Integrin Regulation of β-Catenin Signaling in Ovarian Carcinoma

Abstract

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...

Matrix Rigidity Activates Wnt Signaling through Down-regulation of Dickkopf-1 Protein

“…Furthermore, we have recently used ␤1 integrin antibody-conjugated microspheres to mimic multivalent cell matrix engagement such as occurs when EOC cells contact three-dimensional CI. Integrin clustering resulted in loss of E-cadherin junctional integrity, nuclear translocation of ␤-catenin, and transcriptional activation of genes involved in Wnt signaling including the ligand Wnt5a and the co-receptor LRP-6 (33). Together with the current results, these data support a functional link between matrix rigidity, ␤1 integrin clustering, down-regulation of DKK1, and enhanced Tcf/Lef transcriptional activity.…”

Wnt/β-Catenin Signaling Mediates Osteoblast Differentiation Triggered by Peptide-induced α5β1 Integrin Priming in Mesenchymal Skeletal Cells

“…Several mechanisms may link integrins to Wnt signaling. Notably, ligand binding to integrins may activate integrin-linked kinase (37), resulting in GSK-3␤ inactivation (38) and ␤-catenin/LEF transcriptional activity (39,40). Consistently, integrin-linked kinase knockdown was found to reduce ␤-catenin/TCF/LEF-dependent transcription in osteoblastic cells (41,42).…”

Axin Pathway Activity Regulates in Vivo pY654-β-catenin Accumulation and Pulmonary Fibrosis

“…Finally, although Src kinase activity is not required for ␤-catenin/TCF transcriptional activity, active Src 3 Y. Xi, unpublished observation. may promote ␤-catenin signaling by altering cell contacts or in some systems inactivating GSK3␤ apparently independently of Wnt ligands (39). Hence, the role of Src kinase in ␤-catenin signaling is complex and seemingly cell type-dependent.…”