PDF(Pubmed)
Abstract：
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.
摘要：
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），形成支持癌变的渗漏血管。对控制将EC重编程为TEC的转录调节剂了解甚少。我们确定叉头盒F1（FOXF1）是EC到TEC过渡的关键调节剂。FOXF1在正常肺血管系统中高表达，但在非小细胞肺癌（NSCLC）的TEC中降低。低FOXF1与NSCLC患者的低总生存率相关。在老鼠身上,内皮特异性FOXF1缺失降低周细胞覆盖率，血管通透性增加和缺氧，并促进肺部肿瘤的生长和转移。FOXF1的内皮特异性过表达使肿瘤血管正常化并抑制肺癌的进展。FOXF1缺陷通过Fzd4的直接转录激活降低了TECs中的Wnt/β-catenin信号传导。通过Fzd4cDNA的内皮特异性纳米颗粒递送恢复FOXF1缺陷型TEC中的FZD4表达拯救了TECs中的Wnt/β-catenin信号,使肿瘤血管正常化并抑制肺癌的进展。总之,FOXF1增加肿瘤血管稳定性，并通过刺激TECs中的FZD4/Wnt/β-catenin信号传导抑制肺癌进展。FZD4cDNA的纳米颗粒递送有望用于NSCLC的未来治疗。
