Carcinoma Invasion and Metastasis: A Role for Epithelial-Mesenchymal Transition?

Abstract

Carcinogenesis involves the accretion of unprogrammed genetic and epigenetic changes, which lead to dysregulation of the normal control of cell number. But a key clinical turning point in carcinoma progression is the establishment by emigrant cells of secondary growth sites (i.e., metastasis). The metastatic “cascade” comprises numerous steps, including escape from the primary tumor site, penetration of local stroma, entry of local vascular or lymphatic vessels (intravasation), aggregation with platelets, interaction with and adhesion to distant endothelia, extravasation, recolonization, and expansion (1), all the time avoiding effective immune clearance and being able to survive in these multiple contexts.The epithelial-mesenchymal transition (EMT) is a phenotype switch clearly recognized for many decades in developmental biology as instrumental in effecting rapid morphogenetic changes in Metazoan embryos (2). The EMT, which is marked by complex and coordinated set of molecular changes leading to cell behavioral changes, is a portmanteau concept that can be applied to the metastatic behavior of carcinoma cells at a number of junctures.To appreciate this, it is important first to have a clear idea of what the terms epithelium and mesenchyme mean in general, and what they do not mean. Second, it is important to understand what specific features or functions are always, sometimes, or never associated with these states. This, of course, extends to molecules and genes whose expression can be used as markers signifying the epithelial or mesenchymal state of the cells in question.An epithelium is a collection of cells forming a relatively thin sheet or layer due to the constituent cells being mutually and extensively adherent laterally by cell-to-cell junctions. The layer is polarized, the two sides showing nonidentical properties so that the sides can be defined as, say, inside or outside, or more precisely, apical and basal. This is reflected in the individual cells that all show an identical apicobasal polarity, an extension of which is the presence on the basal surface of a complete or nearly complete layer of specialized extracellular matrix (ECM), the basal lamina.Cell-to-cell adhesion molecules typically involve (but are not restricted to) members of the cadherin axis, which are distributed widely but with a particular aggregation complex usually as a circumferential belt at the lateral border. The principal ECM adhesion sites (involving integrin complexes) are strongly biased to the basal face, mediating adhesion to basal lamina molecules, such as laminin. The actin cytoskeleton is also strongly apicobasally polarized, in part mirroring the circumferential cell-to-cell adhesion complexes. Intermediate filaments typically include cytokeratin types.This arrangement gives an overall impression of strong regimentation of the cells, and it is often assumed that the cells in an intact epithelium are virtually immobile. Despite this, there is a repertoire of epithelial plasticity. In some circumstances, cells in an epithelial layer can alter shape, such as change from flat to columnar, or pinch in at one end and expand at the other. However, these tend to occur in cell groups rather than individually, and their effect is to produce the compaction/expansion and foldings that are the mainstay of morphogenetic movements such as neurulation: In these cases, the epithelial integrity is maintained and there seems to be broad preservation of cellular neighbors, at least in the short term. However, movement relative to adjacent landmarks can occur. This often occurs with the cells remaining largely associated with their original neighbors, as in epibolic spreading (i.e., the movement is relative to features outside the particular epithelium). However, real movement in the sense that cells in an epithelium change their nearest epithelial neighbors without disrupting the integrity of the layer do occur (see ref. 3).Mesenchyme cells form a relatively diffuse tissue network: There is no complete cellular layer, and the cells typically have only points on their surface engaged in adhesion to their neighbors. These adhesions may also involve cadherin associations (i.e., with molecular family similarity to those of epithelial cells). Adhesion sites to ECM (also involving integrins) are widely distributed at points all around the cells, as is the ECM that is a meshwork structurally unlike the basal lamina and that typically involves interstitial collagens and fibronectin. The actin cytoskeleton is not apicobasally polarized and does not show circumferential organization. Instead, the actin may form a cortical network and perhaps trans-cytoplasmic actin bundles; these may have a provisional polarity termed “front-back” by Hay (4), and this polarity may be approximately aligned between neighboring cells, especially when the mesenchymal cell population is moving in a concerted manner. The intermediate filament make-up typically in