Urokinase induces receptor mediated brain tumor cell migration and invasion

• Published in: Journal of neuro-oncology 1998-12, Vol.40 (3), p.215-226
• Main Authors: MACDONALD, T. J, DECLERCK, Y. A, LAUG, W. E
• Format: Article
• Language: English
• Subjects: Astrocytoma; Biological and medical sciences; Brain cancer; Brain Neoplasms - metabolism; Brain Neoplasms - pathology; Brain Neoplasms - physiopathology; Brain tumors; Cell adhesion & migration; Cell migration; Cell Movement - drug effects; Cell Movement - physiology; Cell surface; Collagen; Drug Combinations; Extracellular matrix; Extracellular Matrix - metabolism; Humans; Laminin; Medical sciences; Neoplasm Invasiveness - physiopathology; Neurology; Phosphatidylinositol; Phospholipase C; Proteoglycans; Proteolysis; Receptors, Cell Surface - physiology; Receptors, Urokinase Plasminogen Activator; Substantia alba; Tumor cell lines; Tumor cells; Tumor Cells, Cultured; Tumors of the nervous system. Phacomatoses; U-Plasminogen activator; Urokinase-Type Plasminogen Activator - pharmacology
• ISSN: 0167-594X; 1573-7373
• DOI: 10.1023/A:1006150506789

The plasminogen activation (PA) system plays an important role in tumor invasion by initiating pericellular proteolysis of the extracellular matrix (ECM) and inducing cell migration. Malignant brain tumors overexpress PA members and characteristically invade by migrating on ECM-producing white matter tracts and blood vessel walls. To determine whether urokinase-type plasminogen activator (uPA) and its receptor (uPAR) directly modulate the migration of brain tumor cells, we examined six human brain tumor cell lines, 2 astrocytomas (SW1088, SW1783), 2 medullobastomas (Daoy, D341Med), and 2 glioblastomas (U87MG, U118MG), for their surface uPAR expression, endogenous PA activity, and functional proteolytic activity by an ECM-degradation assay. Migration on Transwell membranes and invasion of Matrigel was then tested by pre-incubating the cells with increasing concentrations of either uPA, the proteolytically inactive amino-terminal fragment (ATF) of uPA, or the uPAR cleaving enzyme, phosphatidylinositol-specific phospholipase C (PI-PLC). All of the cell lines, except D341Med, express surface uPAR protein and uPA activity. High levels of uPAR and uPA activity correlated with cellular degradation of ECM, cell migration, and Matrigel invasion. Cell migration and invasion were enhanced by uPA or ATF in a dose dependent manner, while PI-PLC treatment abolished the uPA effect and inhibited migration and invasion. We conclude that ligation of uPAR by uPA directly induces brain tumor cell migration, independent of uPA-mediated proteolysis; and in concert with ECM degradation, markedly enhances invasion. Conversely, removing membrane bound uPAR from the surface of the cells studied inhibited their ability to migrate and invade even in the presence of proteolytically active uPA.