Molecular aspects of tumor cell invasion and metastasis.

Invasion and metastasis are the greatest obstacles to successful tumor treatment. Although advances have been made in conventional tumor therapies and surgical techniques, most cancer deaths still result from metastatic disease. Our lack of understanding of the molecular mechanisms involved in tumor cell invasion and metastasis has hindered the development of effective antimetastatic therapies; however, recent discoveries in this field are leading to potential therapeutic strategies. The process of metastasis is now believed to begin early in the growth of the primary tumor.'-3 However, the genetic changes that result in uncontrolled proliferation associated with tumorigenesis do not, by themselves, produce the metastatic phenotype. The acquisition of this trait may require additional genetic changes beyond those related to tumor growth. As in growth control, these changes may involve the addition of positive modulators (oncogenes) or the loss of negative effectors (tumor growth suppressors and invasion and metastasis suppressors). The transition from in situ tumor growth to metastatic disease is defined by the ability of the tumor cells of the primary site to invade local tissues and to cross tissue barriers. To initiate the metastatic process, carcinoma cells must first penetrate the epithelial basement membrane and then invade the interstitial stroma. Loss of epithelial basement membranes is a hallmark of invasion. Traversal of basement membranes may require active proteolysis of this dense matrix of type IV collagen, glycoproteins, and proteoglycans. For distant metastases, intravasation requires tumor cell invasion of the subendothelial basement membrane that must also be negotiated during tumor cell extravasation at the secondary site. The development of malignancy is also as-