SUPPRESSION OF GLIOBLASTOMA ANGIOGENICITY AND TUMORIGENICITY BY INHIBITION OF ENDOGENOUS EXPRESSION OF VASCULAR ENDOTHELIAL GROWTH-FACTOR

The development of new capillary networks from the normal microvascula ture of the host appears to be required for growth of solid tumors. Tu mor cells influence this process by producing both inhibitors and posi tive effectors of angiogenesis. Among the latter, the vascular endothe lial growth factor (VEGF) has assumed prime candidacy as a major posit ive physiological effector. Here, we have directly tested this hypothe sis in the brain tumor, glioblastoma multiforme, one of the most highl y vascularized human cancers. We introduced an antisense VEGF expressi on 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 hum an 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 relati on to the reduction of VEGF secretion and tumor formation. Moreover, r evertant cells that recovered the ability to secrete VEGF regained eac h of these tumorigenic properties. These results suggest that VEGF pla ys a major angiogenic role in glioblastoma.