EVALUATION OF THE PROGNOSTIC SIGNIFICANCE OF SOME BIOLOGICAL FACTORS IN LOCAL AND GENERALIZED CLEAR CELL RENAL CANCER

Purpose of the study. To evaluate the prognostic significance of biological factors VEGF-A, sVEGF-R1, VEGF-D, FGF, EGF, EGFR, IGF-1, IGF-2, IGFBP-1, IGFBP-2, somatotropin-releasing factor (GHRH) in kidney tissues (tumour tissue, tissue of the perifocal zone and conditionally intact tissue) in local and generalized clear cell renal cancer using ROC analysis.

Materials and methods. Two groups of patients were included in the study. Group 1 comprised 50 patients with local kidney cancer (T1–3N0M0), while group 2 comprised 50 patients with metastatic kidney cancer (T1–4N0M1). 10% cytosolic fractions of the kidney tumour tissue were examined. The content of growth factors — somatotropinreleasing factor (GHRH), somatotropin-releasing factor (GHRH) — was determined by the ELISA assay using standard test systems. An assessment of prognostically unfavourable factors that significantly affect the generalization of the tumour process was carried out using binary logistic regression and ROC analysis.

Results. The performed ROC analysis revealed diagnostically significant progression biomarkers and their critical values for clear cell renal cancer (for conditionally intact tissue, these values were: VEGF-A ≤ 9107.9 pg/g of tissue; VEGF-R1 ≤ 122.8 ng/g of tissue; FGF ≤ 364.7 pg/g of tissue; IGF-2 ≤ 148 ng/g of tissue; for perifocal tissue, VEGF-A ≤ 5839.6 pg/g of tissue; for tumour tissue, VEGF-A > 9622.5 pg/g of tissue, FGF ≤ 435.1 pg/g of tissue, somatotropin-releasing factor (GHRH) ≤ 158.6 ng/g of tissue). The obtained data contribute to optimization of the disease prognosis.

Conclusion. It is established that the most prognostically significant markers of clear cell renal cancer progression include VEGF-A, FGF, somatotropin-releasing factor (GHRH), which can serve as an additional criterion for the differential diagnosis of progression and monitoring of clear cell renal cancer.   

1. Malignant neoplasms in Russia in 2018. Eds. Kaprina A. D., Starinsky V. V., Petrova G. V. Moscow, 2019. (In Russian). Available at: http://www.oncology.ru/service/statistics/malignant_tumors/2018.pdf

2. Jacobsen J., Grankvist K., Rasmuson T., Bergh A., Landberg G., Ljungberg B. Expression of vascular endothelial growth factor protein in human renal cell carcinoma. BJU Int. 2004 Feb;93 (3):297–302. https://doi.org/10.1111/j.1464–410X.2004.04605.x

3. Igarashi H., Esumi M., Ishida H., Okada K. Vascular endothelial growth factor overexpression is correlated with von Hippel-Lindau tumor suppressor gene inactivation in patients with sporadic renal cell carcinoma. Cancer. 2002 Jul 1;95(1):47–53. https://doi.org/10.1002/cncr.10635

4. Ferrara N. VEGF-A: a critical regulator of blood vessel growth. Eur Cytokine Netw. 2009 Dec;20(4):158–163. https://doi.org/10.1684/ecn.2009.0170

5. Paradis V., Lagha N. B., Zeimoura L., Blanchet P., Eschwege P., Ba N., et al. Expression of vascular endothelial growth factor in renal cell carcinomas. Virchows Arch. 2000 Apr;436(4):351– 356. https://doi.org/10.1007/s004280050458

6. Spirina L. V., Kondakova I. V., Usynin Y. A., Vintizenko S. I. Angiogenesis regulation in renal and bladder cancers. Siberian Oncology Journal. 2008;4:65–69 (In Russian).

7. Yagasaki H., Kawata N., Takimoto Y., Nemoto N. Histopathological analysis of angiogenic factors in renal cell carcinoma. Int J Urol. 2003 Apr;10(4):220–227. https://doi.org/10.1046/j.0919–8172.2003.00608.x

8. Maslyakova G. N., Medvedeva A. V. The study of aggressiveness factors for the diagnosis and prognosis of the course of kidney tumors (analysis of literature data). Bulletin of medical Internet conferences. 2013;3(4):845–848 (In Russian).

9. Matsumoto K., Suzuki K., Koike H., Okamura K., Tsuchiya K., Uchida T., et al. Prognostic significance of plasma placental growth factor levels in renal cell cancer: an association with clinical characteristics and vascular endothelial growth factor levels. Anticancer Res. 2003 Dec;23(6D):4953–4958.

10. Morozov A. P., Shibaev A. N., Kushlinsky N. E. Clinical significance of insulin-like growth factor and 1ftub1nd1ng protein 1 in prostate cancer. Clinical Gerontology. 2008;14(10):28–31 (In Russian).

