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 March 2, 2020; First 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

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 6

Vascular ZEB1 depletion enhances drug delivery and potentiates antitumor effect of cisplatin.

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Vascular ZEB1 depletion enhances drug delivery and potentiates antitumor...
(A and B) Immunofluorescent images (A) and comparison (B) of doxorubicin penetration in the intratumoral regions of LLC tumors grown in Zeb1WT versus Zeb1iΔEC mice (5 mice each). Doxorubicin was intravenously injected 15 minutes before euthanization. The doxorubicin+ area is presented as a percentage of total sectional area. Nuclei, DAPI (blue). (C and D) Gross images (C) and growth curves (D) of LLC tumors grown subcutaneously for 21 days in Zeb1WT and Zeb1iΔEC mice. Mice were treated with vehicle or 1 mg/kg cisplatin once every 4 days for a total of 3 times (5 mice each). (E) Comparison of tumor weight of the indicated LLC tumors harvested at day 21 after implantation (5 mice each). (F and G) Immunofluorescent images (F) and comparison (G) of intratumoral accumulation of cisplatin in LLC tumors of cisplatin-treated Zeb1WT versus Zeb1iΔEC mice (5 mice each). (H and I) H&E-stained images (H) and quantification (I) of hemorrhagic necrosis in LLC tumors of vehicle- or cisplatin-treated Zeb1WT and Zeb1iΔEC mice as described in C (5 mice each). Asterisks denote hemorrhagic foci. (J and K) Immunofluorescent images (J) and quantification (K) of BV density in LLC tumors of vehicle- or cisplatin-treated Zeb1WT and Zeb1iΔEC mice as described in C (5 mice each). All data are represented as mean ± SD. *P < 0.05; **P < 0.01. Differences were tested using unpaired 2-sided Student’s t test (B and G), 2-way ANOVA with Tukey’s post hoc test (D), and 1-way ANOVA with Tukey’s post hoc test (E, I, and K).