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. 1997 Aug 5;94(16):8761-6.
doi: 10.1073/pnas.94.16.8761.

Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal

L E Benjamin  1 , E Keshet
Affiliations

Conditional switching of vascular endothelial growth factor (VEGF) expression in tumors: induction of endothelial cell shedding and regression of hemangioblastoma-like vessels by VEGF withdrawal

L E Benjamin et al. Proc Natl Acad Sci U S A. .

Abstract

We have recently shown that VEGF functions as a survival factor for newly formed vessels during developmental neovascularization, but is not required for maintenance of mature vessels. Reasoning that expanding tumors contain a significant fraction of newly formed and remodeling vessels, we examined whether abrupt withdrawal of VEGF will result in regression of preformed tumor vessels. Using a tetracycline-regulated VEGF expression system in xenografted C6 glioma cells, we showed that shutting off VEGF production leads to detachment of endothelial cells from the walls of preformed vessels and their subsequent death by apoptosis. Vascular collapse then leads to hemorrhages and extensive tumor necrosis. These results suggest that enforced withdrawal of vascular survival factors can be applied to target preformed tumor vasculature in established tumors. The system was also used to examine phenotypes resulting from over-expression of VEGF. When expression of the transfected VEGF cDNA was continuously "on," tumors became hyper-vascularized with abnormally large vessels, presumably arising from excessive fusions. Tumors were significantly less necrotic, suggesting that necrosis in these tumors is the result of insufficient angiogenesis.

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Figures

Figure 1
Figure 1
The effect of VEGF165 over-expression on tumor and vessel growth. (Left) Reverse transcriptase–PCR analysis of VEGF165 mRNA in a C6 pTET-VEGF clone grown in the presence (“off”) and absence (“on”) of tetracycline. Arrowheads point at coamplified fragments of VEGF165 and L19 ribosomal protein. (Right) Hematoxylin and eosin staining of sections from C6 tumors grown in Nude mice either in the absence (A) or presence (B) of tetracycline. Note particularly the extensive necrosis in A (to the right of the figure) and the abnormal large vessels in B.
Figure 2
Figure 2
Vessel regression and tumor necrosis following shut off of VEGF expression. Hematoxylin and eosin staining of sections from C6 tumors grown in Nude mice for 2 weeks in the absence of tetracycline and resected 0 h (A), 24 h (B), 48 h (C), 72 h (D), 4 days (E), and 5 days (F) after administration of tetracycline to shut off expression of VEGF from the transfected VEGF165. n, Necrosis.
Figure 3
Figure 3
Endothelial cell detachment and erythrocyte escape from blood vessels. (A–D) Sections from a tumor resected 24 h after VEGF shut off. A and D were stained with hematoxylin and eosin. Endothelial cells were visualized in B by staining with anti-von Willebrand antibodies and in C by staining with B. simplicifolia isolectin B4. Arrows point at endothelial cells being shed into the lumen.
Figure 4
Figure 4
Extra-vascular TUNEL-positive endothelial cells. (Left) TUNEL-positive endothelial cell (arrow) in the wall of a partially degenerated vessel, 24 h after VEGF shut off (counterstained with hematoxylin and eosin). (Center and Right) Double-labeling of a tumor section with TUNEL (using a fluorescein isothiocyanate-flurophore) (Center) and anti-von Willebrand (VWF) antibody (using a rhodamine flurophore) (Right).
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