 Calle EE, Rodriguez C, Walker-Thurmond K, Thun MJ. Overweight, obesity, and mortality from cancer in a prospectively studied cohort of U. S. adults. N Engl J Med 2003; 348: 1625-1638
• 10 Cao L, Liu X, Lin EJ et al Environmental and genetic activation of a brain-adipocyte BDNF/leptin axis causes cancer remission and inhibition. Cell 2010; 142: 52-64
• 11 Cavaco S, Eriksson T, Skalli A. Life cycle development of obesity and its determinants in six European countries. Econ Hum Biol 2014; 14: 62-78
• 12 Cerhan JR, Moore SC, Jacobs EJ et al A pooled analysis of waist circumference and mortality in 650,000 adults. Mayo Clin Proc 2014; 89: 335-345
• 13 Coghill AE, Newcomb PA, Campbell PT et al Prediagnostic non-steroidal anti-inflammatory drug use and survival after diagnosis of colorectal cancer. Gut 2011; 60: 491-498
• 14 Cohen DH, LeRoith D. Obesity, type 2 diabetes, and cancer: the insulin and IGF connection. Endocr Relat Cancer 2012; 19 F27−45
• 15 Coussens LM, Werb Z. Inflammation and cancer. Nature 2002; 420: 860-867
• 16 De Angelis R. Sant M, Coleman MP et al Cancer survival in Europe 1999−2007 by country and age: results of EUROCARE–5-a population-based study. Lancet Oncol 2014; 15: 23-34
• 17 De Pergola G. Silvestris F. Obesity as a major risk factor for cancer. J Obes 2013 2013; 291546
• 18 Duthie GG, Gardner PT, Kyle JA. Plant polyphenols: are they the new magic bullet?. Proc Nutr Soc 2003; 62: 599-603
• 19 El-Serag HB, Hampel H, Javadi F. The association between diabetes and hepatocellular carcinoma: a systematic review of epidemiologic evidence. Clin Gastroenterol Hepatol 2006; 4: 369-380
• 20 El Mjiyad N. Caro-Maldonado A, Ramirez-Peinado S, Munoz-Pinedo C. Sugar-free approaches to cancer cell killing. Oncogene 2011; 30: 253-264
• 21 Evans JM, Donnelly LA, Emslie-Smith AM, Alessi DR, Morris AD. Metformin and reduced risk of cancer in diabetic patients. BMJ 2005; 330: 1304-1305
• 22 Fearon K, Arends J, Baracos V. Understanding the mechanisms and treatment options in cancer cachexia. Nat Rev Clin Oncol 2013; 10: 90-99
• 23 Finucane MM, Stevens GA, Cowan MJ et al National, regional, and global trends in body-mass index since 1980: systematic analysis of health examination surveys and epidemiological studies with 960 country-years and 9.1 million participants. Lancet 2011; 377: 557-567
• 24 Friberg E, Orsini N, Mantzoros CS, Wolk A. Diabetes mellitus and risk of endometrial cancer: a meta-analysis. Diabetologia 2007; 50: 1365-1374
• 25 Friedenreich CM, Orenstein MR. Physical activity and cancer prevention: etiologic evidence and biological mechanisms. J Nutr 2002; 132: 3456S-3464S
• 26 Gschwind A, Fischer OM, Ullrich A. The discovery of receptor tyrosine kinases: targets for cancer therapy. Nat Rev Cancer 2004; 4: 361-370
• 27 Gupta RA, Dubois RN. Colorectal cancer prevention and treatment by inhibition of cyclooxygenase-2. Nat Rev Cancer 2001; 1: 11-21
• 28 Han X, Stevens J, Truesdale KP et al Body mass index at early adulthood, subsequent weight change and cancer incidence and mortality. Int J Cancer 2014; 135: 2900-2909
• 29 Hojman P, Dethlefsen C, Brandt C et al Exercise-induced muscle-derived cytokines inhibit mammary cancer cell growth. Am J Physiol Endocrinol Metab 2011; 301 E504−510
• 30 Huxley RR, Ansary-Moghaddam A, Clifton P et al The impact of dietary and lifestyle risk factors on risk of colorectal cancer: a quantitative overview of the epidemiological evidence. Int J Cancer 2009; 125: 171-180
• 31 Jang M, Cai L, Udeani GO et al Cancer chemopreventive activity of resveratrol, a natural product derived from grapes. Science 1997; 275: 218-220
• 32 Jeon CY, Lokken RP, Hu FB, van Dam RM. Physical activity of moderate intensity and risk of type 2 diabetes: a systematic review. Diabetes Care 2007; 30: 744-752
• 33 Johnson JA, Bowker SL. Intensive glycaemic control and cancer risk in type 2 diabetes: a meta-analysis of major trials. Diabetologia 2011; 54: 25-31
• 34 Kelley DE, Goodpaster BH, Storlien L. Muscle triglyceride and insulin resistance. Annu Rev Nutr 2002; 22: 325-346
• 35 Kim JW, Dang CV. Cancer's molecular sweet tooth and the Warburg effect. Cancer Res 2006; 66: 8927-8930
• 36 Kuehr L, Wiskemann J, Abel U et al Exercise in patients with non-small cell lung cancer. Med Sci Sports Exerc 2014; 46: 656-663
• 37 Lancaster GI, Febbraio MA. The immunomodulating role of exercise in metabolic disease. Trends Immunol 2014; 35: 262-269
• 38 Larsson SC, Mantzoros CS, Wolk A. Diabetes mellitus and risk of breast cancer: a meta-analysis. Int J Cancer 2007; 121: 856-862
• 39 Larsson SC, Orsini N, Wolk A. Diabetes mellitus and risk of colorectal cancer: a meta-analysis. J Natl Cancer Inst 2005; 97: 1679-1687
