Down‐regulation of desmosomal molecules in oral and pharngeal squamous cell carcinomas as a marker for tumour growth and distant metastasis

Depondt, J; Shabana, A.H.M.; Florescu-Zorila, Silvana; Géhanno, P.; Forest, Nadine

doi:10.1046/j.0909-8836.1999.eos1070305.x

Cited by 42 publications

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“…In general, tumors in Perp þ /À mice displayed the characteristics typical of malignant tumors, including a high percentage of mitotic figures and nuclear pleiomorphism (data not shown), and were indistinguishable from the tumors observed in wild-type mice. We also examined a subset of these tumors for loss of heterozygosity Cell Death and Differentiation (2006) 13,[1614][1615][1616][1617][1618] (LOH) at the Perp locus by Southern blot analysis, and found no LOH in the 10 tumors examined (data not shown). Together, these findings indicate that Perp heterozygosity does not predispose mice to spontaneous tumorigenesis.…”

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Adult mice lacking the p53/p63 target gene Perp are not predisposed to spontaneous tumorigenesis but display features of ectodermal dysplasia syndromes

2006

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“…This notion is consistent with several studies showing that desmosomal components are downregulated during tumorigenesis, suggesting that compromised desmosomal adhesion may promote tumor metastasis. 13 In future, it will be of great interest to investigate Perp's contribution to tumorigenesis in later stage cancers.…”

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Adult mice lacking the p53/p63 target gene Perp are not predisposed to spontaneous tumorigenesis but display features of ectodermal dysplasia syndromes

2006

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“…Downregulation of desmosomal components desmoplakins (dp), desmogleins (dg) and desmocollins was shown to correlate with dedifferentiation, tumor progression and metastatic potential. [32][33][34][35][36][37] However, some reports showed unchanged staining of these components in a variety of tumors, suggesting that loss of demosomes is not necessary for tumor invasion and metastasis. 38,39 In carcinomas, mutations of genes encoding for desmosomal proteins have not been reported.…”

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E‐cadherin is a selective and strongly dominant prognostic factor in squamous cell carcinoma: A comparison of E‐cadherin with desmosomal components

Bosch

Andl

Abel

et al. 2005

Intl Journal of Cancer

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E-cadherin-mediated and desmosomal cell-cell adhesion have been implicated in the suppression of invasive and metastatic behavior of squamous cell carcinomas. Whether the adhaerens junction represented by E-cadherin and the desmosomes interplay or have distinct and separate roles in squamous cell cancer progression is still unclear. We have studied a cohort of 200 primary tumors and 56 lymph node metastases from different anatomic sites of the head and neck region for changes in synthesis of E-cadherin, desmoplakin and desmoglein by immunohistochemistry (IHC). Selected cases were studied by indirect immunofluorescence (IIF) and electron microscopy (EM). Only frozen sections were evaluated since they gave stronger and reproducible staining results. IHC data obtained were compared to clinical parameters. While some reduction in immunostaining was found in virtually all invasive tumors, at least partial expression, including that of E-cadherin, persisted in most late stage tumors and in lymph node metastases. Reduced desmosomal staining correlated with desmosomes reduced in numbers, size or in structural defects by EM analysis. By univariate analysis, reduction in synthesis of both E-cadherin and the desmosomal components that were generally linked (i.e., they showed positive rank correlations) were significantly associated with clinical parameters including overall and disease-free survival. However, by multivariate analysis including a Cox proportional hazards regression model (backward selection), the desmosomal components were not significant as independent prognostic factors. By contrast, E-cadherin was strongly associated with patient prognosis. In line with the highly significant association of reduced E-cadherin synthesis with an increased relative risk of follow up events, i.e., regional lymph node (p ‫؍‬ 0.0007) and distant metastasis (p < 0.0001), as well as local recurrences (p < 0.0001), the prognostic strength of E-cadherin was independent of and stronger than histological grading, N stage, tumor site, and even stronger than the TNM stage. Based on these results, evaluation of E-cadherin in squamous cell carcinomas by immunostaining is recommended as a significant prognostic marker. © 2004 Wiley-Liss, Inc.Key words: E-cadherin; cell adhesion; desmosomes; prognosis; squamous cell cancer Organization and function of epithelia depends on the integrity of junctional structures. 1,2 Among them the 2 types of "adhering junctions", i.e., the adhaerens junctions and the desmosomes contribute to intercellular adhesion and tissue stability. Key elements in intercellular adhesion are transmembrane glycoproteins of the cadherin family. The "classical" E-cadherin (ecad) maintains intercellular adhesion in the adhaerens junction, and the desmogleins (dg) and desmocollins (dc) are the principal cadherins of the desmosomes. [3][4][5][6][7][8][9][10][11][12][13] Regarding adhaerens junctions, numerous studies have shown that loss of adhesion can be caused by deletions or mutations, 14 -17 silencing by CpG methylatio...

