China-Sweden International Joint Research Center for Brain Diseases, Key Laboratory of Ministry of Education for Medicinal Plant Resource and Natural Pharmaceutical Chemistry, National Engineering Laboratory for Resource Developing of Endangered Chinese Crude Drugs in Northwest of China, College of Life Sciences, Shaanxi Normal University, Xi'an, 710119, China.
Department of Immunology, Genetics and Pathology, Science for Life Laboratory, Uppsala University, Rudbeck Laboratory, 75185, Uppsala, Sweden.
Neuro Oncol. 2023 Jun 2;25(6):1073-1084. doi: 10.1093/neuonc/noac288.
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.
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.
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.
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.
抗肿瘤治疗药物向脑肿瘤的全身递送受到血脑屏障（BBB）的阻碍，BBB 是脑内皮细胞（EC）的器官特异性特化。药理学化合物无法穿过 BBB 是胶质母细胞瘤（GBM）患者预后不佳的一个罪魁祸首。因此，迫切需要鉴定新的血管靶点，以克服 BBB 在肿瘤中对 GBM 治疗带来的挑战。
在 CT2A 和 PDGFB 驱动的 RCAS/tv-a 原位胶质瘤模型中研究替莫唑胺（TMZ）的递送。对来自鼠胶质瘤的 EC 进行转录组分析。开发了 Mfsd2a 缺陷型、Cav1 缺陷型和 Mfsd2a EC 特异性诱导型小鼠，以研究潜在的分子机制。
我们证明，通过 LGK974 抑制 Wnt 信号可以增加 TMZ 的递送，并在两种鼠胶质瘤模型中使胶质瘤对化疗敏感。对来自鼠胶质瘤的 EC 的转录组分析显示，Wnt 信号抑制通过上调 PLVAP 和下调 MFSD2A 增强血管转胞运输。在小鼠中，Mfsd2a 缺陷增强了肿瘤中的 TMZ 递送，而 EC 中 Mfsd2a 的组成型表达抑制了 Wnt 途径抑制诱导的 TMZ 递送增强。此外，Wnt 信号抑制增强了肿瘤 EC 中 caveolin-1（Cav1）阳性小窝介导的转胞运输。此外，Wnt 信号抑制剂或 Mfsd2a 缺陷不能增强 Cav1 缺陷型小鼠肿瘤中的 TMZ 渗透。
这些结果表明，Wnt 信号通过 Cav1 阳性小窝介导的 EC 转胞运输途径调节 MFSD2A 依赖性 TMZ 递送。我们的发现表明，Wnt 信号可以作为一种有前途的治疗靶点，以改善 GBM 治疗的药物递送。
