THE ROLE OF TUMOR MICROENVIRONMENT FACTORS IN THE DEVELOPMENT OF OVARIAN AND BREAST CANCER

Malignant diseases of the female reproductive system remain one of the leading causes of death among women due to late diagnosis and limited effectiveness of standard treatment methods. Current studies focus on the molecular mechanisms of disease progression, including angiogenesis.

The aim of this study was to investigate the expression of angiogenesis, hypoxia, and matrix metalloproteinase factors in locally advanced resistant ovarian cancer and breast cancer.

Material and methods. The study was conducted on tissue samples from patients with serous ovarian adenocarcinoma (stages II–III) or ductal breast carcinoma. Immunohistochemistry was used to assess the expression of VEGF, ANGP2, HIF-1a, and MMP12. Data were analyzed using the Mann-Whitney U test and Pearson correlation analysis.

Results. We have noted a significant increase in the expression of VEGF, ANGP2 and HIF-1a in tumor and surrounding tissues, as well as a decrease in the expression of MMP12 in the vascular endothelium. This indicates a significant role of angiogenesis in the progression of the disease and the possibility of its use as a therapeutic target.

1. Radu M.R. [et al.]. Ovarian Cancer: Biomarkers and Targeted Therapy.Biomedicines.2021;9(6):693. (In Engl). DOI: 10.3390/biomedicines9060693.

2. Tyulyandina A.S. Nastoyashchee i budushchee targetnoi terapii v pervoi linii lecheniya raka yaichnikov. Farmateka. 2013; 8:39-42. (In Russ).

3. Nishida N. [et al.]. Angiogenesis in cancer. Vasc. Health Risk Manag. 2006;2:213-219. (In Engl). DOI: 10.2147/vhrm.2006.2.3.213.

4. Wada S. [et al.]. Rationale for Antiangiogenic Cancer Therapy with Vaccination Using Epitope Peptides Derived from Human Vascular Endothelial Growth Factor Receptor 2. Cancer Res. 2005;65:4939-4946. (In Engl). DOI: 10.1158/0008-5472.CAN-04-3759.

5. Carey P. [et al.]. Metalloproteinases in Ovarian Cancer. Int. J. Mol. Sci. 2021;22(7):3403. (In Engl). DOI: 10.3390/ijms22073403.

6. Cannistra S.A. [et al.]. Phase II Study of Bevacizumab in Patients With Platinum-Resistant Ovarian Cancer or Peritoneal Serous Cancer. J. Clin. Oncol. 2007;25:5180-5186. (In Engl). DOI: 10.1200/JCO.2007.12.0782.

7. Wang Q. [et al.]. Targeted therapies in gynecological cancers: A comprehensive review of clinical evidence. Signal Transduct. Target. Ther. 2020;5:1–34. (In Engl). DOI: 10.1038/s41392-020-0199-6.

8. Kulikov V.A., Belyaeva L.E. Metabolicheskoe pereprogrammirovanie rakovykh kletok. Vestn. VGMU. 2013;12 (2):6–18. (in Russ.).

9. Wang J. Y. [et al.]. Functional significance of VEGF-a in human ovarian carcinoma: role in vasculogenic mimicry. Cancer Biol. Ther. 2008;7:758–766. (In Engl). DOI: 10.4161/cbt.7.5.5765.

10. Sallinen H. [et al.]. Serum angiopoietin-2 and soluble VEGFR-2 levels predict malignancy of ovarian neoplasm and poor prognosis in epithelial ovarian cancer. BMC Cancer. 2014;14:696. (In Engl). DOI: 10.1186/1471-2407-14-696.

11. Cortez A.J. [et al.]. Advances in ovarian cancer therapy. Cancer Chemother. Pharmacol. 2018;81:17–38. (In Engl). DOI: 10.1007/s00280-017-3501-8.

12. Monk B.J. [et al.]. Anti-angiopoietin therapy with trebananib for recurrent ovarian cancer (TRINOVA-1): a randomised, multicentre, double-blind, placebo-controlled phase 3 trial. Lancet Oncol. 2014;15:799–808. (In Engl). DOI: 10.1016/S1470-2045(14)70244-X.

13. Wedge S.R. [et al.]. AZD2171: a highly potent, orally bioavailable, vascular endothelial growth factor receptor-2 tyrosine kinase inhibi Engl). DOI: 10.5483/BMBRep.2020.53.6.060.

14. Lim D. [et al.]. Angiogenesis and vasculogenic mimicry as therapeutic targets in ovarian cancer. BMB Rep. 2020;53(6):291–298. (In Engl). DOI: 10.5483/BMBRep.2020.53.6.060.

15. Maniotis A. J. [et al.]. Vascular channel formation by human melanoma cells in vivo and in vitro: vasculogenic mimicry. Am. J. Pathol. 1999;155:739–752. (In Engl). DOI: 10.1016/S0002-9440(10)65173-5.

16. Young T. N. [et al.]. Characterization of Gelatinases Linked to Extracellular Matrix Invasion in Ovarian Adenocarcinoma: Purification of Matrix Metalloproteinase 2. Gynecol. Oncol. 1996;62:89–99. (In Engl). DOI: 10.1006/gyno.1996.0195.

17. Deryugina E. I. [et al.]. Up-regulation of vascular endothelial growth factor by membrane-type 1 matrix metalloproteinase stimulates human glioma xenograft growth and angiogenesis. Cancer Res. 2002;62:580–588. (In Engl).

18. Fang J. [et al.]. Matrix metalloproteinase-2 is required for the switch to the angiogenic phenotype in a tumor model. Proc. Natl. Acad. Sci. USA. 2000;97:3884–3889. (In Engl). DOI: 10.1073/pnas.97.8.3884.

19. Aliyev K.A., Asanova E.R., Makalish T.P., Zyablitskaya E.Yu. Morphological assessment of angiogenesis factor expression in tumor and microenvironment of breast fibroadenoma and ductal carcinoma: An observational cohort study. Kuban Scientific Medical. Bulletin. 2024;31(5):26–40. (in Russ.). DOI: 10.25207/1608-6228-2024-31-5-26-40