The relationship of obesity and prostate cancer (review)

Obesity is a critical risk factor for prostate cancer (PCa). Adipose tissue plays an important role in tumor development, including growth, invasion, and metastasis. Diet and dietary components affect the progression of prostate cancer; however, the mechanisms underlying these associations remain unclear. Extraprostatic prostate tumor cells form a new microenvironment in the periprostatic adipose tissue, which alters these interactions and promotes tumor progression.

Hyperinsulinemia leads to an increase in the level of free or biologically active insulin-like growth factor (IGF-1) due to a decrease in the production of IGF-binding proteins. Hypoandrogenism promotes the development of a more aggressive type of prostate cancer (higher Gleason scores). Adipokines of adipose tissue and cytokines (for example, interleukin-6 (IL-6) and tumor necrosis factor (TNF-α), angiogenic factors (for example, vascular endothelial growth factor (VEGF), apelin (AGTRL1) and other factors (for example, leptin and adiponectin) have multiple effects on prostate cancer cells. Tumor cells interact directly or indirectly with adipocytes.

Yellow (inactive) bone marrow is adipose tissue with separate islands of reticular tissue. It is located in the medullary canals of the tubular bones and in parts of the cells of the cancellous bone. Bone tissue is the object of the most frequent metastasis in prostate cancer, and with age, the content of fat cells in it increases. Bone marrow adipose tissue interacts with tumor cells, osteoblasts and other stromal cells and participates in the organization of the tumor microenvironment. Adipokines are key molecules in the interaction between tumor cells and adipose tissue, which is carried out through various mechanisms. A better understanding of the role of adipose tissue in the induction and progression of prostate cancer will lead to effective therapeutic strategies for this disease.

obesity, body mass index (BMI), adipocytes, adipokines, insulin-like growth factor (IGF-1), testosterone, prostate cancer

1. Злокачественные новообразования в России в 2017 году (заболеваемость и смертность). / Под ред. Каприна А.Д., Старинского В.В., Петровой Г.В. — М.: МНИОИ им. П.А. Герцена − филиал ФГБУ «НМИЦ радиологии» Минздрава России; 2018. [Kaprin AD, Starinskiy VV, Petrova GV, editors. Zlokachestvennye novoobrazovaniya v Rossii v 2017 godu (zabolevaemost’ i smertnost’). Moscow: MNIOI im. P.A. Gertsena – filial FGBU «NMITs radiologii» Minzdrava Rossii; 2018. (In Russ.)]

2. Seer.cancer.gov [Internet]. Nacional Cancer Institute [cited 2020 Aug 19]. Available from: https://seer.cancer.gov.

3. Altekruse SF, Kosary CL, Krapcho M, et al. SEER Cancer Statistics Review, 1975-2007. Bethesda: National Cancer Institute; 2010.

4. Kitagawa Y, Namiki M. Prostate-specific antigen-based population screening for prostate cancer: current status in Japan and future perspective in Asia. Asian J Androl. 2015;17(3):475-480. DOI:10.4103/1008-682X.143756

5. Swindle P, Eastham JA, Ohori M, et al. Do margins matter? The prognostic significance of positive surgical margins in radical prostatectomy specimens. J Urol. 2005;174(3):903-907. DOI:10.1097/01.ju.0000169475.00949.78

6. Sung MT, Eble JN, Cheng L. Invasion of fat justifies assignment of stage pT3a in prostatic adenocarcinoma. Pathology. 2006;38(4):309-311. DOI:10.1080/00313020600820914

7. Kyrgiou M, Kalliala I, Markozannes G, et al. Adiposity and cancer at major anatomical sites: umbrella review of the literature. BMJ. 2017;356:j477. DOI:10.1136/bmj.j477

