Modern view of the problem: the influence of obesity as a key component of metabolic syndrome on the development and progression of endometrial cancer
https://doi.org/10.18027/2224-5057-2024-010
Abstract
Unlike many other malignancies, the incidence and mortality of endometrial cancer continues to rise. This unfortunate trend is in no small part the result of the worldwide obesity epidemic, which is caused by reduced physical activity, poor diet and chronic stress. Currently, more than 50 % of endometrial cancer cases are associated with obesity, which is recognized as an independent risk factor for the development of this disease. Adipose tissue is not only the main place of storage of excess energy, but also a full-fledged endocrine organ that affects the metabolism, immune response and production of biologically active substances involved in cell growth and differentiation, angiogenesis, apoptosis and carcinogenesis. In this review, we assess the impact of obesity as a key component of metabolic syndrome on the development and progression of endometrial cancer. There are several mechanisms by which obesity enlarges the risk of endometrial cancer, including increased endogenous sex steroid hormones, hyperglycemia, insulin resistance, adipokine secretion, and chronic inflammation.
The purpose of this review is to analyze publications, reflecting the already known aspects of the biological effect of obesity, as well as new data from recent years.
Keywords
About the Authors
A. Yu. PavlovRussian Federation
Andrei Yurevich Pavlov
117997; 86, Profsoyuznaya St.; Moscow
A. G. Dzidzariya
Russian Federation
Aleksandr Gudisovich Dzidzariya
117997; 86, Profsoyuznaya St.; Moscow
S. Yu. Kalinchenko
Russian Federation
Svetlana Yurevna Kalinchenko
117198; 6 Miklukho‑Maklaya St.; Moscow
P. V. Muravyeva
Russian Federation
Polina Vladimirovna Muraveva
117997; 86, Profsoyuznaya St.; Moscow
References
1. The state of cancer care for the population of Russia in 2022. Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shachzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2022.239 p. (In Russ.)
2. Neufeld I.V., Rogozhina I.E., Zhirnyakov A.I. and others. Obstetric and gynecological anamnesis from the perspective of risk factors for cardiovascular diseases. Bulletin of Tambov University. Series: Natural and technical sciences 2014;19(3):986–990. (in Russ.)
3. Morice P., Leary A., Creutzberg C., et al. Endometrial cancer. Lancet 2016;387(10023):1094–1108. doi: 10.1016/s0140-6736(15)00130-0
4. Wang L, Du Z.-H., Qiao J.-M., Gao S. Association between metabolic syndrome and endometrial cancer risk : a systematic review and meta-analysis of observational studies. Aging (Albany NY) 2020;12(10):9825–9839. doi: 10.18632/aging.103247
5. Yunusova N.V., Kondakova I.V., Kolomiets L.A., et al. The role of metabolic syndrome variant in the malignant tumors progression. Diabetes Metab Syndr 2018;12(5):807–812. doi: 10.1016/j.dsx.2018.04.028.
6. Article r. Diagnosis and treatment of metabolic syndrome. Russian recommendations. Cardiovascular therapy and prevention. 2007;3–28. (in Russ.). URL: https://cardiovascular.elpub.ru/jour/article/view/1088
7. Ward K.K., Roncancio A.M., Shah N.R., et al. Bariatric surgery decreases the risk of uterine malignancy. Gynecol Oncol 2014;133(1):63–6. doi: 10.1016/j.ygyno.2013.11.012
8. Hausman D.B., DiGirolamo M., Bartness T.J., et al. The biology of white adipocyte proliferation. Obes Rev 2001;2(4):239–254. doi: 10.1046/j.1467-789x.2001.00042.x
9. Smetnik V.P. The importance of adipose tissue in the formation of hormonal status in women. Effective pharmacotherapy in obstetrics and gynecology 2007;4:6–13. (in Russ.)
