The cadherin-catenin adhesion system in signaling and cancer

Abstract

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 expressionMutations 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 in...

Differentiation of normal and cancer cells induced by sulfhydryl reduction: biochemical and molecular mechanisms

“…OVCAR3 cells were treated once with 20 mM NAC, and Caco-2 cells were treated once with 10 mM NAC structure in colon carcinoma cells and of the cornified envelope in keratinocytes; (iii) the basal relocation of the nucleus in Caco-2 cells together with the formation of a robust apical vesicular apparatus; (iv) an overall rearrangement of cytoskeleton to fulfill the requirements of newly formed structures; (v) the appearance of several cell-cell and cellsubstratum junctions; and, finally, (vi) the disappearance of the oncogenic b-catenin from the nucleus and its only presence at the cell-cell junctions. Taken together, the relocation of b-catenin at the level of junctions and the increased concentration of E-cadherin represent both markers and inducers of differentiation [22][23][24][25][26] suggesting the establishment of a positive feedback in the differentiation process. The increase in cell-cell and cell-substratum adhesions identifies a more adhesive and less motile phenotype.…”

“…24,25,37 Among other functions related to the proliferation/differentiation transition, the nonreceptor tyrosine kinase c-Src has a pivotal role in b-catenin relocation. 38,39 Robust in vitro evidences bind the modulation of c-Src kinase activity to the redox state of a group of four cysteine residues close to its catalytic site, a key target for a mutually counteracting reversible control operated by oxidizing and reducing agents.…”

Transactivation of MCP‐1/CCL2 by β‐catenin/TCF‐4 in human breast cancer cells

“…[21][22][23] The accumulation of cytoplasmic b-catenin and its translocation to the nucleus has been associated with epithelial cell migration and invasion in various physiological and pathological processes including tumour progression. 21,[23][24][25][26] Several b-catenin/TCF target genes have now been identified. They pertain to various families of proteins including matrix metalloproteases, cytoskeletal proteins or angiogenic cytokines and chemokines (IL-8, MMP-7, MMP-14, CD44, cyclin D1, c-myc, claudin-1, vimentin, MMP26, VEGF.…”

Luteinising hormone-releasing hormone analogue reverses the cell adhesion profile of EGFR overexpressing DU-145 human prostate carcinoma subline

“…Cadherins comprise a family of transmembrane cell surface glycoproteins that mediate calcium (Ca 2 þ )-dependent, homotypic cell -cell interactions through their extracellular domains, and regulate a variety of biological processes during development, morphogenesis, and tumour metastasis (Gumbiner, 1996;Yap et al, 1997;Conacci-Sorrell et al, 2002). Ca 2 þ -dependent cell -cell adhesion usually consists of rapid localisation of surface Ecadherin molecules to the regions of contact, resulting in homotypic binding that fosters the maintenance of normal cellular structure.…”

“…As carcinomas progress to the invasive and metastatic stages, select adhesive epithelial cells usually undergo a mesenchymal-like transition that enables their movement from the primary tumour mass (Comoglio and Boccaccio, 2001;Conacci-Sorrell et al, 2002). During this process in breast, gastric, and pancreatic metastatic carcinomas, E-cadherin expression is frequently downregulated or even undetectable Lowy et al, 2002).…”