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

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 pati...

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Bibliographic Details
Published in:The Journal of clinical investigation 2020-03, Vol.130 (3), p.1252-1270
Main Authors: Fu, Rong, Li, Yi, Jiang, Nan, Ren, Bo-Xue, Zang, Chen-Zi, Liu, Li-Juan, Lv, Wen-Cong, Li, Hong-Mei, Weiss, Stephen, Li, Zheng-Yu, Lu, Tao, Wu, Zhao-Qiu
Format: Article
Language:English
Subjects:
Angiogenesis
Antibodies
Antineoplastic agents
Antitumor activity
Apoptosis
Biomedical research
Bone morphogenetic proteins
Cancer
Cancer diagnosis
Cancer metastasis
Cancer therapies
Cell death
Chemotherapy
Cisplatin
Development and progression
Drug delivery
Drug delivery systems
Endothelium
Evaluation
Females
Hypoxia
Immune checkpoint
Lung cancer
Metastases
Metastasis
PD-1 protein
Perfusion
Toxicity
Transcription factors
Transforming growth factors
Tumors
Zinc finger proteins
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Summary: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.
ISSN:0021-9738
1558-8238
DOI:10.1172/jci131507