Dysfunction of the cell-cell adhesion complex in lethal prostate cancer

Three major families of cell adhesion molecules can be differentiated, the integrins, the Cadherins and the immunoglobulin superfamily. Integrins mediate mainly cellsubstrate adhesion, other integrins are involved in cell-cell adhesion and some have both binding capacities. A wide variety of molecules, which are contained in the immunoglobulin superfamily, participate in cell-cell recognition, cellular immunity, neural development, leukocyte trafficking, signal transduction and other functions. Cadherins, which are the major cell-cell adhesion molecules in a variety of tissues including the glandular epithelium of the prostate, play an important role in tissue compaction, cell differentiation and maintenance of tissue, and are thought to be involved in cell migration and cell regulation [11]. Cadherins are transmembraneous glycoproteins, which interact in a calcium-dependent, homotypic fashion. Common to all Cadherins is the molecular structure of three protein domains, the extracellular amino terminus, the transmembraneous domain and the intracellular carboxy terminus. The Cadherin binding site [10] lies within the extracellular domain and is responsible for selective, calcium dependent Cadherin binding in a homophylic fashion. Besides the critical role in developmental processes, this observation is of special interest in the potential explanation of the mechanism of implantation of metastasis in neoplastic diseases. The different tissue distribution of metastasis of various tumors may be related to the interaction of cell-adhesion molecules, which are present in tumor cells and host tissue cells. Additionally alterations in the expression of cell adhesion molecules may be related to loss of adhesive properties of the tumor cells in the primary neoplastic lesions, resulting in tumor invasiveness and circulating tumor cells. The intracytoplasmic C-terminus of the Cadherin molecules is the most conserved region of the peptide sequence. This domain contains an important binding site for a family of intracellular proteins, the catenins [7]. Three catenins were identified, α-, β-, and γ-catenin. Catenins bind to the Cadherins as shown for the classical Cadherins, and mediate the contact between the cell adhesion molecules and the microfilaments of the cytoskeleton. This interaction was demonstrated previously to be necessary for the functioning of the cell-adhesion complex. Truncation of Cadherins at the carboxy-terminus results in a substantial loss of the adhesive properties [9], which was shown to be reversed by co-transfection of cadherin-catenin fusion proteins [1], demonstrating that association of catenins to Cadherins is a keystep in the function of intact adhesion complexes. In contrast, alterations in catenin molecules can lead to disruption of the cell-cell adhesion, resulting in tumor aggressiveness and invasiveness in neoplastic diseases.