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“…The lack of cell-cell adhesion is an important characteristic of cancer cells, and the lack of expression of cell adhesion components, such as cadherins or catenins, is linked to tumor invasion, progression, and poor prognosis (1)(2)(3). Adherens junctions and desmosomes are key mediators of intercellular adhesion in epithelial tissue.…”

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Bortezomib Inhibits Cell-Cell Adhesion and Cell Migration and Enhances Epidermal Growth Factor Receptor Inhibitor–Induced Cell Death in Squamous Cell Cancer

2007

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The lack of cell-cell adhesion and increased migration are key characteristics of cancer cells. The loss of expression of cell adhesion components and overexpression of components critical for cell migration, such as focal adhesion kinase (FAK), correlate with poor prognosis. Because alteration of protein turnover affects the expression levels and, in turn, may influence protein function, we investigated the effects of the proteasome inhibitor bortezomib on cell adhesion and migration in oral squamous cell cancer cell lines SCC68 and SCC15. Following treatment with bortezomib, protein levels of adherens junction components such as E-cadherin were unchanged. The desmosomal linker protein desmoplakin level was increased, whereas the protein level of the desmosomal cadherin, desmoglein 2, was diminished. Reduced desmoglein 2 levels correlated with the diminished strength of mechanical cell-cell adhesion. The protein level of the epidermal growth factor receptor (EGFR) increased after proteasome inhibition and EGFR inhibition with the EGFR-specific tyrosine kinase inhibitor PKI166 was able to restore cell-cell adhesion. Furthermore, we found that the combination of PKI166 with bortezomib enhanced the rate of cell death. Although the FAK protein level was unchanged following bortezomib treatment, recruitment of FAK phosphorylated at tyrosine residue 397 to the periphery of the cell was induced. Migration was reduced following treatment with bortezomib, which could potentially be explained by a prominent but disorganized actin fiber network revealed through immunofluorescence. Collectively, our results suggest that proteasome inhibition using bortezomib affects cell adhesion and cell migration profoundly and provides a rationale for its clinical use in conjunction with an EGFR inhibitor. [Cancer Res 2007;67(2):727-34]

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Down‐regulation of desmosomal molecules in oral and pharngeal squamous cell carcinomas as a marker for tumour growth and distant metastasis

Cited by 42 publications

References 0 publications

Adult mice lacking the p53/p63 target gene Perp are not predisposed to spontaneous tumorigenesis but display features of ectodermal dysplasia syndromes

Adult mice lacking the p53/p63 target gene Perp are not predisposed to spontaneous tumorigenesis but display features of ectodermal dysplasia syndromes

E‐cadherin is a selective and strongly dominant prognostic factor in squamous cell carcinoma: A comparison of E‐cadherin with desmosomal components

Bortezomib Inhibits Cell-Cell Adhesion and Cell Migration and Enhances Epidermal Growth Factor Receptor Inhibitor–Induced Cell Death in Squamous Cell Cancer

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