Mechanisms of metastasis.

The complex process of tumour cell metastasis requires a number of prerequisites. Following malignant transformation with concomitant cell cycle dysregulation, a metastatic phenotype is dependent on an altered behaviour at various cellular levels. On the one hand, this includes differences in the expression of certain adhesion molecules. Typically, a reduced expression of adhesion molecules (such as cadherins), which are responsible for cell-to-cell interactions, is observed. Simultaneously, a distinct pattern of integrin-mediated, cell-to-matrix interactions are found. These changes result in an increased migratory ability of the cells, which further depends on the controlled degradation of extracellular matrix components by proteases. In particular, the matrix metalloproteinases and the serine proteases are noteworthy in this context. Regulation of protease activity involves interactions of tumour cells with components of the extracellular matrix. Finally, interactions between tumour cells and cells of the surrounding connective tissue mediated by cytokines and growth factors are important, especially in the process of angiogenesis. Only those tumour cells which fulfil all the requirements mentioned above are able to leave the site of the primary tumour, to migrate towards the blood and lymphatic vessels, to enter the circulation and, finally, to cause distant organ metastasis.