Lysophosphatidic Acid Initiates Epithelial to Mesenchymal Transition and Induces ß-Catenin-mediated Transcription in Epithelial Ovarian Carcinoma.

During tumor progression, epithelial ovarian cancer (EOC) cells undergo epithelial-to-mesenchymal transition (EMT), which influences metastatic success. Mutation-dependent activation of Wnt/ß-catenin signaling has been implicated in gain of mesenchymal phenotype and loss of differentiation in several solid tumors; however, similar mutations are rare in most EOC histotypes. Nevertheless, evidence for activated Wnt/ß-catenin signaling in EOC has been reported, and immunohistochemical analysis of human EOC tumors demonstrates nuclear staining in all histotypes. This study addresses the hypothesis that the bioactive lipid lysophosphatidic acid (LPA), prevalent in the EOC microenvironment, functions to regulate EMT in EOC. Our results demonstrate that LPA induces loss of junctional ß-catenin, stimulates clustering of ß1 integrins, and enhances the conformationally active population of surface ß1 integrins. Furthermore, LPA treatment initiates nuclear translocation of ß-catenin and transcriptional activation of Wnt/ß-catenin target genes resulting in gain of mesenchymal marker expression. Together these data suggest that LPA initiates EMT in ovarian tumors through ß1-integrin-dependent activation of Wnt/ß-catenin signaling, providing a novel mechanism for mutation-independent activation of this pathway in EOC progression.

PTN signaling: Components and mechanistic insights in human ovarian cancer.

Molecular vulnerabilities represent promising candidates for the development of targeted therapies that hold the promise to overcome the challenges encountered with non-targeted chemotherapy for the treatment of ovarian cancer. Through a synthetic lethality screen, we previously identified pleiotrophin (PTN) as a molecular vulnerability in ovarian cancer and showed that siRNA-mediated PTN knockdown induced apoptotic cell death in epithelial ovarian cancer (EOC) cells. Although, it is well known that PTN elicits its pro-tumorigenic effects through its receptor, protein tyrosine phosphatase receptor Z1 (PTPRZ1), little is known about the potential importance of this pathway in the pathogenesis of ovarian cancer. In this study, we show that PTN is expressed, produced, and secreted in a panel of EOC cell lines. PTN levels in serous ovarian tumor tissues are on average 3.5-fold higher relative to normal tissue and PTN is detectable in serum samples of patients with EOC. PTPRZ1 is also expressed and produced by EOC cells and is found to be up-regulated in serous ovarian tumor tissue relative to normal ovarian surface epithelial tissue (P < 0.05). Gene silencing of PTPRZ1 in EOC cell lines using siRNA-mediated knockdown shows that PTPRZ1 is essential for viability and results in significant apoptosis with no effect on the cell cycle phase distribution. In order to determine how PTN mediates survival, we silenced the gene using siRNA mediated knockdown and performed expression profiling of 36 survival-related genes. Through computational mapping of the differentially expressed genes, members of the MAPK (mitogen-activated protein kinase) family were found to be likely effectors of PTN signaling in EOC cells. Our results provide the first experimental evidence that PTN and its signaling components may be of significance in the pathogenesis of epithelial ovarian cancer and provide a rationale for clinical evaluation of MAPK inhibitors in PTN and/or PTPRZ1 expressing ovarian tumors.

Integrin regulation of beta-catenin signaling in ovarian carcinoma.

Reversible modulation of integrin-regulated cell-matrix adhesion and epithelial (E)-cadherin-mediated cell-cell adhesion plays a critical role in the establishment of ovarian cancer metastases. In contrast to most epithelial cell-derived tumors that down-regulate E-cadherin expression during progression, acquisition of E-cadherin expression accompanies malignant transformation of the ovarian surface epithelium and is maintained in peritoneal metastases. Metastatic epithelial ovarian cancer cells are disseminated intraperitoneally and preferentially adhere via integrins to interstitial collagens in the peritoneal cavity. This study was undertaken to determine whether integrin engagement influences E-cadherin and ß-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3ß, elevated levels of nuclear ß-catenin, increased ß-catenin-regulated promoter activation, and transcriptional activation of Wnt/ß-catenin target genes. Blocking ß-catenin transcriptional control with inhibitor of ß-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ß-catenin nuclear signaling in EOC invasion and metastasis. These studies support a model wherein cell-matrix engagement regulates the functional integrity of cell-cell contacts, leading to increased ß-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/ß-catenin signaling in the absence of activating mutations in this pathway.

Diverse mechanisms for activation of Wnt signalling in the ovarian tumour microenvironment.

Wnt signalling pathways have been shown to play key roles in both normal development and tumorigenesis. Progression of many human cancers is associated with defined mutations in Wnt pathway components that result in dysregulated ß-catenin-mediated gene transcription. Although Wnt pathway mutations are rare in epithelial ovarian cancer (with the exception of the endometrioid histotype), accumulating evidence supports a role for Wnt signalling in ovarian tumorigenesis in the absence of genetic mutations. The present review summarizes evidence in support of activated Wnt signalling in ovarian tumours and discusses alternative mechanisms for Wnt pathway activation in the ovarian tumour microenvironment.