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1.  MUC16 mucin (CA125) regulates the formation of multicellular aggregates by altering β-catenin signaling 
After shedding from the primary tumor site, ovarian cancer cells form three-dimensional multicellular aggregates that serve as vehicle for cancer cell dissemination in the peritoneal cavity. MUC16 mucin (CA125) is aberrantly expressed by most advanced serous ovarian cancers and can promote proliferation, migration and metastasis. MUC16 associates with E-cadherin and β-catenin, two proteins involved in regulation of cell adhesion and the formation of multicellular aggregates. However, the role of MUC16 in the formation of multicellular aggregates remains to be defined. Here, we show that MUC16 alters E-cadherin cellular localization and expression. Consistent with this, MUC16 knockdown inhibited the formation of multicellular aggregates and, conversely, forced expression of MUC16 C-terminal domain (CTD) enhanced the formation of multicellular aggregates. MUC16 knockdown induces β-catenin relocation from the cell membrane to the cytoplasm, decreases its expression by increasing degradation and decreases β-catenin target gene expression. MUC16 CTD inhibits GSK-3β-mediated phosphorylation and degradation of β-catenin, leading to increased β-catenin levels. Importantly, knockdown of β-catenin inhibited multicellular aggregation. These findings indicate that MUC16 promotes the formation of multicellular aggregates by inhibiting β-catenin degradation.
PMCID: PMC4300699  PMID: 25628932
MUC16; membrane-bound mucin; ovarian cancer; multicellular aggregates; B-catenin; E-cadherin
2.  Profiling of cytokines in human epithelial ovarian cancer ascites 
Background
The behavior of tumor cells is influenced by the composition of the surrounding tumor environment. The importance of ascites in ovarian cancer (OC) progression is being increasingly recognized. The characterization of soluble factors in ascites is essential to understand how this environment affects OC progression. The development of cytokine arrays now allows simultaneous measurement of multiple cytokines per ascites using a single array.
Methods
We applied a multiplex cytokine array technology that simultaneously measures the level of 120 cytokines in ascites from 10 OC patients. The ascites concentration of a subset (n = 5) of cytokines that was elevated based on the multiplex array was validated by commercially available ELISA. The ascites level of these 5 cytokines was further evaluated by ELISA in a cohort of 38 patients. Kaplan-Meier analysis was used to assess the association of cytokine expression with progression-free survival (PFS) in this cohort.
Results
We observed a wide variability of expression between different cytokines and levels of specific cytokines also varied in the 10 malignant ascites tested. Fifty-three (44%) cytokines were not detected in any of the 10 ascites. The level of several factors including, among others, angiogenin, angiopoietin-2, GRO, ICAM-1, IL-6, IL-6R, IL-8, IL-10, leptin, MCP-1, MIF NAP-2, osteprotegerin (OPG), RANTES, TIMP-2 and UPAR were elevated in most malignant ascites. Higher levels of OPG, IL-10 and leptin in OC ascites were associated with shorter PFS. IL-10 was shown to promote the anti-apoptotic activity of malignant ascites whereas OPG did not.
Conclusion
Our data demonstrated that there is a complex network of cytokine expression in OC ascites. Characterization of cytokine profiles in malignant ascites may provide information from which to prioritize key functional cytokines and understand the mechanism by which they alter tumor cells behavior. A better understanding of the cytokine network is essential to determine the role of ascites in OC progression.
PMCID: PMC3433103  PMID: 22957308
Ascites; ovarian cancer; tumor environment; cytokines; mulitplex array; IL-10
3.  Targeted ovarian cancer treatment: the TRAILs of resistance 
Ovarian cancer (OC) is the leading cause of death from gynecological malignancies. Although most patients respond to the initial therapy when presenting with advanced disease, only 10-15% maintain a complete response following first-line therapy. Recurrence defines incurable disease in most cases. Despite improvements with conventional chemotherapy combinations, the overall cure rate remained mostly stable over the years. Increased long-term survival in OC patients will only be achieved through a comprehensive understanding of the basic mechanisms of tumor cell resistance. Such knowledge will translate into the development of new targeted strategies. In addition, because OC is considered to be a heterogeneous group of diseases with distinct gene expression profiles, it is likely that different approaches to treatment for distinct sub-types will be required to optimize response. One of the new promising anti-cancer therapies is the tumor necrosis factor-related apoptosis-inducing ligand (TRAIL). TRAIL has the ability to selectively induce apoptosis in tumor cells with little toxicity to normal cells. Death receptor ligands such as TRAIL rely on the activation of the apoptotic signaling pathway to destroy tumor cells. TRAIL induces the formation of a pro-apoptotic death-inducing signaling complex (DISC) via its death receptors, TRAIL receptor 1 (TRAIL R1) and TRAIL receptor 2 (TRAIL R2). The formation of the DISC activates caspase-8 which requires further signal amplification through the mitochondrial pathway for an efficient activation of effector caspases in OC cells. The initial enthusiasm for TRAIL has been hampered by accumulating data demonstrating TRAIL resistance in various tumor types including OC cells. There is, therefore, a need to identify markers of TRAIL resistance, which could represent new hits for targeted therapy that will enhance TRAIL efficacy. In addition, the identification of patients that are more likely to respond to TRAIL therapy would be highly desirable. In this review, we discuss the different molecular and cellular mechanisms leading to TRAIL resistance in OC. In particular, we address the mechanisms involved in intrinsic, acquired and environment-mediated TRAIL resistance, and their potential implication in the clinical outcome.
PMCID: PMC3236573  PMID: 22206047
Ovarian cancer; death receptors; resistance; TRAIL

Results 1-3 (3)