Type 2 diabetes mellitus and non-muscle invasive bladder cancer: characteristics of the epidermal growth factor system components content in blood, urine, and tumor

Cover Page

Cite item

Full Text

Abstract

Background. The incidence of bladder cancer (BC) and type 2 diabetes mellitus (T2DM) are rising consistently worldwide. It is not uncommon for these two pathologies to be found in combination. T2DM is a contributing factor in many cancer types. It is currently understood that the development of non-muscle invasive BC (NMIBC) occurs primarily through the activation of oncogenes that involve the epidermal growth factor (EGF) system. However, the effect of T2DM on the EGF system in the context of NMIBC remains unclear.

Aim. To investigate the specific content of the EGF system components in the blood, urine, and tumor tissue of patients with NMIBC with concomitant T2DM.

Materials and methods. The participants were divided into the main group – patients with NMIBC and T2DM (n = 11), and the control group – patients with NMIBC without T2DM (n = 11). The comparison group comprised of patients with T2DM only (n = 8). All parameters were evaluated in comparison to those of healthy donors (n = 12). The levels of EGF (Ray Bio, Germany) and its soluble receptor (sEGFR) (RAD Systems, USA) were quantified in blood, urine and 10 % tumor tissue homogenates using standard EIA kits on an automatic analyzer, the Infinite F50 (Tecan Austria GmbH, Austria).

Results. In 80 % of control group patients, blood EGF levels increased 2.8-fold compared to donors, while in 20 % they remained unchanged. Blood EGF content in patients with comorbid pathology and the comparison group (T2DM only) was comparable and at the same time 2.1–2.7 times lower than in most patients from the control group. In all BC patients, blood sEGFR concentration was 1.4 times lower than in donors and T2DM patients, but increased in urine: 2.9-fold in BC patients without T2DM and 3.5-fold in BC patients with T2DM. Patients with NMIBC and T2DM had 1.5 times less EGF and 2.0 times less sEGFR than NMIBC patients without T2DM.

Conclusion. The patients with NMIBC and T2DM were deficient in EGF (in blood, urine, and tumor tissue) and sEGFR (in blood and tumor tissue), compared to the patients with NMIBC without T2DM who demonstrated increased levels of EGF (in blood, urine, and tumor tissue). The development of NMIBC was associated with an increase in urinary sEGFR concentrations, irrespective of T2DM status.

About the authors

I. V. Kaplieva

National Medical Research Centre for Oncology, Ministry of Health of Russia

Author for correspondence.
Email: kaplirina@yandex.ru
ORCID iD: 0000-0002-3972-2452
SPIN-code: 5047-1541

Irina Viktorovna Kaplieva, Head of Laboratory of Malignant Tumor Pathogenesis Study

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

E. M. Ataeva

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: lena.ataevae1996@yandex.ru
ORCID iD: 0009-0007-2642-6295

Graduate student

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

E. M. Frantsiyants

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: super.gormon@yandex.ru
ORCID iD: 0000-0003-3618-6890

Deputy General Director for Science

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

L. K. Trepitaki

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: legolab69@yandex.ru
ORCID iD: 0000-0002-9749-2747

Researcher at Laboratory of Study of Malignant Tumor Pathogenesis

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

Yu. A. Petrova

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: flora-73@yandex.ru
ORCID iD: 0000-0002-2674-9832

Senior researcher at Laboratory of Malignant Tumor Pathogenesis Study

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

A. N. Shewchenko

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: alexshew@mail.ru
ORCID iD: 0000-0002-9468-134X

Head of the Oncourology Department

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

P. S. Kachesova

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: vnp.61@yandex.ru
ORCID iD: 0000-0001-6928-5014

Researcher at Laboratory of Malignant Tumor Pathogenesis Study

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

D. A. Shvyrev

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: dima2410@bk.ru
ORCID iD: 0000-0002-4012-4257

