Molecular aspects of cancer metastasis: extracellular regulation of the E-cadherin/catenin complex.

Cancer is a disease of growth and differentiation. The respective activation or inactivation of oncogenes and tumor-suppressor genes transforms a normal tissue into a benign, i.e. noninvasive tumor. Invasion-promoter and invasion-suppressor genes are related to differentiation more than to growth regulation. Their respective activation or inactivation transforms a benign tumor into an invasive, i.e. malignant, one (Mareel et aI., 1993). Invasive tumors are malignant because they escape therapeutic control through local extension or formation of distant metastases. We consider cancer invasion within the frame of a microecosystem that functions through the molecular crosstalk between cancer cells and host cells. Such crosstalks establish invasion-suppressor and invasion-promoter complexes, implicated in cell-cell and cell-substrate adhesion, migration and proteolysis. It is crucial that the elements of such complexes are produced by both the cancer cells and the host cells. The epithelial cell-cell adhesion molecule E-cadherin forms a signal transducing complex with the catenins, with other cytoplasmic proteins as well as with transmembrane receptors (Figure 1). This complex may act as an invasionsuppressor as evidenced by observations on experimental and clinical cancers (Bracke et aI., 1996). The complex can be regulal5d at multiple levels through its different elements: mutations in cadherin or catenin genes, mRNA stability, phosphorylation of B-catenin, intracellular and extracellular associations with other proteins (Takeichi et aI., 1995).