Expression of the proteolytic factors, tPA and uPA, PAI-1 and VEGF during malignant glioma progression

Various proteases and their inhibitors have been shown to be important in t umor invasion. Angiogenesis is further a prerequisite for the growth and pr ogression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spat ial and temporal expression of factors representative of the plasmin/plasmi nogen system and of an angiogenic factor in the BT4C glioma model. This tum or is invasive with a high grade of neovascularization. Tissue-type plasmin ogen activator urokinase-type plasminogen activator and plasminogen activat or inhibitor-1 mRNA were expressed in glioma cells during the entire tumor growth. Early in the tumor development the expression was found throughout the small tumor (approximately 10 mm(3)) while later in the time course the expression was found predominantly in the invasive tumor border of the tum or. The iir situ zymography demonstrated that the plasminogen activators we re translated into functional proteins. Vascular endothelial growth factor mRNA was expressed following a similar spatial and temporal pattern with an early expression in the entire small tumor while later, in larger tumors, it was exclusively expressed in the invasive tumor edge. In normal brain, t he ventricular ependyma, meningies, as well as scattered neurons expressed tissue-type plasminogen activator mRNA. Vascular endothelial growth factor mRNA was observed in the choroid plexus, and in scattered cells in normal b rain tissue. Our finding may suggest a functional co-operation of tissue-ty pe plasminogen activator, urokinase-type plasminogen activator, plasminogen activator inhibitor-1 and vascular endothelial growth factor during glioma progression. This model could be of value when evaluating different treatm ent modalities aimed at blocking the migrating capacity and growth of glial tumors. (C) 1999 Published by Elsevier Science Ltd. All rights reserved.