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

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 1

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Regression of immature blood vessels in a xenografted glioma tumor. (a) ...
Regression of immature blood vessels in a xenografted glioma tumor. (a) A tumor grown under conditions of constitutive high-VEGF expression showing a mixture of α-SMA–positive and α-SMA–negative blood vessels. The α-SMA–negative vessel (arrow) is shown at a higher magnification in the inset (counterstained with H&E) to highlight the integrity of its endothelium. (b and c) A tumor 72 h after VEGF withdrawal. Both covered (right arrows) and uncovered (left arrows) vessels are still observed. However, the uncovered vessel shows clear evidence of disintegration (better seen in c depicting the same vessel in a serial section counterstained with H&E). (d) A tumor 5 days after VEGF withdrawal. Note that most surviving vessels are α-SMA–positive. (e) VMIs were determined, as described in Methods, in high-power fields of sections obtained either before or 5 days after VEGF withdrawal (scoring 270 or 87 vessels, respectively). Calculated VMIs were 0.30 (SEM = 0.04) and 0.94 (SEM = 0.05), respectively. H&E, hematoxylin and eosin; SMA, smooth muscle actin; VEGF, vascular endothelial growth factor; VMI, vessel maturation indices.