8. Дедов И.И., Мельниченко Г.А., Шестакова М.В., и др. Национальные клинические рекомендации по лечению морбидного ожирения у взрослых. 3-ий пересмотр (лечение морбидного ожирения у взрослых). // Ожирение и метаболизм. — 2018. — Т. 15. — №1. — С. 53-70. [Dedov II, Mel’nichenko GA, Shestakova MV, et al. Russian national clinical recommendations for morbid obesity treatment in adults. 3rd revision (Morbid obesity treatment in adults). Obesity and metabolism. 2018;15(1):53-70. (In Russ.)] DOI:10.14341/omet2018153-70

9. Gilbert CA, Slingerland JM. Cytokines, obesity, and cancer: new insights on mechanisms linking obesity to cancer risk and progression. Annu Rev Med. 2013;64:45-57. DOI:10.1146/annurev-med-121211-091527

10. Wang YY, Lehuede C, Laurent V, et al. Adipose tissue and breast epithelial cells: a dangerous dynamic duo in breast cancer. Cancer Lett. 2012;324(2):142-151. DOI:10.1016/j.canlet.2012.05.019

11. 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(17):1625-1638. DOI:10.1056/NEJMoa021423

12. Allott EH, Masko EM, Freedland SJ. Obesity and prostate cancer: weighing the evidence. Eur Urol. 2013;63(5):800-809. DOI:10.1016/j.eururo.2012.11.013

13. Vidal AC, Howard LE, Moreira DM, et al. Obesity increases the risk for high-grade prostate cancer: results from the REDUCE study. Cancer Epidemiol Biomarkers Prev. 2014;23(12):2936-2942. DOI:10.1158/1055-9965.EPI-14-0795

14. Rundle A, Jankowski M, Kryvenko ON, et al. Obesity and future prostate cancer risk among men after an initial benign biopsy of the prostate. Cancer Epidemiol Biomarkers Prev. 2013;22(5):898-904. DOI:10.1158/1055-9965.EPI-12-0965

15. Renehan AG, Tyson M, Egger M, et al. Body-mass index and incidence of cancer: a systematic review and meta-analysis of prospective observational studies. Lancet. 2008;371(9612):569-578. DOI:10.1016/s0140-6736(08)60269-x

16. MacInnis RJ, English DR. Body size and composition and prostate cancer risk: systematic review and meta-regression analysis. Cancer Causes Control. 2006;17(8):989-1003. DOI:10.1007/s10552-006-0049-z

17. Bergström A, Pisani P, Tenet V, et al. Overweight as an avoidable cause of cancer in Europe. Int J Cancer. 2001;91(3):421-430. DOI:10.1002/1097-0215(200002)9999:9999<::aid-ijc1053>3.0.co;2-t

18. Baillargeon J, Platz EA, Rose DP, et al. Obesity, adipokines, and prostate cancer in a prospective population-based study. Cancer Epidemiol Biomarkers Prev. 2006;15(7):1331-1335. DOI:10.1158/1055-9965.EPI-06-0082

19. Engeland A, Tretli S, Bjorge T. Height, body mass index, and prostate cancer: a follow-up of 950000 Norwegian men. Br J Cancer. 2003;89(7):1237-1242. DOI:10.1038/sj.bjc.6601206

20. Andersson SO, Wolk A, Bergstrom R, et al. Body size and prostate cancer: a 20-year follow-up study among 135006 Swedish construction workers. J Natl Cancer Inst. 1997;89(5):385-389. DOI:10.1093/jnci/89.5.385

21. Bergström A, Pisani P, Tenet V, et al. Overweight as an avoidable cause of cancer in Europe. Int J Cancer. 2001;91(3):421-430. DOI:10.1002/1097-0215(200002)9999:9999<::aid-ijc1053>3.0.co;2-t

22. Banez LL, Hamilton RJ, Partin AW, et al. Obesity-related plasma hemodilution and PSA concentration among men with prostate cancer. JAMA. 2007;298(19):2275-2280. DOI:10.1001/jama.298.19.2275

23. Gong Z, Neuhouser ML, Goodman PJ, et al. Obesity, diabetes, and risk of prostate cancer: results from the prostate cancer prevention trial. Cancer Epidemiol Biomarkers Prev. 2006;15(10):1977-1983. DOI:10.1158/1055-9965.EPI-06-0477

