Levels of VEGF-A, VEGF-C, sVEGFR-1, and sVEGFR-2 in tumor tissue and serum of patients with rare endometrial carcinomas.

Abstract

e17628 Background: Uterine serous carcinoma (USC) and clear cell carcinoma (CCC) are rare and clinically aggressive forms of endometrial cancer. Under normal conditions, endometrial cells produce angiogenic growth factors to ensure physiological regeneration of the uterine mucosa. Vasculogenic mimicry—a process mediated by the VEGF-A/sVEGFR-1 signaling pathway and independent of sVEGFR-2 activation—may play a role in the pathogenesis of these rare endometrial carcinomas. The objective of this study was to evaluate the levels of vascular endothelial growth factors (VEGFs) and their soluble receptors (sVEGFRs) in tumor tissue and peripheral blood of patients with USC and CCC. Methods: Levels of VEGF-A, VEGF-C, sVEGFR-1, and sVEGFR-2 in tumor tissue and serum were determined by enzyme-linked immunosorbent assay (ELISA) in 21 patients with grade 3 USC and 20 patients with CCC. A comparison group consisted of 20 patients with grade 3 endometrioid carcinoma (EC). Reference values were obtained from intact endometrium samples of 20 women undergoing surgery for uterine fibroids (tissue controls) and blood samples from 20 women without oncological diseases (serum controls). The mean age of participants was 55 ± 7.8 years. All participants provided written informed consent. Statistical analysis was performed using parametric and nonparametric tests with adjustments for multiple comparisons. Results: Regardless of the histological subtype, VEGF-A levels in tumor tissue were two-fold higher than in intact endometrium. VEGF-C levels in USC and CCC tumors were 3.2-fold higher than reference values and 80% higher than in EC tumors. The concentration of sVEGFR-2 was significantly reduced in the tissue of rare carcinomas (on average 1.6-fold compared to reference values), while no differences were found in EC tumors. sVEGFR-1 levels in tumor tissue from USC and CCC patients were 3- to 4.8-fold higher than in EC and 4.3- to 6.7-fold higher than reference values. In serum, VEGF-A levels in patients with USC and CCC were 1.7- and 3.1-fold higher, respectively, compared to the EC group, and 3.8- to 12-fold higher than reference values. Serum sVEGFR-1 levels were also elevated, exceeding reference values by 1.4- to 6.7-fold. Serum VEGF-C levels were, on average, 1.6-fold higher than reference values in all examined patients. The concentration of sVEGFR-2 in the blood did not differ from control values in any group. Conclusions: The significant increase in sVEGFR-1 levels coupled with the decrease in sVEGFR-2 levels in USC and CCC tumor tissue suggests the possible activation of vasculogenic mimicry. This mechanism may contribute to the high aggressiveness of these tumors and explain their limited sensitivity to antiangiogenic therapy targeting the classical VEGF/VEGFR-2 pathway.