The cadherin-catenin adhesion system in signaling and cancer.

The adhesion of cells to their neighbors determines cellular and tissue morphogenesis and regulates major cellular processes including motility, growth, differentiation, and survival. Cell-cell adherens junctions (AJs), the most common (indeed, essentially ubiquitous) type of intercellular adhesions, are important for maintaining tissue architecture and cell polarity and can limit cell movement and proliferation. AJs assemble via homophilic interactions between the extracellular domains of calcium-dependent cadherin receptors on the surface of neighboring cells. The cytoplasmic domains of cadherins bind to the submembranal plaque proteins β-catenin or plakoglobin (γ-catenin), which are linked to the actin cytoskeleton via α-catenin (Figure 1; refs. 1, 2). The transmembrane assembly of cadherin receptors with the cytoskeleton is necessary for the stabilization of cell-cell adhesions and normal cell physiology. Malignant transformation is often characterized by major changes in the organization of the cytoskeleton, decreased adhesion, and aberrant adhesion-mediated signaling. Disruption of normal cell-cell adhesion in transformed cells may contribute to tumor cells’ enhanced migration and proliferation, leading to invasion and metastasis. This disruption can be achieved by downregulating the expression of cadherin or catenin family members or by activation of signaling pathways that prevent the assembly of AJs. The importance of the major epithelial cell cadherin, E-cadherin (E-cad, the product of the CDH1 gene), in the maintenance of normal cell architecture and behavior is underscored by the observation that hereditary predisposition to gastric cancer results from germline mutations in CDH1. Loss of E-cad expression eliminates AJ formation and is associated with the transition from adenoma to carcinoma and acquisition of metastatic capacity (3). Reestablishment of AJs in cancer cells by restoration of cadherin expression (4) exerts tumor-suppressive effects, including decreased proliferation and motility. In this Perspective, we discuss the molecular mechanisms underlying the role of the cadherin-catenin system in the regulation of cell proliferation, invasion, and intracellular signaling during cancer progression. Downregulation of AJ assembly by mutations, hypermethylation, and transcriptional repression of E-cad expression Mutations in CDH1 that compromise the adhesive function of E-cad have been observed in human gastric carcinoma cell lines, lobular breast cancer, and familial gastric cancer (5). Certain tumors, for example invasive lobular carcinoma of the breast, and tumor cell lines that display mutations in one allele of CDH1 also acquire a deletion in the other allele, consistent with a two-hit mechanism for the loss of E-cad and suggesting that CDH1 behaves as a classical tumor suppressor gene. While acquisition of loss-of-function mutations and the subsequent loss of heterozygosity are important mechanisms for silencing E-cad expression in tumor cells, progression to the metastatic phenotype can also involve a reversible downregulation of E-cad expression at the transcriptional level, sometimes achieved by methylation of the CDH1 promoter. DNA methylation often causes downregulation of tumor suppressor genes in cancer cells by changing chromatin structure, thereby making the DNA inaccessible for transcription factors and RNA polymerase II (6). Hypermethylation of the CDH1 promoter has been observed in human breast, prostate, and hepatocellular tumors that carry a wild-type CDH1 gene. This methylation is reversible and can vary according to changes in the tumor microenvironment. For example, Graff et al. (7) found that when primary cultures of human breast carcinoma cells displaying a methylated CDH1 promoter were cultured as spheroids, which requires homotypic cell-cell adhesion, promoter methylation decreased, allowing expression of E-cad. In some cases, for example in patients with hereditary diffuse gastric cancers that carry germline mutations in one allele of the CDH1 gene, the remaining allele is inactivated by DNA methylation (8). Finally, inhibition of DNA methylation can suppress the initiation of tumor development in a mouse model system for colorectal cancer, suggesting that methylation provides an attractive target for anticancer therapy. Transcriptional silencing of CDH1 may also result from aberrant expression of transcription factors that The cadherin-catenin adhesion system in signaling and cancer