Cadher1ns And Intercellular Adhesion

Oral SCC is formed from stratifed squamous epithelium and as such utilizes the E-cadherin system to maintain cell-cell adhesion. Cadherins are concentrated into junctional plaque structures that can be visualized by electron microscopy as zonula adherens and desmosomes [114,115]. The Cadherin family has been organized into classical Cadherins and desmosomes, but both groups of receptors share highly conserved transmembrane and extracellular regions and interact with a class of cytoplasmic link proteins termed catenins. Cadherin function requires interaction with the actin cytoskeleton. Consequently, Cadherin function is regulated from the cytoplasmic side and depends on the interaction with catenins, which bind to the cytoplasmic domain of Cadherins, thereby forming links to the cytoskeleton [reviewed in 116,117], For adherens junctions, these link proteins are P-catenins and plakoglobin (y-catenin). P-Catenin and plakoglobin, but not a-catenin, bind directly to the cytoplasmic N-terminal domain of E-cadherin; a-catenin can associate with the N-terminal regions of p-catenin and plakoglobin, which is essential in order for Cadherins to interact with the cytoskeleton. The Armadillo repeat region of P-catenins and plakoglobin mediates their association with E-cadherin and their complexing with the adenomatous polyposis coli (APC) tumor suppressor protein. The association of

APC with p-catenin appears to regulate its stability. The Armadillo repeats in plakoglobin are also crucial for its binding to desmosomal cadherins (desmogleins and desmo-collins). Finally, the amino-terminal region of a-catenin links cadherin-catenin complexes with the actin filaments via a-actinin (Fig. 6.1, see also color insert).

Catenins are now known to be key regulatory molecules that mediate the transduction of extracellular contacts between cadherins during epithelial reorganization and also provide for the linkage of cadherins to intracellular signaling pathways [reviewed in 118-120]. Importantly, catenins transmit signals that regulate gene expression. Thus, p-catenin binds both cadherin and other catenins, but when P-catenin is in excess, it binds the LEF family of transcription factors, and this complex of catenin and transcription factor is transported to the nucleus where it effects gene expression. In contrast, expression of the wnt-1 protooncogene increases the level and function of catenins, thereby stabilizing cadherin-mediated cell-cell adhesion. Wnt signaling involves GSK3-P, and through the phosphorylation of P-catenin, its own turnover is regulated. Also, axin binds p-catenin, APC, and GSK3-p directly, and this tetrameric complex regulates stabilization of P-catenin [121,122], Finally, pl20ctn or pi20 contains Armadillo repeats, associates with E-cadherin-catenin complexes, is tyrosine phosphorylated in cells transformed with Src or in response to growth factors, and may regulate displacement of P-catenin from E-cadherin complexes [123,124]. In certain tumors, P-catenin appears to act as an oncogene. For example, in colon cancer, APC is mutated, resulting in the elevation of P-catenin, whereas normally APC and GSK3-P facilitate its degradation. However, in colon carcinoma cells and in melanoma cells [125,126], P-catenin is usually highly expressed and forms complexes with Tcf-4 or Lef-1 [127,128], thereby activating gene expression that regulates cell growth or suppresses programmed cell death.

Integrin Cadherin
FIGURE 6.1 Integrin and cadherin adhesion receptors. (See also color insert.)

A. Cadherins and Regulation of Invasion

Cadherins are required for cells to remain tightly associated in normal and malignant epithelia, and in their absence the many other cell-junction proteins expressed in epithelial cells are generally not capable of supporting intercellular adhesion [115], Cell dissociation and scattering, with loss of cell-cell adhesion and junctional communication, are required for the invasiveness and metastasis of malignant tumor cells. It is well established that the downregulation of cell-cell adhesion in tumor cells favors their dissemination [114], E-cadherin is an important suppressor of epithelial tumor cell motility, invasion, and metastasis [129], The loss of E-cadherin or its dysfunction leads to increased motility and invasiveness of carcinoma cells, and transfection of cadherin cDNA into deficient carcinoma cells can reverse the invasive phenotype and reduce tumorigenicity [130], However, a number of tumors can disperse and invade, despite an abundant expression of cadherin molecules at their cell surface. In these cases, several defects in cadherin function have been identified that could account for the suppression of cadherin activity, including loss of a-catenin [131,132] and elevated tyrosine phosphorylation of P-catenin, pl20CAS, and cadherin [133-136], In well- and moderately differentiated human SCC, studies have found that a modest but variable expression of E-cadherin is preserved as lesions advance through premalignant to invasive and metastatic stages [137-140], However, in head and neck SCC, different levels of E-cadherin expression have been reported. Some of this variation in staining pattern may be due to the sensitivities of the different antibodies or methods used. In some studies with human head and neck SCC, a loss or decrease of E-cadherin expression was found during tumor progression, and metastatic lesions tended to have reduced levels of this adhesion receptor [141]. This suggests that in some cases, the tumor cells, possibly under stimulation by cytokines, could temporarily uncouple cadherins, thereby permitting distant metastasis followed by reexpression of the cadherin. Alternatively, the E-cadherin junctional complex may be present but somehow defective (due to dysfunctional catenins), allowing facile dissociation of the invasive cells following stimulation by effectors like integrin-ECM interaction and/or activation by cytokines (Fig 6.2).

B. Integrin-Cadherin Cross Talk

The integrin family of receptors, as detailed earlier, is clearly important in the process of invasion. Relatively little is known, however, about the interaction and cross talk between the two different adhesion receptor families, inte-grins and cadherins. Several studies now indicate an important dialogue between the two receptor types. For example, a number of studies have shown that cadherins can modulate or replace integrin function. In terminal differentiation of skin keratinocytes, cadherins play a role in the downregula-tion of integrin expression [142], Cadherin-mediated adhesion can substitute for integrin-mediated, anchorage-dependent growth [8]. In another study, it was reported that both integrins and cadherins regulate contact-mediated inhibition of cell migration [143], These reports suggest the possible existence of signaling pathways between integrin receptors and cadherin-mediated cell-cell contacts. Conversely, integrins can alter cadherin function. Thus, in migrating neural crest cells, (31 and (33 integrins elicit intracellular signals that regulate the surface distribution and activity of N-cadherin [144], von Schlippe et al. [145] reported that the treatment of melanoma cell monolayers with blocking monoclonal antibody to av integrin induced E-cadherin-mediated spheroid formation. In a different study, it was found that the reexpression of ยก31 integrin in integrin-null epithelial cell lines induced the disruption of polarity, intercellular adhesion, and cell scattering by the downregulation of cadherin and catenin function, which appeared to involve the activation of Racl and RhoA [146], This phenomenon was not solely the result of stimulated cell motility; interaction of the (31 integrin with ligand was required. In addition, this study showed that (31 integrin-null cells formed abundant adhesions, whereas cells that had reex-pressed the integrin exhibited a more scattered phenotype. In another study, Dufour et al. [147] found that the type of cadherin (cadherin-7 or N-cadherin) expressed defined whether fibronectin would induce cell motility and dispersion. Genda et al. [148] found that integrin (31 and (35 activity in HCC

Adhesion regulates invasion f lerin

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