10. Key T.J., Allen N.E., Verkasalo P.K., Banks E. Energy balance and cancer: the role of sex hormones. Proceed Nutrit Societ 2001;60(01):81–89. doi: 10.1079/PNS200068
11. Key T.J., Pike M.C. The dose-effect relationship between “unopposed” oestrogens and endometrial mitotic rate: its central role in explaining and predicting endometrial cancer risk. Br J Cancer 1988;57(2):205–212. doi: 10.1038/bjc.1988.44
12. Akhmedkhanov A., Zeleniuch-Jacquotte A., Toniolo P. Role of exogenous and endogenous hormones in endometrial cancer : review of the evidence and research perspectives. Ann N Y Acad Sci 2001;943:296–315. doi: 10.1111/j.1749-6632.2001.tb03811.x
13. Cleary M.P., Grossmann M.E. Minireview: obesity and breast cancer: the estrogen connection. Endocrinology 2009;150(6):2537–2542. doi: 10.1210/en.2009-0070
14. Agnew H.J., Kitson S.J., Crosbie E.J. Gynecological malignancies and obesity. Best Pract Res Clin Obstet Gynaecol 2023;88:102337. doi: 10.1016/j.bpobgyn.2023.102337
15. Yu J. SL., Cui W. Proliferation, survival and metabolism: the role of PI3K/AKT/mTOR signalling in pluripotency and cell fate determination. Development 2016;143(17):3050–3060. doi: 10.1242/dev.137075
16. Sarris E.G., Saif M.W., Syrigos K.N. The biological role of PI3K pathway in lung cancer. Pharmaceuticals (Basel) 2012;5(11):1236–1264. doi: 10.3390/ph5111236
17. Alayev A., Holz M.K. mTOR signaling for biological control and cancer. J Cell Physiol 2013;228(8):1658–1664. doi: 10.1002/jcp.24351
18. Ryu T.Y., Park J., Scherer P.E. Hyperglycemia as a risk factor for cancer progression. Diabetes Metab J 2014;38(5):330 –336. doi: 10.4093/dmj.2014.38.5.330
19. Mutter G.L., Lin M.C., Fitzgerald J.T., et al. Altered PTEN expression as a diagnostic marker for the earliest endometrial precancer. J. Natl Cancer Inst 2000;92(11):924–930. doi: 10.1093/jnci/92.11.924
20. Norimatsu Y., Moriya T., Kobayashi T.K., et al. Immunohistochemical expression of PTEN and β-catenin for endometrial intraepithelial neoplasia in Japanese women. Ann Diagn Pathol 2007;11(2):103–108. doi: 10.1016/j.anndiagpath.2006.06.009
21. Radzinsky V.E., Panova E.A., Totchiev G.F., et al. The role of the PTEN gene in hyperplastic processes of the endometrium against the background of metabolic syndrome. Gynecology Endocrinology 2012;69(1):87–89. (in Russ.)
22. Kershaw E.E., Flier J.S. Adipose tissue as an endocrine organ. J Clin. Endocrinol Metab 2004;89(6):2548–2556. doi: 10.1210/jc.2004-0395
23. Li J., Han X. Adipocytokines and Breast Cancer. Curr Probl Cancer 2018;42(2):208–214. doi: 10.1016/j.currproblcancer.2018.01.004
24. Pang L., Chang X. Resistin expression in epithelial ovarian cancer promotes the proliferation and migration of ovarian cancer cells to worsen prognosis. J Cancer 2021;12(22):6796–6804. doi: 10.7150/jca.62496
25. Wang Y.-Y., Hung A.C., Lo S., Yuan S.-S.F. Adipocytokines visfatin and resistin in breast cancer: Clinical relevance, biological mechanisms, and therapeutic potential. Cancer Lett 2021;498:229–239. doi: 10.1016/j.canlet.2020.10.045
26. Michalakis K., Mintziori G., Kaprara A., et al. The complex interaction between obesity, metabolic syndrome and reproductive axis : a narrative review. Metabolism 2013;62(4):457–78. doi: 10.1016/j.metabol.2012.08.012
