Abstract
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.
Highlights
Glioblastoma (GBM), the most aggressive and lethal type of brain tumors, is characterized by extensive vascular abnormality in both morphological and molecular levels [1]
Tumor neoangiogenesis can be determined by the cerebral blood volume (CBV), which can be calculated from dynamic susceptibility contrast MRI (DSC-MRI) [6, 7]
Gene Ontology analysis of these 343 endothelial cells (ECs)-enriched gene transcripts uncovered that the top significantly enriched biological process categories were all related to EC function, as well as numerous other endothelial related terms including blood vessel morphogenesis, circulatory system morphogenesis, tube development, and angiogenesis (Figure 1C and Table S2)
Summary
Glioblastoma (GBM), the most aggressive and lethal type of brain tumors, is characterized by extensive vascular abnormality in both morphological and molecular levels [1]. MRI is a powerful non-invasive diagnostic tool for GBM and it is routinely used in clinical, providing in vivo portraits of tumors with multidimensional information including structure, location, composition, functional/physiological features as well as vascular parameters [4, 5]. As a result of diffusion of contrast molecules out of vessels and accumulation within extracellular space in tumors, contrastenhancing hyper-intense regions on T1-weighted (T1W) sequences are presented in most GBM [9]. These contrastenhancing regions are the typical target for surgical resection [9]
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