24. Wright ME, Chang SC, Schatzkin A, et al. Prospective study of adiposity and weight change in relation to prostate cancer incidence and mortality. Cancer. 2007;109(4):675-684. DOI:10.1002/cncr.22443

25. Burton A, Martin R, Galobardes B, et al. Young adulthood body mass index and risk of cancer in later adulthood: historical cohort study. Cancer Causes Control. 2010;21(12):2069-2077. DOI:10.1007/s10552-010-9625-3

26. Okasha M, McCarron P, McEwen J, Smith GD. Body mass index in young adulthood and cancer mortality: a retrospective cohort study. J Epidemiol Community Health. 2002;56(10):780-784. DOI:10.1136/jech.56.10.780

27. Hekal IA, Ibrahiem EI. Obesity-PSA relationship: a new formula. Prostate Cancer Prostatic Dis. 2010;13(2):186-190. DOI:10.1038/pcan.2009.53

28. Grubb RL, 3rd, Black A, Izmirlian G, et al. Serum prostate-specific antigen hemodilution among obese men undergoing screening in the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial. Cancer Epidemiol Biomarkers Prev. 2009;18(3):748-751. DOI:10.1158/1055-9965.EPI-08-0938

29. Hu MB, Liu SH, Jiang HW, et al. Obesity affects the biopsy-mediated detection of prostate cancer, particularly high-grade prostate cancer: a dose-response meta-analysis of 29,464 patients. PLoS One. 2014;9(9):e106677. DOI:10.1371/journal.pone.0106677

30. Freedland SJ, Platz EA, Presti JC, et al. Obesity, Serum Prostate Specific Antigen and Prostate Size: Implications for Prostate Cancer Detection. J Urol. 2006;175(2):500-504. DOI:10.1016/s0022-5347(05)00162-x

31. Rodriguez C, Patel AV, Calle EE, et al. Body mass index, height, and prostate cancer mortality in two large cohorts of adult men in the United States. Cancer Epidemiol Biomarkers Prev. 2001;10(4):345-353.

32. Cao Y, Ma J. Body mass index, prostate cancer-specific mortality, and biochemical recurrence: a systematic review and meta-analysis. Cancer Prev Res (Phila). 2011;4(4):486-501. DOI:10.1158/1940-6207.CAPR-10-0229

33. Collin SM, Martin RM, Metcalfe C, et al. Prostate-cancer mortality in the USA and UK in 1975–2004: an ecological study. Lancet Oncol. 2008;9(5):445-452. DOI:10.1016/s1470-2045(08)70104-9

34. Fesinmeyer MD, Gulati R, Zeliadt S, et al. Effect of Population Trends in Body Mass Index on Prostate Cancer Incidence and Mortality in the United States. Cancer Epidemiol Biomarkers Prev. 2009;18(3):808-815. DOI:10.1158/1055-9965.epi-08-0784

35. Renehan AG, Frystyk J, Flyvbjerg A. Obesity and cancer risk: the role of the insulin–IGF axis. Trends Endocrinol Metab. 2006;17(8):328-336. DOI:10.1016/j.tem.2006.08.006

36. Roberts DL, Dive C, Renehan AG. Biological mechanisms linking obesity and cancer risk: new perspectives. Annu Rev Med. 2010;61:301-316. DOI:10.1146/annurev.med.080708.082713

37. Sharad S, Srivastava A, Ravulapalli S, et al. Prostate cancer gene expression signature of patients with high body mass index. Prostate Cancer Prostatic Dis. 2011;14(1):22-29. DOI:10.1038/pcan.2010.44

38. De Pergola G, Silvestris F. Obesity as a major risk factor for cancer. J Obes. 2013;2013:291546. DOI:10.1155/2013/291546

