The role of the E-cadherin/catenin complex in gastrointestinal cancer

Cancer is a genetic disease. The unstable genome of cancer cells causes tum our progression through multiple alterations in suppressor and promoter gen es, leading to loss of homeostatic and gain of oncogenic functions. Invasio n is the critical step in the acquisition of malignancy. It implicates a co ntinuous molecular conversation of the cancer cells with other cells and wi th the extracellular matrix in which adhesion molecules are crucial. One of these, E-cadherin, is discussed in the present review. E-cadherin is a tra nsmembrane glycoprotein that forms a complex with cytoplasmic proteins, ter med catenins because they link E-cadherin to the actin cytoskeleton. E-cadh erin/catenin-mediated intercellular adhesion and communication is mainly ho mophylic homotypic, There is compelling evidence from experiments in vitro as well as in vivo to accept that the E-cadherin/ catenin complex acts as a n invasion suppressor. The mechanism of this action is not only through cel l-cell adhesion but also through transduction of signals to the cell's moti lity system. In the replication error positive human colon cancer cell line HCT-8, the alpha E-catenin gene CTNNA1 is an invasion suppressor gene. Her e, the transition from the non-invasive to the invasive state was prevented by introduction into the unstable non-invasive cells of either an extra CT NNA1 or a wild type hMSH6 mismatch repair gene, beta-catenin also participa tes at a complex which comprises the adenomatous polyposis cancer protein A PC, In colorectal cancer, mutation of either APC or beta-catenin is oncogen ic. Downregulation of the E-cadherin/catenin complex may occur in several w ays amongst which are gene mutations, methylation of 5'CpG dinucleotides wi thin the promotor region of E-cadherin, tyrosine phosphorylation of beta-ca tenin, cell surface expression of proteoglycans sterically hindering E-cadh erin and proteolytic release of fragments from the extracellular part of E- cadherin. Upregulation of the E-cadherin/catenin complex has been realized with a series of agents, some of which can be used therapeutically. In most human gastrointestinal cancers the E-cadherin/catenin or related co mplexes are disturbed and this underscores their pivotal role in the progre ssion of these tumours. Mutations of the E-cadherin gene, including germlin e mutations, occur in diffuse gastric carcinoma, CpG methylation around the promotor region of E-cadherin in hepatocellular carcinomas and mutations o f the APC tumour suppressor gene or in the beta-catenin oncogene in most co lorectal cancers. The literature agrees about the disturbance of immunohist ochemical patterns of E-cadherin and catenin expression in gastrointestinal cancers. Conflicting opinions do, however, exist about the prognostic valu e of such immunohistochemical aberrations. We doubt that immunohistochemist ry of E-cadherin or catenins add prognostic value to the already used histo logical grading systems. In our opinion the major benefit from understandin g of the E-cadherin/catenin-mediated pathways of invasion will be the devel opment of new anti-invasive treatment strategies.