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.
Subject(s)
Ovarian Neoplasms/metabolism , Receptors, Interleukin-6/metabolism , 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 , Paracrine Communication , Phenotype , Prognosis , Receptors, Interleukin-6/genetics , Vascular Endothelial Growth Factor A/biosynthesis , Young AdultABSTRACT
PURPOSE: We retrospectively analyzed oncologic and reproductive outcomes of fertility-seeking premenopausal women with complex atypical hyperplasia (CAH) or Grade 1 endometrial adenocarcinoma (G1EA) who underwent medical management with high-dose medroxyprogesterone acetate (MPA) therapy. METHODS: Patients were given a dose of 400-600 mg of MPA orally on a daily basis. They had histologically confirmed CAH or G1EA at presumed stage IA and wished to preserve fertility. Endometrial tissue sampling was carried out by dilation and curettage before and after the treatment and the pathologic response to MPA treatment was assessed. RESULTS: A total of 27 premenopausal patients received MPA therapy. The median follow-up time was 39.2 months (3.4-153.8 months). Complete response was achieved in 81.8 % (9/11) of CAH cases and 68.8 % (11/16) of G1EA. Although no recurrences were found in CAH patients, nine G1EA patients (81.8 %) eventually recurred and underwent total hysterectomy. Neither therapeutic death nor irreversible toxicities were observed during the follow-up periods. Five patients (4 CAH and 1 G1EA) became pregnant and had nine live births. CONCLUSION: The high efficacy of fertility-sparing treatment with MPA was shown demonstrated. MPA therapy can be considered acceptable for the purpose of enabling patients to preserve their fertility. However, the rate of recurrence was high in patients with G1EA. Even in responders, close follow-up is required and a total hysterectomy needs to be considered without delay. Patients should be aware of the risks and limitations of this conservative treatment.
Subject(s)
Carcinoma, Endometrioid/drug therapy , Endometrial Neoplasms/drug therapy , Fertility Preservation , Medroxyprogesterone Acetate/therapeutic use , Adult , Antineoplastic Agents, Hormonal/therapeutic use , Carcinoma, Endometrioid/pathology , Endometrial Hyperplasia/drug therapy , Endometrial Hyperplasia/pathology , Endometrial Neoplasms/pathology , Female , Humans , Hysterectomy , Neoplasm Recurrence, Local/drug therapy , Pregnancy , Retrospective Studies , Treatment Outcome , Young AdultABSTRACT
Ovarian cancer is characterized by widespread peritoneal dissemination and ascites and has a cure rate of only 30%. As has been previously reported, integrin α5 plays a key role in the peritoneal dissemination of ovarian cancer. Our aim was to identify a new miRNA that regulates integrin α5 expression and analyze the therapeutic potential of targeting this miRNA. By using an IHC analysis, we proved that high integrin α5 expression correlates with a poor prognosis in Japanese patients with International Federation of Gynecology and Obstetrics stage III ovarian cancer. Based on an miRNA algorithm search, we identified hsa-mir-92a (miR-92a) as a candidate. The level of miR-92a expression was significantly inversely correlated with ITGA5 expression in various cancer cells. Transfection of precursor miR-92a reduced integrin α5 expression in ovarian cancer cells, which was accompanied by the inhibition of cancer cell adhesion, invasion, and proliferation. miR-92a overexpression reduced the luciferase activity of the ITGA5 3'-untranslated region, suggesting that ITGA5 mRNA is a direct target of miR-92a. In in vivo ovarian cancer xenografts, the enforced expression of miR-92a in HeyA-8 cells suppressed peritoneal dissemination. Although we still have a long way to go before an effective and nontoxic miRNA-based cancer therapy can be introduced into the clinic, the inhibition of integrin α5 expression by targeting miR-92a needs to be explored further for future applications in ovarian cancer treatment.
Subject(s)
Integrin alpha5/metabolism , MicroRNAs/metabolism , Ovarian Neoplasms/genetics , Ovarian Neoplasms/pathology , Peritoneal Neoplasms/secondary , Adult , Aged , Aged, 80 and over , Animals , Base Sequence , Biomarkers, Tumor/metabolism , Cell Adhesion , Cell Line, Tumor , Cell Proliferation , Female , Gene Expression Regulation, Neoplastic , Humans , Integrin alpha5/genetics , Mice , Mice, Nude , MicroRNAs/genetics , Middle Aged , Molecular Sequence Data , Neoplasm Invasiveness , Neoplasm Staging , Peritoneal Neoplasms/pathology , Prognosis , Protein Binding/genetics , Xenograft Model Antitumor Assays , Young AdultABSTRACT
Ovarian cancer is a deadly disease, with a cure rate of only 30%. Despite aggressive treatments, relapse remains almost inevitable in patients with advanced-stage disease. In recent years, great progress has been made towards targeting integrins in cancer treatment, and clinical studies with various integrin inhibitors have demonstrated their effectiveness in blocking cancer progression. Given that the initial critical step of ovarian cancer metastasis is the attachment of cancer cells onto the peritoneum or omentum, in addition to the proven positive clinical results of anti-angiogenic therapy, targeting integrins is likely to be one of the most feasible approaches. This paper summarizes the current understanding of the integrin biology in ovarian cancer metastasis and the various therapeutic approaches attempted with integrin inhibitors. Although no integrin inhibitors have shown favorable results so far, integrin-targeted therapies continue to be a promising approach to be explored for further clinical investigation.
