The major part of cancer morbidity and mortality occurs upon the dissemination of carcinomas from their original sites of development. While any tissue can undergo a neoplastic transformation, the majority of tumors derive from the epithelial cells of tissues. These carcinomas are distinguished from their normal counterparts by a loss of tissue and cell organization () [23
Fig. 1 Carcinomagenesis and progression entails multiple phenotypic changes. Epithelial tissues consist of sheets of normal cells (stippled black) linked together by homotypic binding of E-cadherin (thick black bars). This establishes a polarity that segregates (more ...)
In the normal situation, the epithelial cells are in directed communication with the stromal compartment via an organized structure. Epithelial cells are arranged mainly in sheets (with the exception of skin) with adjacent cells tightly connected via tight junctions and gap junctions. These connections not only serve for communication and limit both cell proliferation and migration, but also establish a cell polarity. At the apical surface in most tissues, the epithelial cells are in contact with body fluids that are either wholly or partly produced by these same cells. These fluids contain biologically factors, growth factors in particular, that are usually inert to the tissue as the receptors for such factors are sequestered on the baso-lateral surfaces. The tight junctions, constructed upon homotypic binding of Epithelial-Cadherins (E-cadherin or CDH1), limit the access of the apical fluids to the basolateral spaces and surfaces and the underlying stromal compartment.
Upon neoplastic transformation, this orderly arrangement is lost. A host of genetic and epigenetic changes occur that lead to loosening and even loss of the tight junctions (for reviews see: [4
]). The consequences of this are manifold. First, the epithelial cells are now exposed to potential autocrine factors, as the localization of ligand production and receptor expression are no longer segregated. Second, the epithelial cells are released from physical restraints with loss of contact inhibition, allowing from cell movement and even proliferation. And third, the stromal elements are now exposed to many epithelial-derived bioactive factors promoting a stromal response. This latter event may change the profile of signals that derive from the stromal compartment, as the composition and differentiation state of the stromal elements change. The net sum of these tissue alterations are that the epithelial cells are directed to assume a less differentiated state that converges towards the mesenchymal phenotype characterized by motility and proliferation with a more fluid cell architecture that has limited cell–cell direct communications. This is the so-called epithelial-to-mesenchymal-like transition (EMT) of carcinomas [41
This carcinoma EMT is distinguished from true EMT situations noted in development by the fact that the cells do not actually subsume a full or physiological role similar to a mesenchymal-derived (usually stromal/fibroblastoid) cell [4
]. Rather the attributes of the cells converge on those noted in stromal cells, and the normal epithelial markers and functions are lost. This situation is not unique to carcinoma de-differentiation; incomplete EMT is also noted during wound healing. During skin repair, for example, the basal keratinocytes bordering the missing tissue downregulate their defining cytokeratin and E-cadherin structures and change their complement of adhesion receptors to assume a mesenchymal-like phenotype that is proliferative, migratory and synthetic for dermal matrix components [1
]. Interestingly, these same cells then ‘revert’ or redifferentiate into basal keratinocytes when the wound defect is re-epithelialized. Thus, the first steps in the dedifferentiation process of carcinoma progression are an EMT process not dissimilar from the post-natal wound-related EMT.
Despite the long-standing recognition of this carcinoma EMT and recent findings as to underlying molecular controls (though these are not specific for EMT) [29
], there is no accepted molecular definition of what constitutes this process [41
]. This may be due to the multitude of pathways carcinomas may take to achieve this aggressive phenotype. A picture is emerging of common molecular findings that account for both the histopathological picture and the cell biology findings. At the minimum, the carcinoma EMT is defined by a loss of normal epithelial architecture, namely both the physiological homogenous asymmetry of the cell and the cell–cell contacts and communications that anchor this. At the molecular level, this is reflected by downregulation or loss of specific cytokeratins and E-cadherin. The latter is of particular importance, because it can be viewed as both a cause and effect of the EMT.
In addition to loss of E-cadherin functionality, the structural proteins in these tumor cells undergo a change, with downregulation or loss of cytokeratins and emergence of the mesenchymal marker vimentin [4
]. Often, N-cadherin upregulation is coincident with EMT and contributes to tumor progression [5
]. However, this adhesion/attachment molecule is not a consistent marker for EMT, also appearing on cells along side E-cadherin. Another cell surface marker that is often linked to the EMT is ZO-1 [19
], though again, this is an inconsistent marker with a more quantitative than qualitative change. A number of differentiation-related transcription factors contribute to this proteome change, though these are specific neither to EMT nor to mesenchymal cells [22
]. As such, in the absence of truly specific markers for either the epitheloid or mesenchymal phenotype, the definition of EMT is one of overall interpretation of cell phenotype. However, for carcinoma cells the most consistent molecular marker is E-cadherin, and our discussion will focus on the expression and functionality of this, though studies should examine additional molecular and phenotypic/morphometric markers when querying EMT.
Loss of E-cadherin disrupts not only cell–cell junctions but also allows for loss of the normal organ architecture. The cells are now free to move both horizontally and vertically within the epithelial layer as they are no longer constrained within a functional syncytium [3
] (). This is a histopathological hallmark of neoplastic transformation. Furthermore, the absence of apical-basal barriers between the cells enables factors produced by the cells to reach cognate receptors normally segregated on the basolateral surfaces. This autocrine signaling often further reinforces the EMT phenotype as stimulation of most receptors with intrinsic tyrosine kinase activity, particularly the ubiquitous EGF receptor system, drive E-cadherin downregulation and epithelial dedifferentiation in themselves [24
]. Lastly, the E-cadherin-based cell connection can control global cell signaling, as the catenins that anchor these plaques possess location-dependent signaling properties [14
] (). At one, albeit simplistic level, E-cadherin-based plaques can be viewed as sequestering β-, γ- and p120-catenins for an epithelial signaling mode and preventing their ‘transformative’ effects on the cell transcriptome. The extent of the global control on cell phenotype exerted by E-cadherin expression can be seen by its designation as a tumor suppressor; forced re-expression of E-cadherin in negative carcinoma cells can revert the neoplastic phenotype [38
]. For these reasons, E-cadherin expression on the cell surface has emerged as a molecular hallmark of the carcinoma EMT, and will be the focus on this minireview.
Fig. 2 E-cadherin sequesters catenins and controls their signaling in addition to forming cell–cell adhesions. (a) E-cadherin sequesters β-and p120-catenins on its intracellular catenin binding domains. In an untransformed cell, p120 is thought (more ...)