Suppression of Glioblastoma Angiogenicity and Tumorigenicity by Inhibition of Endogenous Expression of Vascular Endothelial Growth Factor

• Published in: Proceedings of the National Academy of Sciences - PNAS 1996-08, Vol.93 (16), p.8502-8507
• Main Authors: Cheng, Shi-Yuan, H.-J. Su Huang, Nagane, Motoo, Ji, Xiang-Dong, Wang, Degui, Charles C.-Y. Shih, Arap, Wadih, Huang, Chun-Ming, Cavenee, Webster K.
• Format: Article
• Language: English
• Subjects: Angiogenesis; Animals; Base Sequence; Blood vessels; Brain; Cancer; Cell growth; Cell lines; Cell Movement; Cellular immunity; DNA Primers - chemistry; Endothelial cells; Endothelial Growth Factors - metabolism; Gene Expression Regulation, Neoplastic; Glioblastoma; Glioblastoma - immunology; Glioblastoma - pathology; Humans; Lymphokines - metabolism; Medical research; Messenger RNA; Mice; Mice, Nude; Molecular Sequence Data; Neoplasm Transplantation; Neovascularization, Pathologic; RNA, Antisense; RNA, Messenger - genetics; Secretion; Transplantation, Heterologous; Tumor cell line; Tumor Cells, Cultured; Tumors; Vascular Endothelial Growth Factor A; Vascular Endothelial Growth Factors
• ISSN: 0027-8424; 1091-6490
• DOI: 10.1073/pnas.93.16.8502

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 of the 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 of in 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.