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

Abstract

Various proteases and their inhibitors have been shown to be important in tumor invasion. Angiogenesis is further a prerequisite for the growth and progression of solid tumors. Since these systems are functionally linked, in situ hybridization and in situ zymography were used to investigate the spatial and temporal expression of factors representative of the plasmin/plasminogen system and of an angiogenic factor in the BT4C glioma model. This tumor is invasive with a high grade of neovascularization. Tissue-type plasminogen activator urokinase-type plasminogen activator and plasminogen activator 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 mm3) while later in the time course the expression was found predominantly in the invasive tumor border of the tumor. The in situ zymography demonstrated that the plasminogen activators were 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, the ventricular ependyma, meninges, 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 brain tissue. Our finding may suggest a functional co-operation of tissue-type 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 treatment modalities aimed at blocking the migrating capacity and growth of glial tumors.

Genetic and Plasma Markers of Venous Thromboembolism in Patients with High Grade Glioma

“…All these molecules are involved in the coagulation cascade; although D-dimer is a marker of fibrinolytic activity, all of the other molecules are able to modulate the coagulation process, potentially leading to or revealing a prothrombotic status. Increased levels of VEGF, PAI-1, and tPA could be caused by the production and release of these molecules by the tumor cells (20). In fact, we found these molecules at high levels even in patients carrying a genotype associated with a low-producing phenotype; the presence of the tumor could overcome the genetic background.…”

“…In patients with glioma, the molecules that we investigated could act in concert and interact modifying the coagulation pathways. Glioma cells express VEGF, tPA, and PAI-1 during the tumor growth (20). The increase of VEGF, which in glioblastoma multiforme is sustained also by amplification of epidermal growth factor receptor (38), induces tPA and thus maturation of plasminogen into plasmin (39); in parallel, the inhibitor of tPA (PAI-1) is induced in concert with tPA (21); up-regulation of PAI-1 leads to a prothrombotic status by inhibition of plasminogen activation and, consequently, by reduction of fibrinolytic activity.…”

“…Tumor cells produce tissue factor, which initiates the coagulation cascade. Tumor and tumor-associated endothelial cells are able to produce and release the following factors that influence the activation of coagulation cascade: vascular endothelial growth factor (VEGF), PAI-1, and tPA (20,21 To identify risk factors predisposing patients with highgrade glioma to DVT/PE, we analyzed, by case control study, the genetic polymorphisms of F2, F5, MTHFR, VEGF, PAI-1, and PLAT (the gene coding for tPA) and the plasma levels of D-dimer, lp (a), homocysteine, VEGF, PAI-1, and tPA in patients and in healthy controls. We then correlated genotypes with phenotypes (plasma levels) in both patients and healthy controls, as follows: MTHFR genotypes with homocysteine plasma levels and VEGF, PAI-1, and PLAT genotypes with plasma levels of molecules coded by these genes.…”

Coagulation, Fibrinolysis and Angiogenesis: New Insights from Knockout Mice

“…The clinical observations demonstrate that tPA expression is increased in malignant glioma cells during tumor growth [48]; in proliferative diabetic retinopathy vitreous concentration of tPA is correlated with VEGF level [49], and expression of tPA is increased in atherosclerotic lesions [50]. Experimental data, however, are less definitive.…”

Contrasting roles of plasminogen deficiency in different rheumatoid arthritis models

“…The main function of the PA system is fibrinolysis, which is important for the maintenance of the hemostatic balance (16). However, by acting in concert with other proteinases, the PA system has also been proposed to play a role in the remodeling and degradation of the ECM during many physiologic and pathologic processes, including ovulation (17), skin wound healing (18), tumor invasion (19,20), and inflammatory cell infiltration, fibrin deposition, and joint destruction associated with RA (21). However, despite the rapid progress in our understanding of the involvement of the PA system in RA, the molecular mechanisms by which the PA system participates in the pathogenesis of RA are still poorly understood.…”