Plasminogen activator inhibitor-1 increases the expression of VEGF in human glioma cells

The level of plasminogen activator inhibitor-1 (PAI-1) in tumor tissue has been shown to be an independent negative prognostic factor in different cancers. There are several proposed reasons for this, among these, the influence of PAI-1 on tumor neovascularization and cell migration. We report that PAI-1 stimulates expression and release of vascular endothelial growth factor (VEGF) in the human glioma cell line D54Mg, and thereby stimulates the proliferation of human umbilical vein endothelial cells (HUVEC) in vitro. To search for possible molecular effects of PAI-1 on malignant cells, cDNA array hybridization analysis of D54Mg glioma cells transfected with an adenoviral PAI-1 expression vector was performed. This revealed that the VEGF response was accompanied with the simultaneous upregulation of GADD153, Rho GTPase activating protein 4 (p115), Collagen type VI alpha 1 and cell division cycle 42 (CDC42) transcripts. Exogenous treatment of D54Mg cells with a constitutively active recombinant PAI-1 protein confirmed an upregulation of VEGF expression in a time- and dose-dependent manner, and supernatants from such cultures stimulated the proliferation of human umbilical vein endothelial cells in vitro. In 44 human glioma biopsies, patients, the protein levels of PAI-1 correlated strongly with the levels of VEGF in the tumor tissues. Whereas VEGF expression correlated inversely with survival, there was no statistically significant prediction of survival by PAI-1 in this group of patients. These clinical data support and strengthen the hypothesis that PAI-1 is one of the factors regulating and inducing the VEGF expression in human gliomas. The induction of VEGF expression and thus endothelial cell proliferation may represent an as yet undiscovered mechanism whereby PAI-1 contributes to tumor neoangiogenesis.