Interleukin 6 receptor is an independent prognostic factor and a potential therapeutic target of ovarian cancer

PLoS One. 2015 Feb 6;10(2):e0118080. doi: 10.1371/journal.pone.0118080. eCollection 2015.


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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adult
  • Aged
  • Aged, 80 and over
  • CD11b Antigen / metabolism
  • Cell Line, Tumor
  • Cell Movement / drug effects
  • Cell Proliferation / drug effects
  • Female
  • Gene Expression
  • Humans
  • Immunophenotyping
  • Interleukin-6 / metabolism
  • Interleukin-6 / pharmacology
  • Lipopolysaccharide Receptors / metabolism
  • Macrophages / metabolism
  • Macrophages / pathology
  • Middle Aged
  • Models, Biological
  • Molecular Targeted Therapy
  • Neoplasm Grading
  • Neoplasm Staging
  • Ovarian Neoplasms / diagnosis
  • Ovarian Neoplasms / drug therapy
  • Ovarian Neoplasms / metabolism*
  • Paracrine Communication
  • Phenotype
  • Prognosis
  • Receptors, Interleukin-6 / genetics
  • Receptors, Interleukin-6 / metabolism*
  • Vascular Endothelial Growth Factor A / biosynthesis
  • Young Adult


  • CD11b Antigen
  • Interleukin-6
  • Lipopolysaccharide Receptors
  • Receptors, Interleukin-6
  • Vascular Endothelial Growth Factor A

Grants and funding

This work was supported by a Grant-in-Aid for scientific research from the Ministry of Education, Science, Sports and Culture of Japan (21791555 and 23592447 to KS, 22390308 to HK, and 23659779 to TK). This work was also partly supported by the Osaka Medical Research Foundation for Intractable Diseases (to KS). The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.