血管生成在 3 组髓母细胞瘤发病机制和生存中的作用。
The role of angiogenesis in Group 3 medulloblastoma pathogenesis and survival.
机构信息
Department of Neurosurgery, Duke University, Durham, North Carolina; Preston Robert Tisch Brain Tumor Center, Duke University, Durham, North Carolina; Brain Imaging and Analysis Center, Duke University, Durham, North Carolina; Department of Radiology, Duke University, Durham, North Carolina; Department of Radiology, Stanford University, Palo Alto, California; Department of Medicine, Duke University, Durham, North Carolina; Department of Pediatric Oncology, Hematology, and Clinical Immunology, Medical Faculty, University Hospital Düsseldorf, Düsseldorf, Germany; and Department of Pediatric Neuro-Oncogenomics, German Cancer Consortium and German Cancer Research Center, Heidelberg, Germany; Department of Pathology, Duke University, Durham, North Carolina; Division of Haematology/Oncology, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Division of Neurosurgery, the Arthur and Sonia Labatt Brain Tumour Research Centre, Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, Ontario, Canada; Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Ontario, Canada.
出版信息
Neuro Oncol. 2017 Sep 1;19(9):1217-1227. doi: 10.1093/neuonc/nox033.
BACKGROUND
Of the 4 medulloblastoma subgroups, Group 3 is the most aggressive but the importance of angiogenesis is unknown. This study sought to determine the role of angiogenesis and identify clinically relevant biomarkers of tumor vascularity and survival in Group 3 medulloblastoma.
METHODS
VEGFA mRNA expression and survival from several patient cohorts were analyzed. Group 3 xenografts were implanted intracranially in nude rats. Dynamic susceptibility weighted (DSC) MRI and susceptibility weighted imaging (SWI) were obtained. DSC MRI was used to calculate relative cerebral blood volume (rCBV) and flow (rCBF). Tumor vessel density and rat vascular endothelial growth factor alpha (VEGFA) expression were determined.
RESULTS
Patient VEGFA mRNA levels were significantly elevated in Group 3 compared with the other subgroups (P < 0.001) and associated with survival. Xenografts D283, D341, and D425 were identified as Group 3 by RNA hierarchical clustering and MYC amplification. The D283 group had the lowest rCBV and rCBF, followed by D341 and D425 (P < 0.05). These values corresponded to histological vessel density (P < 0.05), rat VEGFA expression (P < 0.05), and survival (P = 0.002). Gene set enrichment analysis identified 5 putative genes with expression profiles corresponding with these findings: RNH1, SCG2, VEGFA, AGGF1, and PROK2. SWI identified 3 xenograft-independent categories of intratumoral vascular architecture with distinct survival (P = 0.004): organized, diffuse microvascular, and heterogeneous.
CONCLUSIONS
Angiogenesis plays an important role in Group 3 medulloblastoma pathogenesis and survival. DSC MRI and SWI are clinically relevant biomarkers for tumor vascularity and overall survival and can be used to direct the use of antivascular therapies for patients with Group 3 medulloblastoma.
背景
在 4 个髓母细胞瘤亚组中，第 3 组是侵袭性最强的，但血管生成的重要性尚不清楚。本研究旨在确定血管生成的作用，并确定第 3 组髓母细胞瘤肿瘤血管生成和生存的临床相关生物标志物。
方法
分析了来自几个患者队列的 VEGFA mRNA 表达和生存数据。将第 3 组异种移植物颅内植入裸鼠。获得动态对比增强磁共振成像（DSC MRI）和磁敏感加权成像（SWI）。DSC MRI 用于计算相对脑血容量（rCBV）和流量（rCBF）。测定肿瘤血管密度和大鼠血管内皮生长因子α（VEGFA）表达。
结果
与其他亚组相比，患者的 VEGFA mRNA 水平在第 3 组中显著升高（P < 0.001），与生存相关。通过 RNA 层次聚类和 MYC 扩增，将 D283、D341 和 D425 鉴定为第 3 组。D283 组的 rCBV 和 rCBF 最低，其次是 D341 和 D425（P < 0.05）。这些值与组织学血管密度（P < 0.05）、大鼠 VEGFA 表达（P < 0.05）和生存（P = 0.002）相对应。基因集富集分析确定了 5 个表达谱与这些发现相对应的可能基因：RNH1、SCG2、VEGFA、AGGF1 和 PROK2。SWI 确定了 3 个与肿瘤血管结构相关的异种移植独立类别，具有不同的生存（P = 0.004）：组织、弥漫性微血管和异质性。
结论
血管生成在第 3 组髓母细胞瘤发病机制和生存中起重要作用。DSC MRI 和 SWI 是肿瘤血管生成和总生存的临床相关生物标志物，可用于指导第 3 组髓母细胞瘤患者使用抗血管生成治疗。
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