Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies
Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies
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DOI：
10.1172/jci131507
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发表时间：
2020-03-02
影响因子：
15.9
通讯作者：
Wu, Zhao-Qiu
中科院分区：
文献类型：
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作者：
Fu, Rong;Li, Yi;Wu, Zhao-Qiu
目前的抗血管生成治疗受到其细胞生长抑制特性、向肿瘤递送的药物稀缺和副作用的限制。为了解决这些局限性，我们揭示了ZEB 1（一种肿瘤内皮富集的锌指转录因子）在肿瘤进展过程中的作用。我们发现，在肿瘤内皮中具有高ZEB 1表达的肺腺癌患者在肺癌诊断后转移的患病率增加，总生存率显著降低。在荷瘤小鼠中，内皮ZEB 1缺失减少了肿瘤血管生成，同时通过表观遗传学抑制TGF-β信号传导引起持续的肿瘤血管正常化。因此，这导致改善血液和氧气灌注，增强化疗递送和免疫效应细胞浸润，并减少肿瘤生长和转移。此外，靶向血管ZEB 1显着增强无毒低剂量顺铂的抗癌活性。用低剂量抗程序性细胞死亡蛋白1（抗PD-1）抗体治疗引起ZEB 1缺失小鼠的肿瘤消退和显著延长的存活，赋予长期保护性抗癌免疫。总的来说，我们证明了内皮ZEB 1的失活可能为癌症治疗提供替代机会，副作用最小。靶向内皮源性ZEB 1与常规化疗或免疫检查点阻断疗法组合可产生有效且上级的抗癌作用。
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-beta 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.