The urokinase-type plasminogen activator system in cancer metastasis: A review

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Abstract
The urokinase‐type plasminogen activator (u‐PA) system consists of the serine proteinases plasmin and u‐PA; the serpin inhibitors α2‐anti‐plasmin, PAI‐1 and PAI‐2; and the u‐PA receptor (u‐PAR). Two lines of evidence have strongly suggested an important and apparently causal role for the u‐PA system in cancer metastasis: results from experimental model systems with animal tumor metastasis and the finding that high levels of u‐PA, PAI‐1 and u‐PAR in many tumor types predict poor patient prognosis. We discuss here recent observations related to the molecular and cellular mechanisms underlying this role of the u‐PA system. Many findings suggest that the system does not support tumor metastasis by the unrestricted enzyme activity of u‐PA and plasmin. Rather, pericellular molecular and functional interactions between u‐PA, u‐PAR, PAI‐1, extracellular matrix proteins, integrins, endocytosis receptors and growth factors appear to allow temporal and spatial re‐organizations of the system during cell migration and a selective degradation of extracellular matrix proteins during invasion. Differential expression of components of the system by cancer and non‐cancer cells, regulated by paracrine mechanisms, appear to determine the involvement of the system in cancer cell–directed tissue remodeling. A detailed knowledge of these processes is necessary for utilization of the therapeutic potential of interfering with the action of the system in cancers. Int. J. Cancer 72:1–22, 1997. © 1997 Wiley‐Liss Inc.

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