The Role of MicroRNAs in Ovarian Cancer

Ovarian cancer is the most lethal of malignant gynecological tumors. Its lethality may be due to difficulties in detecting it at an early stage and lack of effective treatments for patients with an advanced or recurrent status. Therefore, there is a strong need for prognostic and predictive markers to diagnose it early and to help optimize and personalize treatment. MicroRNAs are noncoding RNAs that regulate target genes posttranscriptionally. They are involved in carcinogenesis, cell cycle, apoptosis, proliferation, invasion, metastasis, and chemoresistance. The dysregulation of microRNAs is involved in the initiation and progression of human cancers including ovarian cancer, and strong evidence that microRNAs can act as oncogenes or tumor suppressor genes has emerged. Several microRNA signatures that are unique to ovarian cancer have been proposed, and serum-circulating microRNAs have the potential to be useful diagnostic and prognostic biomarkers. Various microRNAs such as those in the miR-200 family, the miR-199/214 cluster, or the let-7 paralogs have potential as therapeutic targets for disseminated or chemoresistant ovarian tumors. Although many obstacles need to be overcome, microRNA therapy could be a powerful tool for ovarian cancer prevention and treatment. In this review, we discuss the emerging roles of microRNAs in various aspects of ovarian cancer

Complicated pancreatic fistula after gynecologic surgery for left fallopian tube carcinosarcoma: A case report

Pancreatic fistulas are rare after gynecologic surgeries but are sometimes difficult to manage. A 62-year-old woman was admitted to a local hospital with acute abdominal pain. Computed tomography (CT) images showed subileus and an obstruction site in the transverse/descending colon, with invasion of peritoneal metastasis. A metal stent was placed in the bowel through colonoscopy. Suspecting advanced-stage ovarian cancer, the patient was referred to a tertiary hospital. Diagnostic laparoscopy was performed prior to neoadjuvant chemotherapy. Due to concerns raised by gastrointestinal surgeons regarding the high risk of stent perforation during chemotherapy, an abdominal colectomy of the transverse/descending colon was performed along with the removal of the disseminated tumor and the stent. Post-surgery, the patient was histologically diagnosed with stage IVB left fallopian tube carcinosarcoma. On postoperative day 3, the patient developed a fever, and CT images showed an abscess around the pancreas/spleen, prompting the placement of a drainage tube. The amylase level in the drained fluid was 258,111 U/L, leading to a diagnosis of a pancreatic fistula. Conservative management was undertaken, with drainage, fasting, and octreotide administration. After two months, the drainage tube was removed as the volume of drained fluid had decreased. After four cycles of carboplatin/paclitaxel chemotherapy, CT images showed partial response to chemotherapy, and interval debulking surgery was performed. The necessity of metallic stent placement should be carefully considered as the subileus caused by peritoneal metastasis might be alleviated by the induction of chemotherapy for gynecologic cancer

Gastric-Type Adenocarcinoma of the Uterine Cervix Associated with Poor Response to Definitive Radiotherapy

We aimed to evaluate the response to definitive radiotherapy (RT) for cervical cancer based on histological subtypes and investigate prognostic factors in adenocarcinoma (AC). Of the 396 patients treated with definitive RT between January, 2010 and July, 2020, 327 patients met the inclusion criteria, including 275 with squamous cell carcinoma (SCC) and 52 with AC restaged based on the 2018 International Federation of Gynecology and Obstetrics staging system. Patient characteristics, response to RT, and prognoses of SCC and AC were evaluated. The complete response (CR) rates were 92.4% and 53.8% for SCC and AC, respectively (p p p p p < 0.05). Definitive RT for cervical cancer was significantly less effective for AC than for SCC. GAS was the only independent prognostic factor associated with non-CR in AC

Combining PARP with ATR inhibition overcomes PARP inhibitor and platinum resistance in ovarian cancer models

Patients with ovarium cancer frequently develop resistance to platinum chemotherapy and PARP inhibitors (PARPi). Here, the authors show that the combination of PARP and ATR inhibitors increases the therapeutic response in PARPi and platinum resistant ovarium cancer PDX models

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

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

Proposed paracrine mechanism.

<p>CD11b⁺CD14⁺ cells, which are predominantly macrophages, are one of the major sources of IL-6 production in an ovarian tumor microenvironment and promoted ovarian cancer invasion, proliferation and angiogenesis.</p

Exogenous treatment of IL-6 promotes ovarian cancer cell proliferation, invasion and VEGF production.

<p>(A) A matrigel invasion assay was done using a modified Boyden chamber system. 1 x 10⁵ of SKOV3ip1 (<i>left</i>) or RMUS-S (<i>right</i>) cells were placed on the top chamber in serum-free medium and allowed to invade for 72 h. Various concentrations of IL-6 (1–100 ng/ml) or 60 ng/ml of sIL-6R were applied in the bottom chamber as a chemoattractant. 10 μg/ml of anti-IL-6R antibody or non-immune IgG was co-treated. Non-invading cells were removed using a cotton swab, and invading cells on the underside of the filter were enumerated. Relative numbers of invading cells with respect to the control (no IL-6 treatment) are shown. (B) <i>In vitro</i> cell proliferation assay. 1 x 10⁴ cells of SKOV3ip1 (<i>left</i>) or RMG1 (<i>right</i>) cells were plated in 24-well plates in 10% FBS/DMEM for 24 h and then incubated in serum-free medium in the presence or absence of various concentrations of IL-6 (1–100 ng/ml) with or without anti-IL-6R antibody or non-immune IgG as control for 72 h. Cell proliferation was evaluated by a modified MTS assay. Cell proliferation was expressed as the ratio of the number of viable cells. (C) ELISA assay of VEGF-A. 1 x 10⁵ SKOV3ip1 cells were plated onto 6-well plates and cultured with 2 ml of serum-free medium in the presence or absence of 100 ng/ml of IL-6 for 72 h. Anti-IL-6R antibody or control IgG was co-treated. Conditioned media were collected and the concentration of human VEGF-A was measured by ELISA. Experiments were repeated three times and values are means ± SD of triplicates. n.s.; not significant, *; P < 0.05, **; P < 0.01.</p