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FIGURE 6.2 Adhesion receptors regulate tumor invasion. Local invasion of ECM via integrins initiates dissociation of invading cells, whereas formation of extensive cell-cell adhesions minimizes invasion and promotes a differentiated phenotype.

cells could inhibit cadherin-induced cell-cell adhesion and possibly involved c-Src. Kawano et al. [70] showed that oral SCC cells are able to form E-cadherin-dependent multicellular aggregates when plated onto non-adherent substrates. When these spheroids were confronted with ECM substrates, cell-cell adhesion was reversed. This indicates that the breakdown of cadherin-mediated cell-cell adhesion and active cell scattering by specific ECM ligands are triggered by intracellular signals elicited by cell-surface integrins. Taken together, these results suggest that several different integrin receptors can, after ligation with ligand, trigger the disruption of junctional adhesions and induce motility and invasion.

The mechanism by which each type of receptor regulates the other is not completely understood. Certainly the importance of the cytoskeleton in this process is appreciated in that both integrins and cadherins associate with and dynamically regulate the actin cytoskeleton. In the case of integrins, interfacing with actin is involved, with the formation of focal adhesion plaques that mediate attachment to the ECM. Similarly, cadherins form associations with actin filaments via the interaction with link proteins (catenins) during the formation of junctional adhesions such as zonula adherens [149]. Thus, one possible mechanism by which integrins and cadherins may cross talk is through their common interaction with the actin cytoskeleton [150], Another potential mechanism may involve specific signaling pathways. For example, the adapter protein She, which is involved in growth factor activation by Ras, has been shown to associate with E-cadherin [151]. Additionally, cell-cell contact regulating proliferation has been linked to alterations in cyclin-dependent kinases [152,153], Arregui et al. [154] showed that the nonreceptor tyrosine kinase Fer may be involved in mediating integrin-cadherin coordinate regulation. Using antennapedia fusion peptides, the authors found that sequences of the juxtamembrane domain of N-cadherin induced dysregulation of both cadherin and integrin function that involved dissociation of Fer from cadherin and transfer to integrin heterodimers.

The capacity of integrin and cadherin receptors to reversibly modulate cell phenotype is a phenomenon similar to epithelial-mesenchymal transition (EMT), a term that originally described discrete events occurring during developmental processes (e.g., gastrulation) [155], However, various types of carcinomas frequently undergo a similar process in which differentiated epithelioid cells switch during tumor progression to a dedifferentiated fibroblastic phenotype [156,157], EMT by carcinoma cells is an irreversible process and represents a discrete stage of tumor progression. Previous work has shown that in certain carcinomas, epithelial differentiation correlates with the level of cadherin expression [156]. Alternatively, the conversion can follow exposure of cells to certain growth factors and is not associated with an alteration in cadherin levels [158,159], Kawano et al. [70] suggested a different variant of EMT whereby fibroblastoid cells can be converted to an epithelial pheno-type by substrate deprivation and forced aggregation. After engagement of integrins with the ECM, the cells are restored to an epithelial monolayer as an intermediate and temporary stage, but eventually revert to their original fibroblastoid phenotype. This reversible modulation in cell behavior was associated with the regulation of E-cadherin levels.

C. Regulation of Cadherin Expression

The level of cadherin expression, and therefore important aspects of the cellular phenotype, is determined by a complicated series of regulatory events [reviewed in 160], Mutational inactivation of E-cadherin has been identified in a number of human tumors, including gastric and breast carcinomas, and leads to loss of normal cell-cell adhesion. Also, in human tumors, transcriptional inactivation of cadherin expression can frequently occur. It is well known that E-cadherin expression can be regulated by methylation of the promoter and neighboring CpG regions, thereby causing loss of E-cadherin mRNA [161]. Cadherin levels can also be regulated by changes in the stability of the expressed protein. For example, cadherins become stabilized as they accumulate at junctional plaques, which is presumably related to their immobilization and withdrawal from the short-lived cytoplasmic pool of receptors [70], In other systems, mature E-cadherin has been found to turn over rapidly, and its halflife has been estimated to be in the range of about 5-6 h [162]. Other studies based on morphometric analyses have suggested that cadherins may be stabilized after their incorporation into sites of cell-cell contact [161,163,164]. There are a number of ways by which cadherins could reinforce their stable association in these junctions. For example, as cadherin lattices are formed, stability could be enhanced as the cadherin-catenin complex associates with the actin cytoskeleton; additionally, the dimerization and lateral clustering of cadherins that follow junctional plaque formation may further stabilize receptor localization [165], Several oral SCC tumor cell lines have been shown not to express E-cadherin [8,166], but the mechanism responsible for this has not been characterized. There appears to be a form of cadherin switching. For example, loss of E-cadherin can induce the upregulation of other cadherins, such as N-cadherin [ 167] or cadherin-11 [168]. In the case of oral SCC, N-cadherin is expressed in a subset of oral SCC cells and appears to induce altered morphology and invasion [166,169], In different carcinomas, recent work suggests that N-cadherin regulates scatter response through the FGF-4 receptor [169,170],

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