• 40 Llovet JM, Ricci S, Mazzaferro V et al Sorafenib in advanced hepatocellular carcinoma. N Engl J Med 2008; 359: 378-390
• 41 Lollgen H. Importance and evidence of regular physical activity for prevention and treatment of diseases. Dtsch Med Wochenschr 2013; 138: 2253-2259
• 42 Malek M, Aghili R, Emami Z, Khamseh ME. Risk of cancer in diabetes: the effect of metformin. ISRN Endocrinol 2013; 2013; 636927
• 43 Manser CN, Bauerfeind P. Impact of socioeconomic status on incidence, mortality, and survival of colorectal cancer patients: a systematic review. Gastrointest Endosc 2014; 80: 42-60 e49
• 44 McTiernan A, Kooperberg C, White E et al Recreational physical activity and the risk of breast cancer in postmenopausal women: the Women's Health Initiative Cohort Study. JAMA 2003; 290: 1331-1336
• 45 Moore CJ, Cunningham SA. Social position, psychological stress, and obesity: a systematic review. J Acad Nutr Diet 2012; 112: 518-526
• 46 Nagle CM, Olsen CM, Ibiebele TI, Spurdle AB, Webb PM. Glycemic index, glycemic load and endometrial cancer risk: results from the Australian National Endometrial Cancer study and an updated systematic review and meta-analysis. Eur J Nutr 2013; 52: 705-715
• 47 Nothlings U, Murphy SP, Wilkens LR, Henderson BE, Kolonel LN. Dietary glycemic load, added sugars, and carbohydrates as risk factors for pancreatic cancer: the Multiethnic Cohort Study. Am J Clin Nutr 2007; 86: 1495-1501
• 48 Ohishi W, Cologne JB, Fujiwara S et al Serum interleukin-6 associated with hepatocellular carcinoma risk: a nested case-control study. Int J Cancer 2014; 134: 154-163
• 49 Park EJ, Lee JH, Yu GY et al Dietary and genetic obesity promote liver inflammation and tumorigenesis by enhancing IL-6 and TNF expression. Cell 2010; 140: 197-208
• 50 Pedersen BK, Febbraio MA. Muscles, exercise and obesity: skeletal muscle as a secretory organ. Nat Rev Endocrinol 2012; 8: 457-465
• 51 Pedersen BK, Steensberg A, Fischer C et al Searching for the exercise factor: is IL-6 a candidate?. J Muscle Res Cell Motil 2003; 24: 113-119
• 52 Perez-Hernandez AI, Catalan V, Gomez-Ambrosi J, Rodriguez A, Fruhbeck G. Mechanisms linking excess adiposity and carcinogenesis promotion. Front Endocrinol (Lausanne) 2014; 5: 65
• 53 Pocock SJ, Smeeth L. Insulin glargine and malignancy: an unwarranted alarm. Lancet 2009; 374: 511-513
• 54 Pollak M. Insulin and insulin-like growth factor signalling in neoplasia. Nat Rev Cancer 2008; 8: 915-928
• 55 Renehan A, Smith U, Kirkman MS. Linking diabetes and cancer: a consensus on complexity. Lancet 2010; 375: 2201-2202
• 56 Renehan AG, Tyson M, Egger M, Heller RF, Zwahlen M. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet 2008; 371: 569-578
• 57 Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med 2010; 61: 301-316
• 58 Sharma D, Wang J, Fu PP et al Adiponectin antagonizes the oncogenic actions of leptin in hepatocellular carcinogenesis. Hepatology 2010; 52: 1713-1722
• 59 Singh D. Merck withdraws arthritis drug worldwide. BMJ 2004; 329: 816
• 60 Smith U, Gale EA. Does diabetes therapy influence the risk of cancer?. Diabetologia 2009; 52: 1699-1708
• 61 Surh YJ. Cancer chemoprevention with dietary phytochemicals. Nat rev Cancer 2003; 3: 768-780
• 62 Tomlinson D, Diorio C, Beyene J, Sung L. Effect of exercise on cancer-related fatigue: a meta-analysis. Am J Phys Med Rehabil 2014; 93: 675-686
• 63 Ulrich CM, Bigler J, Potter JD. Non-steroidal anti-inflammatory drugs for cancer prevention: promise, perils and pharmacogenetics. Nat Rev Cancer 2006; 6: 130-140
• 64 Uthman OA, Jadidi E, Moradi T. Socioeconomic position and incidence of gastric cancer: a systematic review and meta-analysis. J Epidemiol Community Health 2013; 67: 854-860
• 65 Viani GA, Afonso SL, Stefano EJ, De Fendi LI. Soares FV. Adjuvant trastuzumab in the treatment of her-2-positive early breast cancer: a meta-analysis of published randomized trials. BMC Cancer 2007; 7 153
• 66 Vona-Davis L, Rose DP. Adipokines as endocrine, paracrine, and autocrine factors in breast cancer risk and progression. Endocr Relat Cancer 2007; 14: 189-206
• 67 Whitlock NC, Baek SJ. The anticancer effects of resveratrol: modulation of transcription factors. Nutr Cancer 2012; 64: 493-502
• 68 WHO. http://www.who.int/cancer/prevention/en/ 2014
• 69 World Cancer Research Fund. Food, Nutrition, Physical Activity, and the Prevention of Cancer: a Global Perspective. 2nd ed. Washington DC: AICR; 2007
• 70 zur Hausen H. Red meat consumption and cancer: reasons to suspect involvement of bovine infectious factors in colorectal cancer. Int J Cancer 2012; 130: 2475-2483