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首页> 外文期刊>The Journal of Clinical Investigation: The Official Journal of the American Society for Clinical Investigation >Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies
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Inactivation of endothelial ZEB1 impedes tumor progression and sensitizes tumors to conventional therapies

机译：内皮 ZEB1 的失活可阻碍肿瘤进展并使肿瘤对常规疗法敏感

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摘要

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.
机译：目前的抗血管生成治疗受到其细胞抑制特性、向肿瘤输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ZEB1（一种富含肿瘤内皮的锌指转录因子）在肿瘤进展中的作用。我们发现，肿瘤内皮中ZEB1表达高的肺腺癌患者在诊断肺癌后转移患病率增加，总生存期明显降低。荷瘤小鼠的内皮 ZEB1 缺失减少了肿瘤血管生成，同时通过表观遗传抑制 TGF-β 信号传导诱导持续的肿瘤血管正常化。因此，这导致了血液和氧气灌注的改善，增强了化疗的递送和免疫效应细胞的浸润，并减少了肿瘤的生长和转移。此外，靶向血管 ZEB1 显着增强了无毒低剂量顺铂的抗癌活性。在ZEB1缺失的小鼠中，用低剂量抗程序性细胞死亡蛋白1（抗PD-1）抗体治疗引发了肿瘤消退并显着延长了生存期，从而赋予了长期保护性抗癌免疫力。总的来说，我们证明了内皮 ZEB1 的失活可能为癌症治疗提供替代机会，同时副作用最小。靶向内皮衍生的 ZEB1 与常规化疗或免疫检查点阻断疗法联合使用可能会产生有效且卓越的抗癌效果。

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