39. Roddam AW, Allen NE, Appleby P, et al. Insulin-like growth factors, their binding proteins, and prostate cancer risk: analysis of individual patient data from 12 prospective studies. Ann Intern Med. 2008;149(7):461-471, W483-468. DOI:10.7326/0003-4819-149-7-200810070-00006

40. Krueckl SL, Sikes RA, Edlund NM, et al. Increased insulin-like growth factor I receptor expression and signaling are components of androgen-independent progression in a lineage-derived prostate cancer progression model. Cancer Res. 2004;64(23):8620-8629. DOI:10.1158/0008-5472.CAN-04-2446

41. Hellawell GO, Turner GD, Davies DR, et al. Expression of the type 1 insulin-like growth factor receptor is up – regulated in primary prostate cancer and commonly persists in metastatic disease. Cancer Res. 2002;62(10):2942-2950.

42. Williams G. Aromatase up-regulation, insulin and raised intracellular oestrogens in men, induce adiposity, metabolic syndrome and prostate disease, via aberrant ER-alpha and GPER signalling. Mol Cell Endocrinol. 2012;351(2):269-278. DOI:10.1016/j.mce.2011.12.017

43. Huggins C. Studies on Prostatic Cancer. Arch Surg. 1941;43(2):209. DOI:10.1001/archsurg.1941.01210140043004

44. Morgentaler A. Testosterone replacement therapy and prostate cancer. Urol Clin North Am. 2007;34(4):555-563, vii. DOI:10.1016/j.ucl.2007.08.002

45. Roddam AW, et al. Endogenous sex hormones and prostate cancer: a collaborative analysis of 18 prospective studies. J Natl Cancer Inst. 2008;100(3):170-183. DOI:10.1093/jnci/djm323

46. Isbarn H, Pinthus JH, Marks LS, et al. Testosterone and prostate cancer: revisiting old paradigms. Eur Urol. 2009;56(1):48-56. DOI:10.1016/j.eururo.2009.03.088

47. Morgentaler A. Turning conventional wisdom upside-down: low serum testosterone and high-risk prostate cancer. Cancer. 2011;117(17):3885-3888. DOI:10.1002/cncr.25975

48. Morgentaler A. Occult Prostate Cancer in Men With Low Serum Testosterone Levels. JAMA. 1996;276(23):1904. DOI:10.1001/jama.1996.03540230054035

49. Park J, Cho SY, Jeong S-h, et al. Low testosterone level is an independent risk factor for high-grade prostate cancer detection at biopsy. BJU Int. 2016;118(2):230-235. DOI:10.1111/bju.13206

50. Isom-Batz G, Bianco FJ, Jr., Kattan MW, et al. Testosterone as a predictor of pathological stage in clinically localized prostate cancer. J Urol. 2005;173(6):1935-1937. DOI:10.1097/01.ju.0000158040.33531.e7

51. Imamoto T, Suzuki H, Fukasawa S, et al. Pretreatment serum testosterone level as a predictive factor of pathological stage in localized prostate cancer patients treated with radical prostatectomy. Eur Urol. 2005;47(3):308-312. DOI:10.1016/j.eururo.2004.11.003

52. Salonia A, Gallina A, Briganti A, et al. Preoperative hypogonadism is not an independent predictor of high-risk disease in patients undergoing radical prostatectomy. Cancer. 2011;117(17):3953-3962. DOI:10.1002/cncr.25985

53. Shin BS, Hwang EC, Im CM, et al. Is a decreased serum testosterone level a risk factor for prostate cancer? A cohort study of korean men. Korean J Urol. 2010;51(12):819-823. DOI:10.4111/kju.2010.51.12.819

54. Theoret MR, Ning YM, Zhang JJ, et al. The risks and benefits of 5alpha-reductase inhibitors for prostate-cancer prevention. N Engl J Med. 2011;365(2):97-99. DOI:10.1056/NEJMp1106783

55. Wang G, Zhao D, Spring DJ, DePinho RA. Genetics and biology of prostate cancer. Genes Dev. 2018;32(17-18):1105-1140. DOI:10.1101/gad.315739.118

