Suppression of glioblastoma angiogenicity and tumorigenicity by inhibition of endogenous expression of vascular endothelial growth factor.

Abstract

The development of new capillary networks from the normal microvasculature of the host appears to be required for growth of solid tumors. Tumor cells influence this process by producing both inhibitors and positive effectors of angiogenesis. Among the latter, the vascular endothelial growth factor (VEGF) has assumed prime candidacy as a major positive physiological effector. Here, we have directly tested this hypothesis in the brain tumor, glioblastoma multiforme, one ofthe most highly vascularized human cancers. We introduced an antisense VEGF expression construct into glioblastoma cells and found that (i) VEGF mRNA and protein levels were markedly reduced, (ii) the modified cells did not secrete sufficient factors so as to be chemoattractive for primary human microvascular endothelial cells, (iii) the modified cells were not able to sustain tumor growth in immunodeficient animals, and (iv) the density ofin vivo blood vessel formation was reduced in direct relation to the reduction of VEGF secretion and tumor formation. Moreover, revertant cells that recovered the ability to secrete VEGF regained each of these tumorigenic properties. These results suggest that VEGF plays a major angiogenic role in glioblastoma.

Methylation and silencing of the Thrombospondin-1 promoter in human cancer

“…Thus, it is quite possible that inactivation of THBS1 involves multiple mechanisms in GBM, and it would be interesting to determine whether THBS1 methylation correlates with P53 mutations (or lack thereof) or chromosome 10 allelic status in GBM. In addition, it would be interesting to compare THBS1 methylation with the expression of other angiogenic factors in GBM such as VEGF (Cheng et al, 1996;Plate et al, 1992) and/or a P53 regulated angiogenesis inhibitor that appears to be distinct from THBS1 (Van Meir et al, 1994).…”

Oncogenes and tumor angiogenesis: the HPV-16 E6 oncoprotein activates the vascular endothelial growth factor (VEGF) gene promoter in a p53 independent manner

“…On the other hand, even a twofold change in the activity of the VEGF promoter may in itself have biological relevance. For example, 2 ± 3-fold reductions in VEGF expression in tumor cells have been shown to produce surprisingly profound suppressive e ects on tumor angiogenesis and tumor growth in vivo (Ferrara et al, 1996;Cheng et al, 1996;Okada et al, 1998;. In HPV-16-positive cells where other genetic and epigenetic changes (e.g.…”

Interleukin‐6 induces transcriptional activation of vascular endothelial growth factor (VEGF) in astrocytes in vivo and regulates VEGF promoter activity in glioblastoma cells via direct interaction between STAT3 and Sp1

“…The ability of a VEGF antisense construct to reduce angiogenicity and tumorigenicity of human U87MG GBM cells suggested that VEGF plays a key role in glioma development. 3 In human brain cancers, a close correlation was found between VEGF expression, tumor vascularization and grade of malignancy, 4 with 95% of GBMs staining positive for VEGF. 5 The signals were localized in both perinecrotic and vital tumor areas suggesting that both hypoxia and other stimuli may control the expression of VEGF in gliomas.…”