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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 Article has an altmetric score of 9

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 4

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Androgen-ablation therapy in prostate cancer leads to selective oblitera...
Androgen-ablation therapy in prostate cancer leads to selective obliteration of immature vessels. Adjacent sections of surgically removed prostate tissues were immunostained for vWF (a and c) or for α-SMA (b and d) to examine individual vessels for coverage with periendothelial cells. One example is shown for an untreated tumor (a and b) (black arrows pointing at uncovered vessels and a blue arrow pointing at a covered vessel) and one for a tumor subjected to androgen-ablation therapy (c and d) (black arrows pointing at a covered vessel). Data from 10 different patients are shown in the histogram (e): five from control untreated tumors (hatched bars) and five from treated tumors (solid bars). To randomize for experimental variability during processing and immunohistochemical detection, pairs of tumors, each containing one control tumor and an androgen-ablated tumor of the same Gleason grade and a matching patient age, were embedded in a single block and coanalyzed on the same slide. The total number of lumenized vessels scored depended on the amount of tumor represented in the section and was as follows: tumor 1 (140), 2 (63), 3 (25), 4 (19), 5 (98), 6 (122), 7 (158), 8 (143), 9 (170), 10 (397). Mouse prostate was used as a control for vascular maturation in normal prostate. On average, untreated tumors contained 38% α-SMA–positive vessels (SEM = 3.5%); androgen-ablated tumors had 79% α-SMA–positive vessels (SEM = 3.3%).

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

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Referenced in 63 patents
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