E-cadherin in contact inhibition and cancer

Abstract

E-cadherin is a key component of the adherens junctions that are integral in cell adhesion and maintaining epithelial phenotype of cells. Homophilic E-cadherin binding between cells is important in mediating contact inhibition of proliferation when cells reach confluence. Loss of E-cadherin expression results in loss of contact inhibition and is associated with increased cell motility and advanced stages of cancer. In this review we discuss the role of E-cadherin and its downstream signaling in regulation of contact inhibition and the development and progression of cancer.

Figure 1. E-cadherin mediates contact inhibition of proliferation

In culture, normal cells stop proliferating once they reach confluence upon homophillic E-cadherin binding, and subsequent formation of tight junctions. This results in mediating growth inhibitory signals and contact inhibition of proliferation (CIP). When cells either lose E-cadherin or E-cadherin is mutated, they continue proliferating, grow on top of each other and lose CIP.

Figure 2. Regulation of the Hippo signaling pathway

The Hippo signaling pathway is activated upon E-cadherin mediated cell adhesion, formation of tight junctions and apical polarity complexes while mechanical stress inhibits the pathway. Activation leads to growth inhibition upon cell contact. When activated, the pathway components form a complex at junctions where Mst phosphorylates Lats which then phosphorylates YAP. Phosphorylated YAP is retained in the cytoplasm, and cell growth is inhibited. When Hippo signaling is inactivated, the complex dissociates, preventing subsequent phosphorylation of Lats and YAP. YAP then translocates to the nucleus, binds TEADs and activates target gene expression and cell proliferation.

Figure 3. E-cadherin in cell migration and establishment of metastasis

A primary tumor can generate either single cells or clusters that spread through the bloodstream to form distant metastases. Loss of, or mutations in E-cadherin facilitate dispersion of tumor cells through altered cell adhesion or EMT. However some dispersed cells retain E-cadherin expression particularly in clusters that are hypothesized to enhance survival in the blood and at metastatic sites. Alternatively, tumor cells might re-express E-cadherin at distant sites and lead to establishment of metastases. Thus regulation of E-cadherin at multiple levels can contribute to the development of metastatic tumors as discussed in more detail in the text.

Figure 4. E-cadherin mediated regulation of the Wnt signaling pathway

In the absence of Wnt, β-catenin is regulated by the combination of binding to the cytoplasmic domain of E-cadherin at the adherens junctions or degraded in the cytoplasm by the destruction complex (adenomatosis polyposis coli (APC), Axin, GSK3β). When Wnt signaling is activated, the destruction complex is inhibited, β-catenin is stabilized in the cytoplasm and translocates to the nucleus for activation of target gene expression. Loss of E-cadherin expression can thus free up β-catenin bound at the cell junctions which in the absence of Wnt signaling would likely be degraded by the destruction complex, or in the presence of Wnt enhance nuclear accumulation and target gene expression.