56. Carruba G. Estrogen and prostate cancer: an eclipsed truth in an androgen-dominated scenario. J Cell Biochem. 2007;102(4):899-911. DOI:10.1002/jcb.21529

57. Yao S, Till C, Kristal AR, et al. Serum estrogen levels and prostate cancer risk in the prostate cancer prevention trial: a nested case-control study. Cancer Causes Control. 2011;22(8):1121-1131. DOI:10.1007/s10552-011-9787-7

58. Bonkhoff H, Berges R. The Evolving Role of Oestrogens and Their Receptors in the Development and Progression of Prostate Cancer. Eur Urol. 2009;55(3):533-542. DOI:10.1016/j.eururo.2008.10.035

59. Weisberg SP, McCann D, Desai M, et al. Obesity is associated with macrophage accumulation in adipose tissue. J Clin Invest. 2003;112(12):1796-1808. DOI:10.1172/JCI19246

60. Ziech D, Franco R, Pappa A, Panayiotidis MI. Reactive oxygen species (ROS)--induced genetic and epigenetic alterations in human carcinogenesis. Mutat Res. 2011;711(1-2):167-173. DOI:10.1016/j.mrfmmm.2011.02.015

61. Kershaw EE, Flier JS. Adipose tissue as an endocrine organ. J Clin Endocrinol Metab. 2004;89(6):2548-2556. DOI:10.1210/jc.2004-0395

62. Li MD. Leptin and beyond: an odyssey to the central control of body weight. Yale J Biol Med. 2011;84(1):1-7.

63. Considine RV, Sinha MK, Heiman ML, et al. Serum immunoreactive-leptin concentrations in normal-weight and obese humans. N Engl J Med. 1996;334(5):292-295. DOI:10.1056/NEJM199602013340503

64. Stattin P, Soderberg S, Hallmans G, et al. Leptin is associated with increased prostate cancer risk: a nested case-referent study. J Clin Endocrinol Metab. 2001;86(3):1341-1345. DOI:10.1210/jcem.86.3.7328

65. Noda T, Kikugawa T, Tanji N, et al. Longterm exposure to leptin enhances the growth of prostate cancer cells. Int J Oncol. 2015;46(4):1535-1542. DOI:10.3892/ijo.2015.2845

66. Lin DW, FitzGerald LM, Fu R, et al. Genetic variants in the LEPR, CRY1, RNASEL, IL4, and ARVCF genes are prognostic markers of prostate cancer-specific mortality. Cancer Epidemiol Biomarkers Prev. 2011;20(9):1928-1936. DOI:10.1158/1055-9965.EPI-11-0236

67. Li H, Stampfer MJ, Mucci L, et al. A 25-year prospective study of plasma adiponectin and leptin concentrations and prostate cancer risk and survival. Clin Chem. 2010;56(1):34-43. DOI:10.1373/clinchem.2009.133272

68. Kern PA, Ranganathan S, Li C, et al. Adipose tissue tumor necrosis factor and interleukin-6 expression in human obesity and insulin resistance. Am J Physiol Endocrinol Metab. 2001;280(5):E745-751. DOI:10.1152/ajpendo.2001.280.5.E745

69. Fried SK, Bunkin DA, Greenberg AS. Omental and subcutaneous adipose tissues of obese subjects release interleukin-6: depot difference and regulation by glucocorticoid. J Clin Endocrinol Metab. 1998;83(3):847-850. DOI:10.1210/jcem.83.3.4660

70. George DJ, Halabi S, Shepard TF, et al. The prognostic significance of plasma interleukin-6 levels in patients with metastatic hormone-refractory prostate cancer: results from cancer and leukemia group B 9480. Clin Cancer Res. 2005;11(5):1815-1820. DOI:10.1158/1078-0432.CCR-04-1560

