The Misregulation of Cell Adhesion Components during Tumorigenesis: Overview and Commentary

Cell adhesion complexes facilitate attachment between cells or the binding of cells to the extracellular matrix. The regulation of cell adhesion is an important step in embryonic development and contributes to tissue homeostasis allowing processes such as differentiation and cell migration. Many mechanisms of cancer progression are reminiscent of embryonic development, for example, epithelial-mesenchymal transition, and involve the disruption of cell adhesion and expression changes in components of cell adhesion structures. Tight junctions, adherens junctions, desmosomes, and focal adhesion besides their roles in cell-cell or cell-matrix interaction also possess cell signaling function. Perturbations of such signaling pathways can lead to cancer. This article gives an overview of the common structures of cell adhesion and summarizes the impact of their loss on cancer development and progression with articles highlighted from the present issue

CD44 Upregulation in E-Cadherin-Negative Esophageal Cancers Results in Cell Invasion

E-cadherin is frequently lost during epithelial-mesenchymal transition and the progression of epithelial tumorigenesis. We found a marker of epithelial-mesenchymal transition, CD44, upregulated in response to functional loss of E-cadherin in esophageal cell lines and cancer. Loss of E-cadherin expression correlates with increased expression of CD44 standard isoform. Using an organotypic reconstruct model, we show increased CD44 expression in areas of cell invasion is associated with MMP-9 at the leading edge. Moreover, Activin A increases cell invasion through CD44 upregulation after E-cadherin loss. Taken together, our results provide functional evidence of CD44 upregulation in esophageal cancer invasion

Central Role of the Plakoglobin-Binding Domain for Desmoglein 3 Incorporation into Desmosomes

The carboxy-termini of classical cadherins and desmocollins have been shown to play an important role in initiating desmosome assembly. In this study we wanted to determine whether the carboxy-terminal cytoplasmic domains of desmoglein 3 are important for targeting it to the desmosome. By generating stably transfected A431 cell lines with chimeric constructs encoding for the extracellular domain of E-cadherin and the transmembrane and intracellular region of human desmoglein 3, we could show that the cytoplasmic tail is sufficient to target the protein to the desmosome. By generating truncations of the carboxy-terminus we investigated the importance of the various intracellular subdomains. Whereas the construct encoding the intracellular cadherin-type segment domain still allowed its incorporation into the desmosome, further truncation, leaving only the intracellular anchor domain, did not. Deletion of the 87 amino acid long plakoglobin-binding site within the intracellular cadherin-type segment domain demonstrated that this region is essential for targeting desmoglein 3 to the desmosome. Absent the plakoglobin-binding site the chimeric molecule colocalizes with β-catenin rather than desmoplakin. We conclude that binding of plakoglobin to desmoglein 3 is an important step in desmosome assembly and leads to the incorporation of desmoglein 3 into the desmosome