Abstract
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.
Highlights
Ovarian cancer is the leading cause of death from gynecologic malignancies
Ovarian cancer ascites were collected from patients who underwent surgery and we found that primary CD11b positive (CD11b+)CD14+ cells, which were predominantly M2-polarized tumor-associated macrophages (TAM), were the major source of IL-6 production in an ovarian tumor microenvironment and robustly promoted ovarian cancer invasion and proliferation
Seven cell lines overexpressed IL-6R compared with a primary ovarian surface epithelium (OSE), indicating that IL-6/IL-6R signaling exerts in a paracrine manner in certain types of ovarian cancer cells, as confirmed by the data that exogenous treatment of IL-6 induced proliferation, invasion and VEGF production of ovarian cancer cells which do not express detectable levels of IL-6
Summary
Ovarian cancer is the leading cause of death from gynecologic malignancies. Recent convincing data support the involvement of the inflammatory stromal microenvironment, caused by PLOS ONE | DOI:10.1371/journal.pone.0118080 February 6, 2015. The majority of patients with ovarian cancer at advanced stages present peritoneal metastatic diseases, often accompanied by massive ascites.[14] Massive ascites of patients consist of cancer cells and fibroblasts, endothelial cells and predominantly immune cells, all of which are crucial for cancer growth, progression and metastasis.[15] Peritoneal macrophages are thought to play a pivotal role in this context, as is evidenced by several studies finding that macrophage depletion in peritoneal ovarian cancer models suppresses cancer progression and accumulation of ascites.[16, 17] Macrophages that infiltrate tumor tissues, which are referred to as tumor-associated macrophages (TAM), are well-known contributors to tumor progression and are associated with the poor prognosis of various cancers.[18, 19] Since TAMs are known to release various proangiogenic cytokines and growth factors, we hypothesized that macrophages could be one of potential responsible sources of enriched IL-6 accumulation in ovarian cancer ascites Against this background, we attempted to analyze the expressional pattern of IL-6R as well as using ovarian cancer TMAs and to evaluate the impact of these expressions on the clinical outcomes of patients. The data presented suggest a rationale for anti-IL-6/IL-6R therapy to suppress the peritoneal spread of ovarian cancer and provide evidence of the therapeutic potential of anti-IL-6R therapy to cure this miserable disease
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