71. Steiner H, Godoy-Tundidor S, Rogatsch H, et al. Accelerated in Vivo Growth of Prostate Tumors that Up-Regulate Interleukin-6 Is Associated with Reduced Retinoblastoma Protein Expression and Activation of the Mitogen-Activated Protein Kinase Pathway. Am J Pathol. 2003;162(2):655-663. DOI:10.1016/s0002-9440(10)63859-x

72. Giri D, Ozen M, Ittmann M. Interleukin-6 Is an Autocrine Growth Factor in Human Prostate Cancer. Am J Patho. 2001;159(6):2159-2165. DOI:10.1016/s0002-9440(10)63067-2

73. Wang Y, Xu A, Knight C, et al. Hydroxylation and Glycosylation of the Four Conserved Lysine Residues in the Collagenous Domain of Adiponectin. J Biol Chem. 2002;277(22):19521-19529. DOI:10.1074/jbc.M200601200

74. Tilg H, Moschen AR. Adipocytokines: mediators linking adipose tissue, inflammation and immunity. Nat Rev Immunol. 2006;6(10):772-783. DOI:10.1038/nri1937

75. Dalamaga M, Diakopoulos KN, Mantzoros CS. The role of adiponectin in cancer: a review of current evidence. Endocr Rev. 2012;33(4):547-594. DOI:10.1210/er.2011-1015

76. Kadowaki T, Yamauchi T, Kubota N, et al. Adiponectin and adiponectin receptors in insulin resistance, diabetes, and the metabolic syndrome. J Clin Invest. 2006;116(7):1784-1792. DOI:10.1172/JCI29126

77. Rider JR, Fiorentino M, Kelly R, et al. Tumor expression of adiponectin receptor 2 and lethal prostate cancer. Carcinogenesis. 2015;36(6):639-647. DOI:10.1093/carcin/bgv048

78. Michalakis K, Venihaki M, Mantzoros C, et al. In prostate cancer, low adiponectin levels are not associated with insulin resistance. Eur J Clin Invest. 2015;45(6):572-578. DOI:10.1111/eci.12445

79. Tan W, Wang L, Ma Q, et al. Adiponectin as a potential tumor suppressor inhibiting epithelial-to-mesenchymal transition but frequently silenced in prostate cancer by promoter methylation. Prostate. 2015;75(11):1197-1205. DOI:10.1002/pros.23002

80. Hanahan D, Weinberg RA. Hallmarks of cancer: the next generation. Cell. 2011;144(5):646-674. DOI:10.1016/j.cell.2011.02.013

81. Taylor RA, Risbridger GP. Prostatic tumor stroma: a key player in cancer progression. Curr Cancer Drug Targets. 2008;8(6):490-497. DOI:10.2174/156800908785699351

82. Bhindi B, Trottier G, Elharram M, et al. Measurement of peri-prostatic fat thickness using transrectal ultrasonography (TRUS): a new risk factor for prostate cancer. BJU Int. 2012;110(7):980-986. DOI:10.1111/j.1464-410X.2012.10957.x

83. Booth A, Magnuson A, Fouts J, Foster M. Adipose tissue, obesity and adipokines: role in cancer promotion. Horm Mol Biol Clin Investig. 2015;21(1):57-74. DOI:10.1515/hmbci-2014-0037

84. Fain JN, Madan AK, Hiler ML, et al. Comparison of the release of adipokines by adipose tissue, adipose tissue matrix, and adipocytes from visceral and subcutaneous abdominal adipose tissues of obese humans. Endocrinology. 2004;145(5):2273-2282. DOI:10.1210/en.2003-1336

85. Venkatasubramanian PN, Brendler CB, Plunkett BA, et al. Periprostatic adipose tissue from obese prostate cancer patients promotes tumor and endothelial cell proliferation: a functional and MR imaging pilot study. Prostate. 2014;74(3):326-335. DOI:10.1002/pros.22756

86. Ribeiro R, Monteiro C, Cunha V, et al. Human periprostatic adipose tissue promotes prostate cancer aggressiveness in vitro. J Exp Clin Cancer Res. 2012;31:32. DOI:10.1186/1756-9966-31-32