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

Barbolina, Maria V.; Burkhalter, Rebecca J.; Stack, M. Sharon

doi:10.1042/bj20110112

Cited by 61 publications

(68 citation statements)

References 166 publications

(165 reference statements)

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“…In contrast to endometrioid ovarian carcinomas, which often harbor mutations in the ␤-catenin gene (23,24,52), activating mutations of Wnt signaling pathway components are rare in serous, clear cell, and mucinous ovarian carcinomas (53,54). Nevertheless, nuclear ␤-catenin has been observed in serous ovarian cancers, and coimmunoprecipitation of Lef-1 and ␤-catenin from serous tumors has been reported (53,(55)(56)(57).…”

Section: Discussionmentioning

confidence: 99%

“…In contrast, Wnt5a, a ligand for the Frizzled receptor, is widely expressed in ovarian tumors and correlates with poor survival (73). Wnt5a is also prevalent in human ovarian cancer ascites fluid (52). There are conflicting data regarding the role of Wnt5a as an activator versus an inhibitor of canonical Wnt signaling (60, 74 -78), and additional studies are needed to clarify the role of this factor in ovarian cancer pathobiology.…”

Section: Discussionmentioning

confidence: 99%

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Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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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 ␤-catenin localization and function. The data demonstrate that multivalent integrin engagement results in increased internalization of E-cadherin, inhibition of GSK-3␤, elevated levels of nuclear ␤-catenin, increased ␤-catenin-regulated promoter activation, and transcriptional activation of Wnt/␤-catenin target genes. Blocking ␤-catenin transcriptional control with inhibitor of ␤-catenin and Tcf-4 reduces cellular invasion, suggesting a key role for ␤-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 ␤-catenin nuclear signaling and enhanced cellular invasive activity. Furthermore, these results provide a mechanism for activation of Wnt/␤-catenin signaling in the absence of activating mutations in this pathway.Epithelial (E) 3 -cadherin is a single-span transmembrane glycoprotein that mediates calcium-dependent cell-cell adhesion via interaction with the extracellular domains of cadherins on the surface of neighboring cells (1, 2). Key functions of E-cadherin include the regulation of cell polarity and the maintenance of epithelial organization (3). Although most normal epithelia express high levels of E-cadherin, this cadherin is absent in the mesenchymally derived normal ovarian surface epithelium, which expresses neural (N)-cadherin. In most carcinomas, E-cadherin expression is down-regulated or lost, facilitating cellular dispersal, invasion, and metastasis (4). However, a unique feature of EOC is that E-cadherin becomes more abundant in primary differentiated carcinomas, with all histotypes displaying strong immunoreactivity (reviewed in Refs. 5, 6). There is less clarity regarding relative E-cadherin levels during ovarian tumor progression and metastasis. Although complete loss of E-cadherin is uncommon, reduced staining is often detected in late stage tumors and in ascites-derived tumor cells (7-9), and negative E-cadherin is predictive of poor overall survival (10, 11).␤-Catenin is found predominantly in association with the E-cadherin cytoplasmic domain at cell-cell junctions (12). In the absence of cell-cell contact and Wnt signaling, cytosolic ␤-catenin forms a complex with adenomatous poliosis coli, Axin/conductin, casein kinases 1␣ and 1⑀, and glyc...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Burkhalter

Symowicz

Hudson

et al. 2011

Journal of Biological Chemistry

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“…9,21 Increased activity of the Wnt/β-catenin pathway can result from upregulation at different steps in the signaling pathway: overexpression of the cell surface receptors LRP5, LRP6, and Frizzled or increased activity of the Wnt target genes survivin, cyclin D1, Axin2, and c-myc. 9,13,22 A crucial component necessary for Wnt ligand transport, secretion, and activity is PORCN, which has been identified as a potential target to inhibit Wnt/β-catenin signaling. 15 Wnt pathway inhibitor success has been limited because of a narrow therapeutic window for activity since normal tissue stability requires Wnt/β-catenin signaling and a lack of predictive biomarkers of response.…”

Section: Discussionmentioning

confidence: 99%

Targeting the Wnt/β-catenin pathway in primary ovarian cancer with the porcupine inhibitor WNT974

Boone

Arend

Johnston

et al. 2016

Laboratory Investigation

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Preclinical studies in ovarian cancer have demonstrated upregulation of the Wnt/β-catenin pathway promoting tumor proliferation and chemoresistance. Our objective was to evaluate the effect of the Wnt/β-catenin pathway inhibitor, WNT974, in primary ovarian cancer ascites cells. Ascites cells from patients with papillary serous ovarian cancer were isolated and treated with 1 μM WNT974 ± 100 μM carboplatin. Viability was evaluated with the ATPlite assay. The IC 50 was calculated using a dose-response analysis. Immunohistochemistry (IHC) was performed on ascites cells and tumor. Expression of R-spondin 2 (RSPO2), RSPO3, PORCN, WLS, AXIN2, and three previously characterized RSPO fusion transcripts were assessed using Taqman assays. Sixty ascites samples were analyzed for response to WNT974. The ascites samples that showed a decrease in ATP concentration after treatment demonstrated no difference from the untreated cells in percent viability with trypan blue staining. Flow cytometry demonstrated fewer cells in the G2 phase and more in the G1 and S phases after treatment with WNT974. Combination therapy with WNT974 and carboplatin resulted in a higher percentage of samples that showed ≥ 30% reduction in ATP concentration than either single drug treatment. IHC analysis of Wnt pathway proteins suggests cell cycle arrest rather than cytotoxicity after WNT974 treatment. QPCR indicated that RSPO fusions are not prevalent in ovarian cancer tissues or ascites. However, higher PORCN expression correlated to sensitivity to WNT974 (P = 0.0073). In conclusion, WNT974 produces cytostatic effects in patient ascites cells with primary ovarian cancer through inhibition of the Wnt/β-catenin pathway. The combination of WNT974 and carboplatin induces cytotoxicity plus cell cycle arrest in a higher percentage of ascites samples than with single drug treatment. RSPO fusions do not contribute to WNT974 sensitivity; however, higher PORCN expression indicates increased WNT974 sensitivity.

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“…Recent studies have shown that both GSK-3 and Axin2 are overexpressed in serous ovarian cancer. These findings implicate activation of Wnt/ -catenin signaling in serous EOC in the absence of activating mutations in either APC, Axin or -catenin (Barbolina et al, 2011).…”

Section: Ovarian Cancermentioning

confidence: 84%