Oncologist, oncology department

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

S. G. Vlasov

National Medical Research Centre for Oncology, Ministry of Health of Russia

Email: stasikvlasov1994rgmu@gmail.com
ORCID iD: 0000-0002-4680-8991

Radiotherapist of Radiotherapy Department No. 2

63 14-ya Liniya St., 344037 Rostov-on-Don

Russian Federation

References

  1. Malignant tumors in Russia in 2023 (morbidity and mortality). Eds.: А.D. Kaprin, V.V. Starinskiy, A.O. Shakhzadova. Moscow: MNIOI im. P.A. Gertsena – filial FGBU “NMITS radiologii” Minzdrava Rossii, 2024. 276 p. (In Russ.).
  2. Sung H., Ferlay J., Siegel R.L. et al. Global Cancer Statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin 2021;71(3):209– 49. doi: 10.3322/caac.21660
  3. Nemtsova M.V., Kushlinskiy N.E. The molecular pathogenesis of bladder cancer. Al’manakh klinicheskoy meditsiny = Almanac of Clinical Medicine 2015;41:79–88. (In Russ.).
  4. Semeniuk-Wojtaś A., Poddębniak-Strama K., Modzelewska M. et al. Tumour microenvironment as a predictive factor for immunotherapy in non-muscle-invasive bladder cancer. Cancer Immunol Immunother 2023;72(7):1971–89. doi: 10.1007/s00262-023-03376-9
  5. Khan R.M.M., Chua Z.J.Y., Tan J.C. et al. From pre-diabetes to diabetes: diagnosis, treatments and translational research. Medicina (Kaunas) 2019;55(9):546. doi: 10.3390/medicina55090546
  6. Frantsiyants E.M., Surikova E.I., Kaplieva I.V. et al. Diabetes mellitus and cancer: a system of insulin-like growth factors. Problemy endokrinologii = Problems of Endocrinology 2021;67(5):34–42. (In Russ.). doi: 10.14341/probl12741
  7. Kit O.I., Frantsiyants E.M., Bandovkina V.A. et al. Method for stimulating hematogenous dissemination of carcinoma in experiment. Patent of the Russian Federation No. 2757676. Publ. 10.20.2021. Bull. No. 29. (In Russ.).
  8. Xu Y., Huo R., Chen X., Yu X. Diabetes mellitus and the risk of bladder cancer: a PRISMA-compliant meta-analysis of cohort studies. Medicine (Baltimore) 2017;96(46):e8588. doi: 10.1097/MD.0000000000008588
  9. Huang W.L., Huang K.H., Huang C.Y. et al. Effect of diabetes mellitus and glycemic control on the prognosis of non-muscle invasive bladder cancer: a retrospective study. BMC Urol 2020;20(1):117. doi: 10.1186/s12894-020-00684-5.
  10. Oh J.J., Kang M.Y., Jo J.K. et al. Association between diabetes mellitus and oncological outcomes in bladder cancer patients undergoing radical cystectomy. Int J Urol 2015;22(12):1112–7. doi: 10.1111/iju.12901
  11. Ferguson K.M., Hu C., Lemmon M.A. Insulin and epidermal growth factor receptor family members share parallel activation mechanisms. Protein Sci 2020;29(6):1331–44. doi: 10.1002/pro.3871
  12. Sami M.M., Sherief M.H., El-Abaseri T.B. et al. Expression of epidermal growth factor receptor and human epidermal growth factor receptor 2 in urothelial bladder carcinoma in an Egyptian cohort: clinical implication and prognostic significance. Urologia 2023;90(2):248–60. doi: 10.1177/03915603221150965
  13. Kosova I.V., Laurent O.B., Sinyakova L.A. et al. Immunohistochemical characteristics of bladder cancer in patients with virus-positive tumors. Onkourologiya = Cancer Urology 2018;14(2):142–54. (In Russ.). doi: 10.17650/1726-9776-20
  14. Ponnaboina D.M., Perumandal S.I. Correlation of HER2 With p53 and p63 in Urothelial Bladder Carcinoma. Cureus 2023;15(4):e38018. doi: 10.7759/cureus.38018
