Prognostic significance of proteolytic enzymes in human brain tumors

Abstract

Proteases and their inhibitors have been shown to play roles in tumor invasion and metastasis in a number of experimental models. Recently, relative increases in the amounts of urokinase type plasminogen activator (uPA) and plasminogen activator inhibitor-1 (PAI-1) in tumor samples have been correlated with poorer, pathological grade, shorter disease-free interval, and shorter survival. To date, all studies investigating the prognostic significance of proteases and their inhibitors have been limited to extracranial cancer. In this article, we review the literature and present our data on the prognostic significance of proteases in human brain tumors. High levels of uPA were seen in malignant glioma and metastatic tumors (n = 82), whereas normal levels of uPA were found in low-grade gliomas. Analysis with magnetic resonance imaging (MRI) demonstrated a significant correlation between high levels of uPA and necrosis and edema (n = 50; P < 0.05). Similarly, patients with high levels of uPA had shorter survival than did patients with low levels of uPA. Tissue-type plasminogen activator (tPA), which was virtually absent in glioblastoma multiforme (GBM), colon lung, and breast metastasis, was found in normal quantities in anaplastic astrocytoma (AA), low-grade glioma (LGG), and meningioma. Melanoma had significantly more tPA activity than normal brain did. A reverse correlation was found between tPA and MRI findings of necrosis, enhancement, and edema. Similarly, patients with no detectable tPA activity had shorter survival than did patients with detectable tPA activity. We conclude that high levels of uPA and absent tPA activity correlate with histologically malignant brain tumors, aggressive characteristics, and shorter survival.

Production and post-surgical modification of VEGF, tPA and PAI-1 in patients with glioma

“…Cell lines represent a good experimental tool to study tumor cells, but the profound genetic modifications of cell lines may render them heterogeneous and not representative of the in vivo conditions: gene expression in these cells could be altered by their permanent in vitro life. Contrasting literature data, concerning the presence and the localization of VEGF, tPA and PAI-1 in tumor specimens, [15][16][17][18][19][20][21][22][23][24] prompted us to further define the capacity of glioma cells to produce and also to secrete VEGF, tPA and PAI-1. These are secreted proteins and thus their localization in a cell type could be due to receptor capture.…”

Transformation of Madin-Darby canine kidney (MDCK) epithelial cells by Epstein-Barr virus latent membrane protein 1 (LMP1) induces expression of Ets1 and invasive growth

“…Since the uPA gene promoter contains a binding site for Ets, and Ets1 is a major transcription factor regulating uPA gene expression, enhanced expression of uPA gene in transformed cells is largely attributed to overexpression of Ets-1 (Watabe et al, 1998;D'Orazio et al, 1997;Stacey et al, 1995). uPA is a serine protease and contributes to tumor invasion by degrading extracellular matrix components, and thus its expression is widely correlated with tumor metastasis (Testa and Quigley, 1990;Bindal et al, 1994). PAI-1 is an inhibitor of uPA, but paradoxically expression of PAI-1 also correlates with tumor metastasis (Sappino et al, 1991;GrondahoHansen et al, 1993;Foekens et al, 1994).…”

The role of integrins in the malignant phenotype of gliomas

“…In this regard, the overexpression of the protease inhibitor, PAI-1, has paradoxically been correlated with increased tumorigenicity of various peripheral tumors (60-66) as well as gliomas (67)(68)(69)(70). As such, the classic anti-invasive role ascribed to protease inhibitors may be somewhat restrictive, as protease inhibitors, such as PAI-1, may also contribute to the migratory/invasive phenotype.…”