Wong AST, Gumbiner BM.. Adhesion-independent mechanism for suppression of tumor cell invasion by E-cadherin. J Cell Biol 161: 1191-1203

Dept. of Cell Biology, School of Medicine, University of Virginia, PO Box 800732, Charlottesville, VA 22903, USA.
The Journal of Cell Biology (Impact Factor: 9.83). 07/2003; 161(6):1191-203. DOI: 10.1083/jcb.200212033
Source: PubMed


Loss of E-cadherin expression or function in tumors leads to a more invasive phenotype. In this study, we investigated whether the invasion suppressor activity of E-cadherin is mediated directly by tighter physical cell adhesion, indirectly by sequestering beta-catenin and thus antagonizing beta-catenin/T cell factor (TCF) signaling, or by other signaling pathways. To distinguish mechanisms, we expressed wild-type E-cadherin and various E-cadherin mutants in invasive E-cadherin-negative human breast (MDA-MB-231) and prostate (TSU-Pr1) epithelial carcinoma cell lines using a tetracycline-inducible system. Our data confirm that E-cadherin inhibits human mammary and prostate tumor cell invasion. We find that adhesion is neither necessary nor sufficient for suppressing cancer invasion. Rather, the invasion suppressor signal is mediated through the beta-catenin-binding domain of the E-cadherin cytoplasmic tail but not through the p120ctn-binding domain. beta-catenin depletion also results in invasion suppression. However, alteration in the beta-catenin/TCF transcriptional regulation of target genes is not required for the invasion suppressor activity of E-cadherin, suggesting the involvement of other beta-catenin-binding proteins.

