Levels of vascular endothelial growth factor, hepatocyte growth factor/scatter factor and basic fibroblast growth factor in human gliomas and their relation to angiogenesis

Abstract

Angiogenesis is a possible target in the treatment of human gliomas. To evaluate the role of 3 growth factors, vascular endothelial growth factor (VEGF), hepatocyte growth factor/scatter factor (HGF/SF) and basic fibroblast growth factor (bFGF), in the angiogenic cascade, we determined their levels in extracts of 71 gliomas by enzyme‐linked immunosorbent assay (ELISA). The levels of bFGF were only marginally different between gliomas of World Health Organization (WHO) grade II (low grade) and grades III and IV (high grade). In contrast, the mean concentrations of VEGF were 11‐fold higher in high‐grade tumors and those of HGF/SF 7‐fold, respectively. Both were highly significantly correlated with microvessel density (p < 0.001) as determined by immunostaining for factor VIII‐related antigen. In addition, VEGF and HGF/SF appeared to be independent predictive parameters for glioma microvessel density as determined by multiple regression analysis. We measured the capacity of all 3 factors to induce endothelial tube formation in a collagen gel. In this assay, bFGF was found to be an essential cofactor with which VEGF as well as HGF/SF were able to synergize independently. According to the concentrations of angiogenic factors, extracts from high‐grade tumors were significantly more potent in the tube formation assay than the low‐grade extracts (p = 0.02). Adding neutralizing antibodies to bFGF, VEGF and HGF/SF together with the extracts, tube formation was inhibited by up to 98%, 62% and 54%, respectively. Our findings suggest that bFGF is an essential cofactor for angiogenesis in gliomas, but in itself is insufficient as it is present already in the sparsely vascularized low‐grade tumors. Upon induction of angiogenesis in high‐grade tumors, bFGF may synergize with rising levels of not only VEGF but possibly also with HGF/SF, which appears here to be an independent angiogenic factor. Int. J. Cancer (Pred. Oncol.) 84:10–18, 1999. © 1999 Wiley‐Liss, Inc.

Hypoxia can induce c‐Met expression in glioma cells and enhance SF/HGF‐induced cell migration

“…Discussion c-Met and its ligand SF/HGF are strongly upregulated in malignant gliomas compared with normal brain and also with low grade gliomas. 6,7,33 However, little is known about the mechanisms how this upregulation occurs. Although studies by one group suggested that c-met was amplified in a subset of glioblastomas, 34 this was not confirmed by others.…”

Fibroblast Growth Factor 2 Activation of Stromal Cell Vascular Endothelial Growth Factor Expression and Angiogenesis

“…Multiple tumor types have been defined as expressing potent angiogenic cytokines such as basic fibroblast growth factor (FGF-2), vascular endothelial growth factor (VEGF), interleukin-8 (IL-8), and angiogenin, among others (Abdulrauf et al, 1998;Dosquet et al, 1997;Kumar et al, 1998;Mattern et al, 1997;Mise et al, 1996;Potgens et al, 1995;Schmidt et al, 1999;Volm et al, 1999). Both FGF-2 and VEGF expression has been strongly correlated with vascular density, metastatic potential, and poor survival in human colon, breast, prostate, and melanoma (Abdulrauf et al, 1998;Dosquet et al, 1997;Mattern et al, 1997;Okita et al, 1998;Schmidt et al, 1999;Ueki et al, 1995;Volm et al, 1999;Xerri et al, 1996).…”

“…Both FGF-2 and VEGF expression has been strongly correlated with vascular density, metastatic potential, and poor survival in human colon, breast, prostate, and melanoma (Abdulrauf et al, 1998;Dosquet et al, 1997;Mattern et al, 1997;Okita et al, 1998;Schmidt et al, 1999;Ueki et al, 1995;Volm et al, 1999;Xerri et al, 1996). FGF-2, which is not secreted through vesicular pathways, can be exported from cells with unique extrusion pathways or large amounts can be released on cell death (Florkiewicz et al, 1995(Florkiewicz et al, , 1998Kiefer et al, 1993).…”

Polyproline‐type helical‐structured low‐molecular weight heparin (LMWH)‐taurocholate conjugate as a new angiogenesis inhibitor

“…To trigger this process, tumor cells release a number of angiogenic growth factors such as vascular endothelial growth factor (VEGF), fibroblast growth factor basic (bFGF) and scatter factors. [6][7][8] Many angiogenic proteins, which are potential targets for pharmacological inhibitory strategies, depend on heparan sulfate for their biological functions. 9,10 Heparan sulfate is found on the cell surface and in the extracellular matrix where it plays a central role in growth factor regulation.…”