Cancer cells re-program normal lung endothelial cells (EC) into tumor-associated endothelial cells (TEC) that form leaky vessels supporting carcinogenesis. Transcriptional regulators that control the reprogramming of EC into TEC are poorly understood. We identified Forkhead box F1 (FOXF1) as a critical regulator of EC-to-TEC transition. FOXF1 was highly expressed in normal lung vasculature but was decreased in TEC within non-small cell lung cancers (NSCLC). Low FOXF1 correlated with poor overall survival of NSCLC patients. In mice, endothelial-specific deletion of FOXF1 decreased pericyte coverage, increased vessel permeability and hypoxia, and promoted lung tumor growth and metastasis. Endothelial-specific overexpression of FOXF1 normalized tumor vessels and inhibited the progression of lung cancer. FOXF1 deficiency decreased Wnt/β-catenin signaling in TECs through direct transcriptional activation of Fzd4. Restoring FZD4 expression in FOXF1-deficient TECs through endothelial-specific nanoparticle delivery of Fzd4 cDNA rescued Wnt/β-catenin signaling in TECs, normalized tumor vessels and inhibited the progression of lung cancer. Altogether, FOXF1 increases tumor vessel stability, and inhibits lung cancer progression by stimulating FZD4/Wnt/β-catenin signaling in TECs. Nanoparticle delivery of FZD4 cDNA has promise for future therapies in NSCLC.

中文翻译：

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FOXF1 通过 FZD4 促进肿瘤血管正常化并预防肺癌进展。


癌细胞将正常肺内皮细胞（EC）重新编程为肿瘤相关内皮细胞（TEC），从而形成支持癌发生的渗漏血管。人们对控制 EC 重编程为 TEC 的转录调控因子知之甚少。我们将 Forkhead box F1 (FOXF1) 确定为 EC 到 TEC 过渡的关键调节因子。 FOXF1 在正常肺血管系统中高表达，但在非小细胞肺癌 (NSCLC) 的 TEC 中表达降低。 FOXF1 水平低与 NSCLC 患者的总体生存率较差相关。在小鼠中，FOXF1的内皮特异性缺失降低了周细胞覆盖率，增加了血管通透性和缺氧，并促进了肺肿瘤的生长和转移。 FOXF1 的内皮特异性过度表达使肿瘤血管正常化并抑制肺癌的进展。 FOXF1 缺陷通过 Fzd4 的直接转录激活减少 TEC 中的 Wnt/β-catenin 信号传导。通过内皮特异性纳米颗粒递送 Fzd4 cDNA 恢复 FOXF1 缺陷型 TEC 中的 FZD4 表达，可挽救 TEC 中的 Wnt/β-连环蛋白信号传导，使肿瘤血管正常化并抑制肺癌的进展。总而言之，FOXF1 通过刺激 TEC 中的 FZD4/Wnt/β-catenin 信号传导来增加肿瘤血管稳定性，并抑制肺癌进展。 FZD4 cDNA 的纳米颗粒递送有望用于非小细胞肺癌 (NSCLC) 的未来治疗。