Table_3_Uncovering a Distinct Gene Signature in Endothelial Cells Associated With Contrast Enhancement in Glioblastoma.xlsx

PurposeGlioblastoma (GBM) is the most aggressive and lethal type of brain tumors. Magnetic resonance imaging (MRI) has been commonly used for GBM diagnosis. Contrast enhancement (CE) on T1-weighted sequences are presented in nearly all GBM as a result of high vascular permeability in glioblastomas. Although several radiomics studies indicated that CE is associated with distinct molecular signatures in tumors, the effects of vascular endothelial cells, the key component of blood brain barrier (BBB) controlling vascular permeability, on CE have not been thoroughly analyzed.
MethodsEndothelial cell enriched genes have been identified using transcriptome data from 128 patients by a systematic method based on correlation analysis. Distinct endothelial cell enriched genes associated with CE were identified by analyzing difference of correlation score between CE-high and CE–low GBM cases. Immunohistochemical staining was performed on in-house patient cohort to validate the selected genes associated with CE. Moreover, a survival analysis was conducted to uncover the relation between CE and patient survival.
ResultsWe illustrated that CE is associated with distinct vascular molecular imprints characterized by up-regulation of pro-inflammatory genes and deregulation of BBB related genes. Among them, PLVAP is up-regulated, whereas TJP1 and ABCG2 are down-regulated in the vasculature of GBM with high CE. In addition, we found that the high CE is associated with poor prognosis and GBM mesenchymal subtype.
ConclusionWe provide an additional insight to reveal the molecular trait for CE in MRI images with special focus on vascular endothelial cells, linking CE with BBB disruption in the molecular level. This study provides a potential new direction that may be applied for the treatment optimization based on MRI features.

研究目的：胶质母细胞瘤（Glioblastoma, GBM）是恶性程度最高、致死性最强的脑部肿瘤类型。磁共振成像（Magnetic Resonance Imaging, MRI）是当前GBM临床诊断中广泛应用的影像学手段。由于胶质母细胞瘤存在较高的血管通透性，T1加权序列上的对比增强（Contrast Enhancement, CE）征象几乎可在所有GBM病例中观测到。尽管已有多项放射组学研究表明对比增强与肿瘤的特异性分子特征存在关联，但作为血脑屏障（Blood Brain Barrier, BBB）中调控血管通透性的核心组分——血管内皮细胞，其对对比增强的影响尚未得到充分解析。

研究方法：本研究采用基于相关性分析的系统性方法，借助128例患者的转录组数据鉴定出内皮细胞富集基因。通过对比高对比增强组与低对比增强组GBM病例的相关性评分差异，筛选出与对比增强相关的特异性内皮细胞富集基因。本研究对自建患者队列开展免疫组化染色，以验证筛选得到的对比增强相关基因。此外，本研究还进行了生存分析，以探究对比增强与患者生存预后之间的关联。

研究结果：本研究证实，对比增强与特征性的血管分子印迹相关，具体表现为促炎基因的上调以及血脑屏障相关基因的表达失调。其中，在高对比增强的GBM患者血管组织中，PLVAP基因表达上调，而TJP1与ABCG2基因表达下调。此外，本研究发现高对比增强与不良预后及GBM间质亚型显著相关。

研究结论：本研究聚焦血管内皮细胞，为揭示磁共振成像中对比增强征象的分子特征提供了全新视角，在分子层面将对比增强与血脑屏障破坏建立了关联。本研究为基于磁共振成像特征优化肿瘤治疗方案提供了潜在的新方向。