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Available from: Alice S T Wong, May 27, 2014
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    • "Several groups studied the transfection of E-cadherin in highly mesenchymal and invasive cells and showed a reversion of the poorly differentiated carcinoma into a welldifferentiated one with a minimally invasive epithelial phenotype [66] [67] [68] [69] [70]. In breast cancer, it has been demonstrated that salinomycin can selectively kill E-cadherin-negative breast epithelial cells as compared with E-cadherin-positive cells in NOD/SCID and Balb/c mice model [71]. "
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    ABSTRACT: Tumor growth and metastatic dissemination rely on cellular plasticity. Among the different phenotypes acquired by cancer cells, epithelial to mesenchymal transition (EMT) has been extensively illustrated. Indeed, this transition allows an epithelial polarized cell to acquire a more mesenchymal phenotype with increased mobility and invasiveness. The role of EMT is quite clear during developmental stage. In the neoplastic context in many tumors EMT has been associated with a more aggressive tumor phenotype including local invasion and distant metastasis. EMT allows the cell to invade surrounding tissues and survive in the general circulation and through a stem cell phenotype grown in the host organ. The molecular pathways underlying EMT have also been clearly defined and their description is beyond the scope of this review. Here we will summarize and analyze the attempts made to block EMT in the therapeutic context. Indeed, till today, most of the studies are made in animal models. Few clinical trials are ongoing with no obvious benefits of EMT inhibitors yet. We point out the limitations of EMT targeting such tumor heterogeneity or the dynamics of EMT during disease progression.
    Journal of Oncology 10/2015; 2015(3):792182. DOI:10.1155/2015/792182
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    • "The retention of E-cadherin in invasive, N-cadherin-expressing cells suggests that the loss of E-cadherin function is inconsequential to N-cadherin-mediated invasive signaling (10,11). However, E-cadherin has been shown to be suppressive of invasion in several tissues, including oral epithelia (20–22). Such data raise the possibility that decreased E-cadherin function may independently contribute to increased proteolytic activity. "
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    ABSTRACT: Oral squamous carcinoma is the sixth most common cancer worldwide, and one of the most common cancers in developing countries. Regional and distant metastases comprise the majority of cases at initial diagnosis and correlate with poor patient outcomes. Oral epithelia is one of many tissue types to exhibit a cadherin switch during tumor progression, in which endogenous cell adhesion proteins, such as E-cadherin, give way to those of mesenchymal origin. The mesenchymal cell adhesion protein N-cadherin is found at the invading front of oral squamous carcinomas and has been strongly correlated with poor patient prognosis. The goal of the present study was to elucidate the mechanism by which N-cadherin may increase extracellular matrix-associated proteolytic activity to facilitate invasiveness in oral tumor development. The overexpression of N-cadherin in two oral squamous carcinoma cell lines increased motility, invasive capacity and synthesis of matrix metalloproteinase-9 (MMP-9) in a manner that was independent of E-cadherin downregulation. The use of EN and NE chimeric cadherin molecules with reciprocally substituted cytoplasmic domains revealed that optimal induction of MMP-9 synthesis required the cytoplasmic region, but not the extracellular region, of N-cadherin. Utilizing an N-cadherin mutant with impaired p120 binding ability, we found that such mutation resulted in a 4-fold decrease in motility compared to wild-type N-cadherin, but did not affect either MMP-9 expression or motility-normalized invasion. Overexpression of wild-type N-cadherin produced a 27-fold increase in the transcriptional activity of β-catenin, concomitant with increases in MMP-9 transcription. These results suggest that N-cadherin may promote motility and invasiveness through distinct mechanisms, and that β-catenin may be an integral mediator of N-cadherin-dependent invasive signaling in oral epithelia.
    International Journal of Oncology 07/2014; 45(4). DOI:10.3892/ijo.2014.2549 · 3.03 Impact Factor
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    • "Increased cell motility and invasiveness in E-cadherin negative tumors and cell lines have been attributed to the loss of cell-cell adhesion. Restoration of E-cadherin expression in cancer cells results in decreased invasiveness, growth suppression and terminal differentiation [10]–[12]. Loss or downregulation of E-cadherin results in release of beta-catenin from a membrane-bound state into cytoplasm. Cytoplasmic beta-catenin can translocate into the nucleus where is known to interact with transcription factors of the leukocyte enchancer factor (LEF)/T-cell factor (TCF) family to regulate transcription of target genes implicated in cell growth control such as cyclin D1 and c-myc [13], [14]. "
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    ABSTRACT: Elucidating the molecular phenotype of cancers with high metastatic potential will facilitate the development of novel therapeutic approaches to the disease. Gene expression profiles link epithelial to mesenchymal transition (EMT) phenotype with high-risk HNSCC. We sought to determine the role of protein biomarkers of EMT in head and neck squamous carcinoma (HNSC) prognosis. Protein expression analysis of EGFR, β-catenin and E-cadherin was performed on a cohort of 102 patients with HNSCC recruited between 1992 and 2005 using automated quantitative protein analysis (AQUA). We evaluated associations with clinicopathological parameters and prognosis. There were 67 patients with primary squamous cell carcinoma of the head and neck in this cohort who met inclusion criteria and for whom we had complete E-cadherin, beta-catenin and EGFR expression data. High E-cadherin expressers had longer 5-year progression-free survival (PFS) compared to those with low E-cadherin (59.7% versus 40.6%, p = 0.04) and overall survival (OS) (69.6% versus 44.3%, p = 0.05). Kaplan-Meier analysis showed that patients with low beta-catenin-expressing tumors trended toward worse 5-year PFS (p = 0.057). High EGFR expressers had inferior OS compared to low EGFR expressers (27.7% vs. 54%, p = 0.029). In the multivariable analysis context, E-cadherin remained an independent predictor of improved OS (HR = 0.204, 95% CI 0.043 to 0.972, p = 0.046) while EGFR trended towards significance for OS. The putative markers of EMT defined within a panel of HNSCC using AQUA are associated with tumors of poor prognosis.
    PLoS ONE 04/2014; 9(4):e94273. DOI:10.1371/journal.pone.0094273 · 3.23 Impact Factor
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