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.
OBJECTIVE
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.


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.
Bellone
Stefania
S
Department of Obstetrics and Gynecology, Division of Gynecologic Oncology, University of Arkansas for Medical Sciences, Little Rock, AR, USA.
Watts
Katherine
K
Cane'
Stefania
S
Palmieri
Michela
M
Cannon
Martin J
MJ
Burnett
Alexander
A
Roman
Juan J
JJ
Pecorelli
Sergio
S
Santin
Alessandro D
AD
D000328:Adult; D018283:Cystadenocarcinoma, Papillary / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D019008:Drug Resistance, Neoplasm; D016889:Endometrial Neoplasms / Q000097:blood* / Q000188:drug therapy / Q000235:genetics / Q000473:pathology; D005260:Female; D006801:Humans; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood* / Q000235:genetics / Q000378:metabolism; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction
D015850:Interleukin-6