27. Perez-Hernandez A.I., Catalan V., Gomez-Ambrosi J., et al. Mechanisms linking excess adiposity and carcinogenesis promotion. Front Endocrinol 2014;5:65. doi: 10.3389/fendo.2014.00065
28. Lee C.H., Woo Y.C., Wang Y., et al. Obesity, adipokines and cancer: an update. Clin Endocrinol (Oxf) 2015;83(2):147–156. doi: 10.1111/cen.12667
29. Renehan A.G., Zwahlen M., Egger M. Adiposity and cancer risk: new mechanistic insights from epidemiology. Nat Rev Cancer 2015;15(8):484–498. doi: 10.1038/nrc3967
30. Dashti S.G., English D.R., Simpson J.A., et al. Adiposity and endometrial cancer risk in postmenopausal women: A sequential causal mediation analysis. Cancer Epidemiology, Biomarkers & Prevention 2021;30(1):104–113. doi: 10.1158/1055-9965.EPI-20-0965
31. Chen D.-C., Chung Y.-F., Yeh Y.-T., et al. Serum adiponectin and leptin levels in Taiwanese breast cancer patients. Cancer Lett 2006;237(1):109–114. doi: 10.1016/j.canlet.2005.05.047
32. Obesity (clinical essays). Eds.: prof. Baranovsky A.Yu., prof. Vorokhbina N.V.St. Petersburg. 2007;240. (in Russ.)
33. Fruhbeck G., Jebb S.A., Prentice A.M. Leptin: physiology and pathophysiology. Clin Physiol 1998;18(5):399–419. doi: 10.1046/j.1365-2281.1998.00129.x
34. Chen J., Munter P., Hamm L.L., et al. Insulin resistance and risk of chronic kidney disease in nondiabetic US adults. J Am Soc Nephrol 2003;14(2):469–477. doi: 10.1097/01.asn.0000046029.53933.09
35. Thompson J.A., Regnault T.R.H. In Utero origins of adult insulin resistance and vascular dysfunction. Semin Reprod Med 2011;29(3):211–224. doi: 10.1055/s-0031-1275522
36. Sharma A., Bahadursingh S., Ramsewak S., Teelucksingh S. Medical and surgical interventions to improve outcomes in obese women planning for pregnancy. Best Pract Res Clin Obstet Gуnаecol 2015;29(4):565–576. doi: 10.1016/j.bpobgyn.2014.12.003
37. Ellis P.E., Barron G.A., Bermano G. Adipocytokines and their relationship to endometrial cancer risk : A systematic review and meta-analysis. Gynecol Oncol 2020;158(2):507–516. doi: 10.1016/j.ygyno.2020.05.033
38. Sharma D., Saxena N.K., Vertino P.M., Anania F.A. Leptin promotes the proliferative response and invasiveness in human EC cells by activating multiple signal-transduction pathways. Endocr Relat Cancer 2006;13(2):629–640. doi: 10.1677/erc.1.01169
39. Khoramipour K., Chamari K., Hekmatikar A.A., et al. Adiponectin: structure, physiological functions, role in diseases, and effects of nutrition. Nutrients 2021;13(4):1180. doi: 10.3390/nu13041180
40. Vavilova T.P., Pleten’ A.P., Mikheev R.K. Biological role of adi-pokines and their association with morbid conditions. Voprosy pitaniia 2017;86(2):5–13. (In Russ)
41. Verbovoy A.F., Tsanava I.A., Verbovaya N.I. Adipokines and metabolie patients with type 2 diabetes mellitus in combination with gout. Ozhirenie imetabolism 2016;13(1):20–24. (In Russ.). doi: 10.14341/OMET2016120-24
42. Parfenov N.S., Tanyanskiy D.A. Adiponectin: beneficial effects on metabolic and cardiovascular dysfunctions. Arterial’naya Gipertenziya 2013;19(1):84–96. (In Russ.)
43. Geagea A.G., Mallat S., Matar C.F., et al. Adiponectin and inflammation in health and disease: an update. Open Medicine Journal 2018;5:20–32. doi: 10.2174/1874220301805010020
44. Titov V.N. The functional difference between visceral fatty cells and subcutaneous adipocytes. Klinicheskaya meditsina 2015;93(2):14–23. (In Russ.)
