PubMed · 15447727
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David R Garrod. 2004. Intercellular junctions in normal epidermis.. https://doi.org/10.1111/j.0906-6705.2004.0250b.x
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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.
Adherens junctions (AJs) are a major cell-cell adhesion structure in epithelial cells that are formed by two major cell-cell adhesion molecules, E-cadherin and nectin. We have previously shown that nectin first forms cell-cell adhesion and then recruits non-trans-interacting E-cadherin to the nectin-based cell-cell adhesion sites, which gradually trans-interact there, eventually forming AJs. We have examined here the effect of trans-interacting nectin on non-trans-interacting E-cadherin endocytosis. Trans-interacting nectin capable of associating with afadin, but not trans-interacting nectin mutant incapable of associating with afadin, inhibited non-trans-interacting E-cadherin endocytosis in intact cells. Afadin is a nectin- and actin filament-binding protein that connects nectin to the actin cytoskeleton. Studies on the mode of action of the nectin-afadin system using cell-free assay revealed that afadin associated with nectin bound Rap1 activated by trans-interacting nectin, interacted with p120ctn, and strengthened the binding of p120ctn to E-cadherin, eventually reducing non-trans-interacting E-cadherin endocytosis. Afadin, which did not bind Rap1, was inactive in this capacity. These results indicate that trans-interacting nectin inhibits non-trans-interacting E-cadherin endocytosis through afadin, Rap1, and p120ctn and thereby further accumulates non-trans-interacting E-cadherin to the nectin-based cell-cell adhesion sites for the formation of AJs.
P-Cadherin/CDH3 belongs to the family of classic cadherins that are engaged in various cellular activities including motility, invasion, and signaling of tumor cells, in addition to cell adhesion. However, the biological roles of P-cadherin itself are not fully characterized. Based on information derived from a previous genome-wide cDNA microarray analysis of microdissected pancreatic ductal adenocarcinoma (PDAC), we focused on P-cadherin as one of the genes most strongly overexpressed in the great majority of PDACs. To investigate the consequences of overexpression of P-cadherin in terms of pancreatic carcinogenesis and tumor progression, we used a P-cadherin-deficient PDAC cell line, Panc-1, to construct a cell line (Panc1-CDH3) that stably overexpressed P-cadherin. Induction of P-cadherin in Panc1-CDH3 increased the motility of the cancer cells, but a blocking antibody against P-cadherin suppressed the motility in vitro. Overexpression of P-cadherin was strongly associated with cytoplasmic accumulation of one of the catenins, p120ctn, and cadherin switching in PDAC cells. Moreover, P-cadherin-dependent activation of cell motility was associated with activation of Rho GTPases, Rac1 and Cdc42, through accumulation of p120ctn in cytoplasm and cadherin switching. These findings suggest that overexpression of P-cadherin is likely to be related to the biological aggressiveness of PDACs; blocking of P-cadherin activity or its associated signaling could be a novel therapeutic approach for treatment of aggressive pancreatic cancers.