11. Bochkareva N. V., Kondakova I. V., Kolomiyets L. A., Muntyan A. B. The system of insulin-like growth factors in pathogenesis and prognosis of epithelial ovarian cancer. Siberian Oncological Journal. 2011;3:74–81 (In Russian).

12. Bustin S. A., Dorudi S., Phillips S. M., Feakins R. M., Jenkins P. J. Local expression of insulin-like growth factor-I affects angiogenesis in colorectal cancer. Tumour Biol. 2002 Jun;23(3):130–138.

13. Almhanna K., Meredith K. L., Hoffe S. E., Shridhar R., Coppola D. Targeting the human epidermal growth factor receptor 2 in esophageal cancer. Cancer Control. 2013 Apr;20(2):111– 116. https://doi.org/10.1177/107327481302000204

14. Gershtein E. S., Androsova L. A., Letyagin V. P., Kushlinsky N. E. Clinical Significance of Epidermal Growth Factor Receptors in Patients with Advanced Breast Cancer: Results of a 6-Year Follow-Up. Bulletin of the Russian Research Center. N. N. Blokhina RAMS. 2000;11(1):27–33 (In Russian).

15. Shcherbakov A. M., Krasilnikov M. A., Kushlinsky N. E. Molecular mechanisms of hormone resistance of breast cancer. Bulletin of Experimental Biology and Medicine. 2013;155(3):363–376 (In Russian).

16. Gapeenko E. V., Derzhavets L. A., Antonenkova N. N. Tumor markers, growth factors, angiogenesis regulators in the diagnosis and monitoring of breast cancer. Oncology magazine. 2013;7(3 (27)):86–95 (In Russian).

17. Timakov M. A., Kozlov I. G., Belokhvostov A. S., Rumyantsev A. G. Medicines aimed at epidermal growth factor receptors in cancer biotherapy of various localization. Russian Immunological Journal. 2010;4(13) (1):3–13 (In Russian).

18. Turner N., Grose R. Fibroblast growth factor signalling: from development to cancer. Nat Rev Cancer. 2010 Feb;10(2):116–129. https://doi.org/10.1038/nrc2780

19. Katoh M., Nakagama H. FGF receptors: cancer biology and therapeutics. Med Res Rev. 2014 Mar;34(2):280–300.

20. Fedyanin M.Yu., Melkova D. N., Serebriyskaya S., Nikolskaya T. A., Tyulyandin S. A. Receptors of fibroblast growth factor in malignant tumors. Malignant Tumors. 2014;4(11):19–34 (In Russian).

21. Leone S., Chiavaroli A., Recinella L., Di Valerio V., Veschi S., Gasparo I., et al. Growth hormone-releasing hormone (GHRH) deficiency promotes inflammation-associated carcinogenesis. Pharmacol Res. 2019 Dec 23;152:104614. https://doi.org/10.1016/j.phrs.2019.104614

22. Metz CE. Fundamental ROC Analysis. 2000 Feb 16;751– 170. https://doi.org/10.1117/3.832716.ch15

23. Khochenkova Yu. A., Chkadua G. Z., Malivanova T. F., Stepanova E. V. VEGF and antitumor immunity. Immunology. 2013;34(3):172–175 (In Russian).

24. Tyrsina E. G., Nikulitsky S. I. The role of regulatory VEGF/ VEGF-R1 — systems in tumor angiogenesis. Oncogynecology. 2015;4:4–12 (In Russian).

25. Kit O. I., Frenchman E. M., Shevchenko A. N., Breus A. A., Pogorelova Yu. A., Neskubina I. V. The level of some growth factors of the VEGF family in clear cell kidney cancer. News of Higher Education Institutions of the North Caucasus Region. Series: Natural Sciences. 2018;1(197):124–129 (In Russian).

26. Breus A. A., Kit O. I., Frantsuz E. M., Shevchenko A. N., Neskubina I. V., Dzhenkova E. A., et al. Sexual differences in the content of components of the insulin-like signaling pathway in kidney tissue with local and generalized clear cell renal cancer. Modern problems of science and education. 2019 5:81 (In Russian). https://doi.org/10.17513/spno.29168

27. Kit O. I., Frenchman E. M., Dimitriadi S. N., Shevchenko A. N., Kaplieva I. V., Tripitaki L. K. Expression of markers of neoangiogenesis and fibrinolytic system in the dynamics of experimental kidney ischemia in rats. Experimental and clinical urology. 2015;1:20–23 (In Russian).

28. Nefedova N. A., Davydova S.Yu. The role of vascular endothelial growth factor (VEGF) and hypoxia inducible factor (HIF) in tumor angiogenesis. Modern problems of science and education. 2015;3:51 (In Russian).

29. Spirina L. V., Kondakova I. V., Usynin E. A., Vintizenko S. I. Regulation of angiogenesis in malignant neoplasms of the kidney and bladder. Siberian Oncology Journal. 2008;4:65–70 (In Russian).