The cadherin-catenin adhesion system in signaling and cancer

Abstract

Invasive growth The adhesion of cells to their neighbors determines cel-lular and tissue morphogenesis and regulates major cel-lular processes including motility, growth, differentia-tion, 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 homo-philic interactions between the extracellular domains of calcium-dependent cadherin receptors on the surface of neighboring cells. The cytoplasmic domains of cad-herins 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 inva-sion 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 nor-mal cell architecture and behavior is underscored by the observation that hereditary predisposition to gas-tric cancer results from germline mutations in CDH1. Loss of E-cad expression eliminates AJ formation and is associated with the transition from adenoma to car-cinoma and acquisition of metastatic capacity (3). Re-establishment 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 mecha-nisms underlying the role of the cadherin-catenin sys-tem 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 suggest-ing that CDH1 behaves as a classical tumor suppressor gene. While acquisition of loss-of-function mutations and the subsequent loss of heterozygosity are impor-tant 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 inacces-sible 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 methyla-tion 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 promot-er were cultured as spheroids, which requires homotyp-ic 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 methyla-tion provides an attractive target for anticancer therapy.