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Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal
Laura E. Benjamin, … , Dov Pode, Eli Keshet
Laura E. Benjamin, … , Dov Pode, Eli Keshet
Published January 15, 1999
Citation Information: J Clin Invest. 1999;103(2):159-165. https://doi.org/10.1172/JCI5028.
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Article

Selective ablation of immature blood vessels in established human tumors follows vascular endothelial growth factor withdrawal

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Abstract

Features that distinguish tumor vasculatures from normal blood vessels are sought to enable the destruction of preformed tumor vessels. We show that blood vessels in both a xenografted tumor and primary human tumors contain a sizable fraction of immature blood vessels that have not yet recruited periendothelial cells. These immature vessels are selectively obliterated as a consequence of vascular endothelial growth factor (VEGF) withdrawal. In a xenografted glioma, the selective vulnerability of immature vessels to VEGF loss was demonstrated by downregulating VEGF transgene expression using a tetracycline-regulated expression system. In human prostate cancer, the constitutive production of VEGF by the glandular epithelium was suppressed as a consequence of androgen-ablation therapy. VEGF loss led, in turn, to selective apoptosis of endothelial cells in vessels devoid of periendothelial cells. These results suggest that the unique dependence on VEGF of blood vessels lacking periendothelial cells can be exploited to reduce an existing tumor vasculature.

Authors

Laura E. Benjamin, Dragan Golijanin, Ahuva Itin, Dov Pode, Eli Keshet

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Figure 5

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Endothelial cell apoptosis after androgen ablation. TUNEL analysis was u...
Endothelial cell apoptosis after androgen ablation. TUNEL analysis was used to detect apoptotic cells in the untreated prostate and 4 weeks after hormone ablation. (a) An untreated prostate showing apoptotic nuclei (red) in glands but not in blood vessels (arrows). (b) An androgen-ablated specimen highlighting two blood vessels with several TUNEL-positive endothelial cells. Note the presence of TUNEL-positive (black arrow) and TUNEL negative (red arrow) in the same blood vessel. a and b were processed together on the same microscope slide to control for histochemical variability. (c) TUNEL (green fluorescence) and α-SMA staining (red fluorescence) showing that an uncovered blood vessel (arrowhead) contains many apoptotic endothelial cells, whereas an adjacent covered blood vessel (arrow) does not. Red autofluorescence of erythrocytes aids in identifying the lumen of these vessels. Eighty-five percent of vessels in which one or more TUNEL-positive endothelial cells were detected were α-SMA–negative. The mean number of TUNEL-positive endothelial cells per vessel was 3.1-fold greater in androgen-ablated tumors. TUNEL, terminal deoxynucleotide transferase–mediated dUTP nick end-labeling.

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ISSN: 0021-9738 (print), 1558-8238 (online)

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