Abstract
Ovarian cancer has the highest mortality rate among gynecologic malignancies. Despite chemotherapy and surgical debulking options, ovarian cancer recurs and disseminates frequently with a poor prognosis. We previously reported a novel role of glucocorticoids (GCs) in metastatic ovarian cancer by upregulating microRNA-708. In this study, we used an immunocompetent syngeneic mouse model and further evaluated the effect and optimal dosages of GCs in treating metastatic ovarian cancer. The treatment of C57BL/6-derived ovarian cancer ID-8 cells with a synthetic GC, dexamethasone (DEX), induced the expression of microRNA-708, leading to decreased cell migration and invasion through targeting Rap1B. Administration of DEX at a low dose, as low as 5 μg/kg body weight, inhibited the primary tumor size and abdominal metastasis in mice bearing ID-8 cell-derived ovarian tumors. In the treated primary tumors, microRNA-708 was upregulated, whereas some proinflammatory cytokines, namely interleukin (IL)-1β and IL-18, were downregulated. The number of tumor-associated macrophages (TAMs) and myeloid-derived suppressor cells (MDSCs) in the tumor microenvironment were reduced. Overall, our study shows that low-dose GCs can suppress ovarian cancer progression and metastasis likely through not only the upregulation of the metastasis suppressor microRNA-708, but also the modulation of TAMs and MDSCs in the tumor microenvironment.
Highlights
Ovarian cancer is the fifth most common cause of cancer-related deaths in women [1]
We previously demonstrated that DEX can induce miR-708, which is downregulated in the advanced stages of ovarian cancer, to inhibit the migration and invasion of human ovarian cancer cells in culture as well as the growth and metastasis of tumors derived from them in an immunocompromised xenograft mouse model [8]
We demonstrated that low-dose GCs suppress both ovarian tumor growth and abdominal metastasis in the immunocompetent syngeneic mouse model
Summary
Ovarian cancer is the fifth most common cause of cancer-related deaths in women [1]. It is categorized into multiple subtypes, with the serous subtype of epithelial-derived ovarian cancer (EOC) being the predominant and most lethal form [2]. The high morbidity of EOC is due to the lack of early detection methods and poor responses to treatment when the tumor spreads. The 5-year survival rate decreases from 90% in the early stage to 14% when the tumors metastasize to distant organs [3]. Many patients with ovarian cancer transiently respond to the frequently used first-line platinum-based chemotherapy; most develop recurrent.
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