Journal Article

Interleukin 6 Receptor Is an Independent Prognostic Factor and a Potential Therapeutic Target of Ovarian Cancer

Sawada, Kenjiro, Suzuki, Noriko, Morishige, Ken-ichirou, Morii, Eiichi, Isobe, Aki, Nakatsuka, Erika, Kimura, Tadashi, Kinose, Yasuto, Sawada, Ikuko, Ohta, Tsuyoshi, Mizuno, Tomoko, Makino, Hiroshi, Toda, Aska, Hashimoto, Kae, Mabuchi, Seiji, Kurachi, Hirohisa, Nakamura, Koji, Ohyagi-Hara, Chifumi, Ogura, Tomonori

2015

Overview

Ovarian cancer remains the most lethal gynecologic cancer and new targeted molecular therapies against this miserable disease continue to be challenging. In this study, we analyzed the expressional patterns of Interleukin-6 (IL-6) and its receptor (IL-6R) expression in ovarian cancer tissues, evaluated the impact of these expressions on clinical outcomes of patients, and found that a high-level of IL-6R expression but not IL-6 expression in cancer cells is an independent prognostic factor. In in vitro analyses using ovarian cell lines, while six (RMUG-S, RMG-1, OVISE, A2780, SKOV3ip1 and OVCAR-3) of seven overexpressed IL-6R compared with a primary normal ovarian surface epithelium, only two (RMG-1, OVISE) of seven cell lines overexpressed IL-6, suggesting that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells. Ovarian cancer ascites were collected from patients, and we found that primary CD11b+CD14+ cells, which were predominantly M2-polarized macrophages, are the major source of IL-6 production in an ovarian cancer microenvironment. When CD11b+CD14+ cells were co-cultured with cancer cells, both the invasion and the proliferation of cancer cells were robustly promoted and these promotions were almost completely inhibited by pretreatment with anti-IL-6R antibody (tocilizumab). The data presented herein suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer, and represent evidence of the therapeutic potential of anti-IL-6R therapy for ovarian cancer treatment.

• Publisher: Public Library of Science,Public Library of Science (PLoS)
• Subject: Adult / Aged / Aged, 80 and over / Antibodies / Ascites / Binding sites / Biotechnology / Cancer / Cancer therapies / CD11b antigen / CD11b Antigen - metabolism / CD14 antigen / Cell Line, Tumor / Cell Movement - drug effects / Cell proliferation / Cell Proliferation - drug effects / Comparative analysis / Cytokines / Disease / Epithelium / Female / Gene Expression / Gynecology / Health aspects / Hormone replacement therapy / Humans / Immunophenotyping / Interleukin / Interleukin 6 / Interleukin-6 - metabolism / Interleukin-6 - pharmacology / Interleukins / Lipopolysaccharide Receptors - metabolism / Macrophages / Macrophages - metabolism / Macrophages - pathology / Medical prognosis / Medical research / Medicine / Metastasis / Middle Aged / Models, Biological / Molecular chains / Molecular Targeted Therapy / Neoplasm Grading / Neoplasm Staging / Obstetrics / Ovarian cancer / Ovarian carcinoma / Ovarian Neoplasms - diagnosis / Ovarian Neoplasms - drug therapy / Ovarian Neoplasms - metabolism / Paracrine Communication / Paracrine signalling / Patients / Peritoneum / Phenotype / Prognosis / Receptors, Interleukin-6 - genetics / Receptors, Interleukin-6 - metabolism / Therapy / University faculty / University graduates / Vascular Endothelial Growth Factor A - biosynthesis / Young Adult