45. Blachnio-Zabielska A.U., Hady H.R., Markowski A.R., et al. Inhibition of ceramide de novo synthesis affects adipocytokine secretion and improves systemic and adipose tissue insulin sensitivity. Int J Mol Sci 2018;19(12):3995. doi: 10.3390/ijms19123995
46. Yunusova N.V., Kondakova I.V., Kolomiets L.A., et al. The role of metabolic syndrome variant in the malignant tumors progression. Diabetes Metab Syndr 2018;12(5):807–812. doi: 10.1016/j.dsx.2018.04.028
47. Coelho M., Oliveira T., Fernandes R. Biochemistry of adipose tissue: an endocrine organ. Arch Med Sci 2013;9(2):191–200. doi: 10.5114/aoms.2013.33181
48. Adolph T.E., Grander C., Grabherr F., Tilg H. Adipokines and non-alcoholic fatty liver disease: multiple interactions. Int J Mol Sci 2017;18(8):1649. doi: 10.3390/ijms18081649
49. Wang Y., Meng R.W., Kunutsor S.K., et al. Plasma adiponectin levels and type 2 diabetes risk: A nested case-control study in a Chinese population and an updated meta-analysis. Sci Rep 2018;8(1):406. doi: 10.1038/s41598-017-18709-9
50. Wang Z., Gao S., Sun C. Et al. Clinical significance of serum adiponectin and visfatin levels in endometrial cancer. Int J Gynecol Obstet 2019;145(1):34–39. doi: 10.1002/ijgo.12772
51. Ray I., Meira L.B., Michael A., Ellis P.E. Adipocytokines and disease progression in endometrial cancer : a systematic review. Cancer Metastasis Rev 2022;41(1):211–242. doi: 10.1007/s10555-021-10002-6
52. Kölbl H., Bartl T. Obesity in gynecologic oncology. Geburtshilfe Frauenheilkd 2020;80(12):1205–1211. doi: 10.1055/a-1124-7139
53. De Nola R., Menga A., Castegna A., et al. The crowded crosstalk between cancer cells and stromal microenvironment in gynecological malignancies: biological pathways and therapeutic implication. Int J Mol Sci 2019;20(10):2401. doi: 10.3390/ijms20102401
54. Landskron G., De la Fuente M., Thuwajit P., et al. Chronic inflammation and cytokines in the tumor microenvironment. J Immunol Res 2014;2014:149185. doi: 10.1155/2014/149185.
55. Romaiuk A., Lуndіn M. Immune microenvironment as a factor of breast cancer progression. Diagn Pathol 2015;10:79. doi: 10.1186/s13000-015-0316-y
56. Felix A.S., Weissfeld J., Edwards, R., Linkov F. Future directions in the field of endometrial cancer research: The need to investigate the tumor microenvironment. Eur J Gynaecol Oncol 2010;31(2):139–144
57. Hlavna M., Kohut L., Lipkova J., et al. Relationship of resistin levels with endometrial cancer risk. Neoplasma 2011;58(2):124–128. doi: 10.4149/neo_2011_02_124
58. Lumeng C.N., Bodzin J.L., Saltiel A.R. Obesity induces a phenotypic switch in adipose tissue macrophage polarization. J Clin Investig 2007;117(1):175–184. doi: 10.1172/JCI29881
59. Dirat B.A., Bochet L., Escourrou G., et al. Unraveling the obesity and breast cancer links: a role for cancer-associated adipocytes? Endocr Dev 2010;19:45–52. doi: 10.1159/000316896.
Review
For citations:
Pavlov A.Yu., Dzidzariya A.G., Kalinchenko S.Yu., Muravyeva P.V. Modern view of the problem: the influence of obesity as a key component of metabolic syndrome on the development and progression of endometrial cancer. Malignant tumours. 2024;14(2):75-82. (In Russ.) https://doi.org/10.18027/2224-5057-2024-010