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Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies
Rong Fu, … , Tao Lu, Zhao-Qiu Wu
Rong Fu, … , Tao Lu, Zhao-Qiu Wu
Published February 10, 2020
Citation Information: J Clin Invest. 2020;130(3):1252-1270. https://doi.org/10.1172/JCI131507.
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Research Article Angiogenesis Therapeutics

Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies

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Abstract

Current antiangiogenic therapy is limited by its cytostatic property, scarce drug delivery to the tumor, and side toxicity. To address these limitations, we unveiled the role of ZEB1, a tumor endothelium–enriched zinc-finger transcription factor, during tumor progression. We discovered that the patients who had lung adenocarcinomas with high ZEB1 expression in tumor endothelium had increased prevalence of metastases and markedly reduced overall survival after the diagnosis of lung cancer. Endothelial ZEB1 deletion in tumor-bearing mice diminished tumor angiogenesis while eliciting persistent tumor vascular normalization by epigenetically repressing TGF-β signaling. This consequently led to improved blood and oxygen perfusion, enhanced chemotherapy delivery and immune effector cell infiltration, and reduced tumor growth and metastasis. Moreover, targeting vascular ZEB1 remarkably potentiated the anticancer activity of nontoxic low-dose cisplatin. Treatment with low-dose anti–programmed cell death protein 1 (anti–PD-1) antibody elicited tumor regression and markedly extended survival in ZEB1-deleted mice, conferring long-term protective anticancer immunity. Collectively, we demonstrated that inactivation of endothelial ZEB1 may offer alternative opportunities for cancer therapy with minimal side effects. Targeting endothelium-derived ZEB1 in combination with conventional chemotherapy or immune checkpoint blockade therapy may yield a potent and superior anticancer effect.

Authors

Rong Fu, Yi Li, Nan Jiang, Bo-Xue Ren, Chen-Zi Zang, Li-Juan Liu, Wen-Cong Lv, Hong-Mei Li, Stephen Weiss, Zheng-Yu Li, Tao Lu, Zhao-Qiu Wu

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Figure 5

Endothelial ZEB1 inactivation reduces LLC tumor angiogenesis while eliciting vessel normalization.

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Endothelial ZEB1 inactivation reduces LLC tumor angiogenesis while elici...
(A) Immunofluorescent images (left) and comparison (right) of CD31+ blood vessel (BV) density in LLC tumors grown for 21 days in Zeb1WT versus Zeb1iΔEC mice (5 mice each). Nuclei, DAPI (blue). (B–D) Immunofluorescent images (left) and comparisons (right) of desmin+ pericyte coverage along BVs (B), collagen type IV+ basement membrane (BM) coverage alongside BVs (C), and claudin 5 distribution on BVs (D) in LLC tumors of Zeb1WT versus Zeb1iΔEC mice (5 mice each). (E) Immunofluorescence images (left) and comparison (right) of extravasated Ter119+ red blood cells in LLC tumors of Zeb1WT versus Zeb1iΔEC mice (5 mice each). The Ter119+ bleeding area is presented as a percentage of total sectional area. (F and G) Immunofluorescent images (left) and comparisons (right) of dextran leakage (F) and lectin perfusion (G) of BVs in LLC tumors of Zeb1WT versus Zeb1iΔEC mice (5 mice each). Dextran and lectin were intravenously injected 30 minutes before euthanization. The dextran+ area or lectin+ vessels are presented as a percentage of total sectional area or CD31+ area, respectively. All data are represented as mean ± SD. **P < 0.01. Differences were tested using unpaired 2-sided Student’s t test.

Copyright © 2021 American Society for Clinical Investigation
ISSN: 0021-9738 (print), 1558-8238 (online)

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