Ovarian cancer spheroids constitute a metastatic niche for transcoelomic spread that also engenders drug resistance. Spheroid-forming cells express active STAT3 signaling and display stem cell–like properties that may contribute to ovarian tumor progression. In this study, we show that STAT3 is hyperactivated in ovarian cancer spheroids and that STAT3 disruption in this setting is sufficient to relieve chemoresistance. In an NSG murine model of human ovarian cancer, STAT3 signaling regulated spheroid formation and self-renewal properties, whereas STAT3 attenuation reduced tumorigenicity. Mechanistic investigations revealed that Wnt signaling was required for STAT3-mediated spheroid formation. Notably, the Wnt antagonist DKK1 was the most strikingly upregulated gene in response to STAT3 attenuation in ovarian cancer cells. STAT3 signaling maintained stemness and interconnected Wnt/β-catenin signaling via the miR-92a/DKK1–regulatory pathways. Targeting STAT3 in combination with paclitaxel synergistically reduced peritoneal seeding and prolonged survival in a murine model of intraperitoneal ovarian cancer. Overall, our findings define a STAT3–miR-92a–DKK1 pathway in the generation of cancer stem–like cells in ovarian tumors, with potential therapeutic applications in blocking their progression. Cancer Res; 77(8); 1955–67. ©2017 AACR.

Epithelial ovarian cancer (EOC) is the most lethal of all gynecologic malignancies. Despite advances in surgical and chemotherapeutic options, most patients with advanced EOC have a relapse within three years of diagnosis. Unfortunately, recurrent disease is generally not curable. Recent advances in maintenance therapy with anti-angiogenic agents or Poly ADP-ribose polymerase (PARP) inhibitors provided a substantial benefit concerning progression-free survival among certain women with advanced EOC. However, effective treatment options remain limited in most recurrent cases. Therefore, validated novel molecular therapeutic targets remain urgently needed in the management of EOC. Signal transducer and activator of transcription-3 (STAT3) and STAT5 are aberrantly activated through tyrosine phosphorylation in a wide variety of cancer types, including EOC. Extrinsic tumor microenvironmental factors in EOC, such as inflammatory cytokines, growth factors, hormones, and oxidative stress, can activate STAT3 and STAT5 through different mechanisms. Persistently activated STAT3 and, to some extent, STAT5 increase EOC tumor cell proliferation, survival, self-renewal, angiogenesis, metastasis, and chemoresistance while suppressing anti-tumor immunity. By doing so, the STAT3 and STAT5 activation in EOC controls properties of both tumor cells and their microenvironment, driving multiple distinct functions during EOC progression. Clinically, increasing evidence indicates that the activation of the STAT3/STAT5 pathway has significant correlation with reduced survival of recurrent EOC, suggesting the importance of STAT3/STAT5 as potential therapeutic targets for cancer therapy. This review summarizes the distinct role of STAT3 and STAT5 activities in the progression of EOC and discusses the emerging therapies specifically targeting STAT3 and STAT5 signaling in this disease setting.

Leukocyte cell-derived chemotaxin 2 (LECT2) is a multifunctional cytokine that can bind to several receptors and mediate distinct molecular pathways in various cell settings. Changing levels of LECT2 have been implicated in multiple human disease states, including cancers. Here, we have demonstrated reduced serum levels of LECT2 in patients with epithelial ovarian cancer (EOC) and down-regulated circulating Lect2 as the disease progresses in a syngeneic mouse ID8 EOC model. Using the murine EOC model, we discovered that loss of Lect2 promotes EOC progression by modulating both tumor cells and the tumor microenvironment. Lect2 inhibited EOC cells’ invasive phenotype and suppressed EOC’s transcoelomic metastasis by targeting c-Met signaling. In addition, Lect2 downregulation induced the accumulation and activation of myeloid-derived suppressor cells (MDSCs). This fostered an immunosuppressive microenvironment in EOC by inhibiting T-cell activation and skewing macrophages toward an M2 phenotype. The therapeutic efficacy of programmed cell death-1 (PD-1)/PD-L1 pathway blockade for the ID8 model was significantly hindered. Overall, our data highlight multiple functions of Lect2 during EOC progression and reveal a rationale for synergistic immunotherapeutic strategies by targeting Lect2.

Radical trachelectomy (RT) is an alternative treatment for preserving fertility in patients with cervical cancer. Because women with operable cervical cancer opting for fertility preservation are scarce, few cases have been reported in Taiwan. Here we report our cases series. We retrospectively evaluated seven patients who underwent vaginal RT and three patients who underwent abdominal RT in a single medical institute for a median follow-up period of 5 years. The oncological outcome was highly satisfactory. All patients survived and are currently disease-free, except for two who had recurrence and received additional concurrent chemoradiation therapy. Other complications included urinary tract infection, cervical stenosis, and unilateral hydronephrosis. All complications were manageable with little long-term effects. However, no pregnancy was observed during the 5-year follow-up period. RT is considered a complicated surgical procedure among gynecological operations. Here we review the literature and describe several factors associated with higher pregnancy rates.

Purpose: The Q-tip test is used to measure urethral hypermobility and can predict surgical outcomes. However, certain factors may affect the reliability of this test. Our aim was to identify independent clinical and urodynamic predictors of the results of the Q-tip test.Methods: Between January 2014 and June 2019, 176 consecutive women with lower urinary tract symptoms who underwent the Q-tip test and urodynamic studies were included in this retrospective study.Results: Multivariable regression analysis revealed that age (regression coefficient, -0.55), point Ba (regression coefficient, 4.1), urodynamic stress incontinence (regression coefficient, 9.9), maximum flow rate (Qmax) (regression coefficient, 0.13), pressure transmission ratio (PTR) at maximum urethral pressure (MUP) (regression coefficient, -0.14), and the score on the fifth question of the Incontinence Impact Questionnaire (IIQQ5; “Has urine leakage affected your participation in social activities outside your home?”; regression coefficient, -4.1) were independent predictors of the Q-tip angle, with a constant of 87.0. The following Spearman rank correlation coefficients were found between the Q-tip angle and the following variables: age, -0.38; point Ba, 0.34; urodynamic stress incontinence, 0.32; Qmax, 0.28; PTR at MUP, -0.28; and IIQQ5, -0.23. A receiver operating characteristic curve (ROC) analysis for the prediction of urodynamic stress incontinence found that the optimum cutoff for PTR at MUP was <81%, with an area under the ROC curve of 0.70.Conclusions: Age, point Ba, urodynamic stress incontinence, Qmax, PTR at MUP, and IIQQ5 were independent predictors of the Q-tip angle. However, none of these could be used as effective surrogates for the Q-tip test due to their lack of a sufficient correlation.

Rare uterine choriocarcinoma can be differentiated gestational from nongestational choriocarcinoma by using short tandem repeats (STRs). A 56-year-old Taiwanese woman underwent staging surgery because of suspicion of high-grade endometrial cancer. The pathology-confirmed uterine tumor with syncytiotrophoblasts and decidual change of the endometrium was harvested. Uterine nongestational choriocarcinoma. The tumor specimen, the patient's blood, and her husband's blood were drawn for STRs analysis using polymerase chain reaction amplification kit. The genotype of the tumor cells was solely maternal and made the diagnosis of uterine nongestational choriocarcinoma. Adjuvant chemotherapy with etoposide, methotrexate, actinomycin D, cyclophosphamide, vincristine regimen achieved good response in the patient. The patient is now recurrence-free for 12 months. STRs aid precise classification of rare choriocarcinoma. We encourage using the method to analyze suspicious choriocarcinoma.