Molecular aspects of tumor cell invasion and metastasis

sociated with tumor-induced angiogenesis that not only allows for expansion of the primary but also permits easy access to the vascular compartment due to defects in the basement membranes of newly formed This may facilitate hematogenous spread of some tumors. To successfully establish a metastatic colony, circulating tumor cells must survive any immunologic assault, arrest at a distant vascular bed, and subsequently extravasate. Ultimately, the cells must invade and proliferate in the tissue of the secondary site. Growth of the metastatic colony beyond 1 cm3 requires that vascularization of the solid tumor take p l a ~e. ~-~ Metastasis is a multistep process involving numerous tumor cell-host cell and cell-matrix as soda ti on^. '-Interactions with the matrix, especially basement membranes, that characterize the process of invasion include the ability of tumor cells to attach, to proteolyze the matrix components, and then to migrate through the matrix defect (Fig. l). 9None of these functions is unique to tumor cell behavior. Attachment, proteolysis, and migration are steps of trophoblast implantation, mammary gland involution, embryonic morphogenesis, and tissue remodeling. '0, "The difference between normal processes and the pathogenic nature of tumor cell invasion must therefore be one of regulation. Thus, an understanding of the controlling factors in the processes of cellular adhesion, matrix proteolysis, and cell migration should allow identification of new targets for therapeutic disruption of metastasis formation. Tumor Cell Adhesion: Integrin, Laminin Receptor, and Cadherin FunctionAttachment to specific glycoproteins of the extracellular matrix, such as fibronectin, collagen, and laminin, is mediated through tumor cell receptors of the inteand non-integrin variety. 14, 15Integrins are a large class of c@ heterodimeric receptors for adhesion molecules with broad specificity and low binding affinity. ''PI6At least 14 01 and 8 p subunits have been identified, which noncovalently associate to produce at least