  15. Izumi K., Zheng Y., Li Y. et al. Epidermal growth factor induces bladder cancer cell proliferation through activation of the androgen receptor. Int J Oncol 2012;41(5):1587–92. doi: 10.3892/ijo.2012.1593
  16. Kyohara M., Shirakawa J., Okuyama T. et al. Soluble EGFR, a hepatokine, and adipsin, an adipokine, are biomarkers correlated with distinct aspects of insulin resistance in type 2 diabetes subjects. Diabetol Metab Syndr 2020;12:83. doi: 10.1186/s13098-020-00591-7
  17. Baron A.T., Wilken J.A., Haggstrom D.E. et al. Clinical implementation of soluble EGFR (sEGFR) as a theragnostic serum biomarker of breast, lung and ovarian cancer. IDrugs 2009;12(5):302–8.
  18. Zanotti L., Paderno A., Piazza C. et al. Epidermal growth factor receptor detection in serum and saliva as a diagnostic and prognostic tool in oral cancer. Laryngoscope 2017;127(11). doi: 10.1002/lary.26797
  19. Bryan R.T., Regan H.L., Pirrie S.J. et al. Protein shedding in urothelial bladder cancer: prognostic implications of soluble urinary EGFR and EpCAM. Br J Cancer 2015;112(6):1052–8. doi: 10.1038/bjc.2015.21
  20. Al-Dwairi A., Alfaqih M.A., Saadeh R.A. et al. Lack of glycemic control in type two diabetes mellitus patients is associated with reduced serum epidermal growth factor level and increased insulin resistance. Biomed Rep 2024;22(1):5. doi: 10.3892/br.2024.1883
  21. Нashmi A.A., Hussain Z.F., Irfan M. et al. Prognostic significance of epidermal growth factor receptor (EGFR) over expression in urothelial carcinoma of urinary bladder. BMC Urol 2018;18:59. doi: 10.1186/s12894-018-0373-0
  22. Vorontsova M.S., Karmakova T.A., Plotnikova E.A. et al. Subcutaneous and orthotopic xenograft models of human bladder carcinoma in nude mice for epidermal growth factor receptor-targeted treatment. Rossijskij bioterapevticeskij zurnal = Russian Journal of Biotherapy 2018;17(2):31–40. (In Russ.). doi: 10.17650/1726-9784-2018-17-2-31-40
  23. Jin P., Liu J., Wang X. et al. HER2 activation factors in arsenite-exposed bladder epithelial cells. Toxicol Sci 2018;166(2):354–69. doi: 10.1093/toxsci/kfy202
  24. Failla C.M., Carbo M., Morea V. Positive and negative regulation of angiogenesis by soluble vascular endothelial growth factor receptor-1. Int J Mol Sci 2018;19(5):1306. doi: 10.3390/ijms19051306
  25. Qu M., Zhou L., Yan X. et al. Advances in HER2-targeted treatment for advanced/metastatic urothelial carcinoma. Bladder (San Franc) 2023;10:e21200012. doi: 10.14440/bladder.2023.871
  26. Kim J.M., Choung S., Joung K.H. et al. Serum Soluble epidermal growth factor receptor level increase in patients newly diagnosed with type 2 diabetes mellitus. Diabetes Metab J 2018;42(4):343–7. doi: 10.4093/dmj.2017.0082
  27. Lee J.C., Joung K.H., Kim J.M. et al. Effect of cholesterol-lowering agents on soluble epidermal growth factor receptor level in type 2 diabetes and hypercholesterolemia. Medicine (Baltimore) 2022;101(34):e30287. doi: 10.1097/MD.0000000000030287

Supplementary files

Supplementary Files
Action
1. JATS XML

Copyright (c)



СМИ зарегистрировано Федеральной службой по надзору в сфере связи, информационных технологий и массовых коммуникаций (Роскомнадзор).
Регистрационный номер и дата принятия решения о регистрации СМИ: серия ПИ № ФС 77-36986 от  21.07.2009.