跨细胞
Wnt信号通路
胶质瘤
癌症研究
下调和上调
替莫唑胺
HDAC1型
小窝
信号转导
小窝蛋白1
生物
化学
细胞生物学
药理学
组蛋白脱乙酰基酶
组蛋白
受体
生物化学
内吞作用
基因
作者
Yuan Xie,Liqun He,Yanyu Zhang,Hua Huang,Fan Yang,Min Chao,Haiyan Cao,Jianhao Wang,Yaling Li,Lingxue Zhang,Lele Xin,Bing Xiao,Xinxin Shi,Xue Zhang,Jiefu Tang,Lene Uhrbom,Anna Dimberg,Liang Wang,Lei Zhang
出处
期刊:Neuro-oncology
[Oxford University Press]
日期:2023-01-02
卷期号:25 (6): 1073-1084
被引量:9
标识
DOI:10.1093/neuonc/noac288
摘要
Abstract Background Systemic delivery of anti-tumor therapeutic agents to brain tumors is thwarted by the blood-brain barrier (BBB), an organotypic specialization of brain endothelial cells (ECs). A failure of pharmacological compounds to cross BBB is one culprit for the dismal prognosis of glioblastoma (GBM) patients. Identification of novel vascular targets to overcome the challenges posed by the BBB in tumors for GBM treatment is urgently needed. Methods Temozolomide (TMZ) delivery was investigated in CT2A and PDGFB-driven RCAS/tv-a orthotopic glioma models. Transcriptome analysis was performed on ECs from murine gliomas. Mfsd2a deficient, Cav1 deficient, and Mfsd2a EC-specific inducible mice were developed to study the underlying molecular mechanisms. Results We demonstrated that inhibiting Wnt signaling by LGK974 could increase TMZ delivery and sensitize glioma to chemotherapy in both murine glioma models. Transcriptome analysis of ECs from murine gliomas revealed that Wnt signaling inhibition enhanced vascular transcytosis as indicated by the upregulation of PLVAP and downregulation of MFSD2A. Mfsd2a deficiency in mice enhances TMZ delivery in tumors, whereas constitutive expression of Mfsd2a in ECs suppresses the enhanced TMZ delivery induced by Wnt pathway inhibition in murine glioma. In addition, Wnt signaling inhibition enhanced caveolin-1 (Cav1)-positive caveolae-mediated transcytosis in tumor ECs. Moreover, Wnt signaling inhibitor or Mfsd2a deficiency fails to enhance TMZ penetration in tumors from Cav1-deficient mice. Conclusions These results demonstrated that Wnt signaling regulates MFSD2A-dependent TMZ delivery through a caveolae-mediated EC transcytosis pathway. Our findings identify Wnt signaling as a promising therapeutic target to improve drug delivery for GBM treatment.
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