The limitations of current anti-angiogenic therapies necessitate other targets with complimentary mechanisms. Here, we show for the first time that soluble E-cadherin (sE-cad) (an 80-kDa soluble form), which is highly expressed in the malignant ascites of ovarian cancer patients, is a potent inducer of angiogenesis. In addition to ectodomain shedding, we provide further evidence that sE-cad is abundantly released in the form of exosomes. Mechanistically, sE-cad-positive exosomes heterodimerize with VE-cadherin on endothelial cells and transduce a novel sequential activation of β-catenin and NFκB signaling. In vivo and clinical data prove the relevance of sE-cad-positive exosomes for malignant ascites formation and widespread peritoneal dissemination. These data advance our understanding of the molecular regulation of angiogenesis in ovarian cancer and support the therapeutic potential of targeting sE-cad. The exosomal release of sE-cad, which represents a common route for externalization in ovarian cancer, could potentially be biomarkers for diagnosis and prognosis.

The current World Health Organization classification indicates that a uterine smooth muscle tumor that cannot be histologically diagnosed as unequivocally benign or malignant should be termed "smooth muscle tumor of uncertain malignant potential" (STUMP). STUMPs represent a heterogeneous group of rare tumors that have been the subject of only a few published studies, some of which lack detailed clinicopathologic details and/or follow-up data. More recently, it has been suggested that immunohistochemical staining may be helpful in the diagnosis of STUMPs. The clinicopathologic features of 16 cases of STUMP that exhibited usual smooth muscle differentiation, diagnosed between 1992 and 2006 from 11 hospitals, were studied and classified into 4 subgroups using terminology and criteria described by Stanford investigators. Immunohistochemical stains for p16, p53, MIB1 (ki-67), and estrogen and progesterone receptors were performed. The results were compared with those in the literature. The tumors were classified as follows: 6 as "atypical leiomyoma with limited experience", 7 as "smooth muscle tumor of low malignant potential", 2 as "atypical leiomyoma, low risk of recurrence," and 1 as "mitotically active leiomyoma, limited experience." Follow-up was 21 to 192 months (mean, 80.8 and median, 51.5). Only 2 tumors recurred, at 15 and 51 months, respectively; both were atypical leiomyoma with limited experience (multifocal moderate-to-severe atypia, no tumor cell necrosis, and mitotic counts of 4 and 5 mitotic figures /10 high-power fields, respectively). Both tumors had areas that were indistinguishable from benign leiomyoma and both had diffuse immunoreactivity for p16 and p53. Six other tumors that had focal staining for these markers all had a benign outcome. Both patients with recurrence were alive at last follow-up (at 40 and 74 mo). All the other patients were alive and disease-free. This and other studies suggest that uterine tumors classified as STUMPs using criteria proposed by Stanford investigators are usually clinically benign but should be considered tumors of low malignant potential because they can occasionally recur, in some cases, years after hysterectomy. After a mean follow-up of 80.8 months, only 2 of 16 tumors in this study recurred. Both of the latter tumors fulfilled the criteria for atypical leiomyoma with limited experience. Notably, the 2 recurrent tumors were the only ones that were strongly immunoreactive for p16 and p53, supporting earlier observations that these markers may be helpful in the prediction of the behavior of STUMPs. Patients diagnosed with STUMPs should receive long-term surveillance.

Aberrant activation of hedgehog (HH) pathway has been implicated in the development of human malignancies. This study aimed at investigating the role of HH molecules in human ovarian carcinogenesis. The expression profiles of HH molecules were examined in ovarian tumor samples and ovarian cancer cell lines and the in vitro effects of HH molecules on cell proliferation, apoptosis, migration, invasion and cell differentiation as well as related downstream target genes were assessed. Overexpression of Patched and Gli1 protein in ovarian cancers correlated with poor survival of the patients (P = 0.008; P = 0.004). Significantly elevated expression of Sonic hedgehog messenger RNA was observed in ovarian cancers compared with normal tissues and benign ovarian tumors and such differential expression was specific to histological types (P < 0.05). Ectopic Gli1 overexpression in ovarian cancer cells conferred increased cell proliferation, cell mobility, invasiveness and change in differentiation in association with increased expression of E-cadherin, vimentin, Bcl-2, caspases as well as β1 integrin, membrane type 1 matrix metalloproteinase (MT1-MMP) and vascular endothelial growth factor (VEGF). Treatment with 3-keto-N-(aminoethyl-aminocaproyl-dihydrocinnamoyl)-cyclopamine induced cancer cell apoptosis, suppressed cell growth, mobility and invasiveness and induced cancer cell dedifferentiation with decreased expression of E-cadherin, cytokeratin 7, Snail, calretinin, vimentin, Bcl-2, caspases, β1 integrin, MT1-MMP and VEGF. Our data suggested that abnormal HH signaling activation plays important roles in the development and progression of ovarian cancers. Gli1 expression is an independent prognostic marker. Inhibition of the HH pathway molecules might be a valid therapeutic strategy for ovarian cancers.

Ovarian cancer is a lethal gynecological malignancy, and to improve survival, it is important to identify novel prognostic and therapeutic targets. In this study, we present a role for p21-activated kinase 4 (Pak4) in ovarian cancer progression. We show a significant association between increased expression of Pak4 and its activated form, phosphorylated (p)-Pak4 Ser ⁴⁷⁴ , with metastasis of ovarian cancers, shorter overall and disease-free survival, advanced stage and high-grade cancers, serous/clear cell histological subtypes, and reduced chemosensitivity. Pak4 overexpression was also observed in ovarian cancer cell lines. Pak4 and p-Pak4 expression were detected both in the nucleus and cytoplasm of ovarian cancer cells, in vitro as well as in vivo. Stable knockdown of Pak4 in ovarian cancer cell lines led to reduced cell migration, invasion, and proliferation, along with reduced c-Src, ERK1/2, and epidermal growth factor receptor (EGFR) activation and decreased matrix metalloproteinase 2 (MMP2) expression. Conversely, Pak4 overexpression promoted ovarian cancer cell migration and invasion in a c-Src, MEK-1, MMP2, and kinase-dependent manner, and induced cell proliferation through the Pak4/c-Src/EGFR pathway that controls cyclin D1 and CDC25A expression. Stable knockdown of Pak4 also impeded tumor growth and dissemination in nude mice. This report reveals the association between Pak4 and important clinicopathologic parameters, suggesting Pak4 to be a significant prognostic marker and potential therapeutic molecular target in ovarian cancer. The implied possible cross-talk between Pak4 and EGFR suggests the potential of dual targeting of EGFR and Pak4 as a unique therapeutic approach for cancer therapy.

Mitochondrial DNA (mtDNA) content in ovarian carcinomas was assessed by quantitative PCR. Results show that mtDNA content in tumour cell was significantly higher than that in normal ovary. Change in mtDNA content was not related with patients' age or tumour stages. However, the average mtDNA copy number in pathological low-grade tumours was over two-fold higher than that in high-grade carcinomas (P=0.012). Moreover, type I carcinomas also had a significantly higher mtDNA copy number than in type II carcinomas (P=0.019). Change in mtDNA content might be an important genetic event in the progression of ovarian carcinomas.