High serum levels of interleukin-6 in endometrial carcinoma are associated with uterine serous papillary histology, a highly aggressive and chemotherapy-resistant variant of endometrial cancer

Abstract

Purpose. To evaluate and compare autocrine expression and production of interleukin-6 (IL-6), a pleiotropic cytokine involved in the resistance to cytotoxic agents and inhibition of anti-tumor immune function in endometrial carcinoma in vitro as well as in vivo. Patients and methods. IL-6 gene expression levels were evaluated in twenty-four primary endometrial tumors including 14 endometrioid carcinomas (EC) and 10 uterine serous papillary carcinoma (USPC) as well as in normal control endometrial cells (NEC) by real-time PCR. Secretion of IL-6 protein by 6 primary endometrial tumor cultures including USPC and EC was measured using a sensitive enzyme-linked immunosorbent assay (ELISA) in vitro. Finally, IL-6 concentration in 71 serum samples including 20 apparently healthy women, 19 women with benign abdominal diseases, 19 women with primary EC, and 13 USPC patients was studied. Results. IL-6 gene expression levels were significantly higher in USPC when compared to EC (mean copy number by RT-PCR = 313 ± 55 vs. 53 ± 11, USPC vs. EC, respectively: P < 0.01). IL-6 serum concentrations between normal healthy females (range 0.01–21.23 pg/ml; mean 3.1 pg/ml) and benign disease patients (range 0.01–95.77 pg/ml; mean 13.07 pg/ml) were not statistically different. In contrast, significantly higher levels of IL-6 were detected in both patients with EC (range 2.86–82.13 pg/ml; mean 20.43 pg/ml) and patients with UPSC (range 16.3–500.1 pg/ml; mean 125.7 pg/ml) when compared to the healthy females ( P < 0.01), with a mean serum IL-6 level in USPC patients 6.1-fold higher when compared to EC patients ( P < 0.03). Accordingly, higher levels of IL-6 secretion were noted in primary USPC cell lines (mean 3121 pg/ml, range between 1099 and 5017 pg/ml/10 5 cells/48 h) when compared to primary EC (mean 88, range between 19 and 112 pg/ml/10 5 cells/48 h) ( P < 0.01) in vitro. Conclusions. IL-6 is highly expressed in USPC, and it is released in high concentration in the serum of USPC patients. IL-6 may be a novel biomarker for USPC. Drugs used to inhibit the expression of IL-6 or the IL-6 signal transduction pathway may potentially be highly beneficial in USPC.