Veeravagu Anand, Hou Lewis C, Hsu Andrew R, Cai Weibo, Greve Joan M, Chen Xiaoyuan, Tse Victor
Department of Neurosurgery, Stanford University School of Medicine, 1201 Welch Road, Stanford, CA 94305, USA.
Neurol Res. 2008 Nov;30(9):952-9. doi: 10.1179/174313208X322761. Epub 2008 Jul 25.
Glioblastoma multiforme (GBM) is a WHO grade IV malignant brain tumor with poor prognosis, despite advances in surgical and adjuvant therapy. GBM is characterized by areas of central necrosis and high levels of angiogenesis, during which increased vascular permeability allows for the extravasation of endothelial progenitor cells to support blood vessel and tumor growth. The purpose of this study was to characterize changes in tumor vascular permeability, vascular density and vessel morphology in vivo during angiogenesis.
An orthotropic murine (GL26) glioblastoma model was used in this study. in vivo serial dynamic contrast-enhanced magnetic resonance imaging (DCE-MRI) in combination with histologic and molecular genetic analyses was performed to correlate in vivo imaging of vascular development.
DCE-MRI revealed a significant change in tumor vessel permeability dependent upon tumor progression and size. Time to max signal intensity displayed a stepwise increase between days 21 and 24 (p<0.05), a critical period before exponential tumor growth during which a significant increase in tumor vascular density and vessel caliber is observed on histology. Furthermore, quantitative real-time PCR revealed a corollary increase in angiogenic signaling molecules before the observed changes on DCE-MRI.
In vivo changes of orthotopic glioma blood vessel permeability as shown by DCE-MRI correlates with histologic quantification of vascular density and vessel caliber as well as with the molecular expression of angiogenic factors. DCE-MRI is a useful tool for non-invasive in vivo monitoring of angiogenesis in pre-clinical tumor models.
多形性胶质母细胞瘤（GBM）是世界卫生组织IV级恶性脑肿瘤，尽管手术和辅助治疗有所进展，但预后仍较差。GBM的特征是中央坏死区域和高水平的血管生成，在此期间血管通透性增加，使得内皮祖细胞外渗以支持血管和肿瘤生长。本研究的目的是在血管生成过程中，在体内表征肿瘤血管通透性、血管密度和血管形态的变化。
本研究使用了原位小鼠（GL26）胶质母细胞瘤模型。进行了体内连续动态对比增强磁共振成像（DCE-MRI），并结合组织学和分子遗传学分析，以关联血管发育的体内成像。
DCE-MRI显示肿瘤血管通透性的显著变化取决于肿瘤进展和大小。最大信号强度出现时间在第21天至24天之间呈逐步增加（p<0.05），这是肿瘤指数生长前的关键时期，在此期间组织学观察到肿瘤血管密度和血管口径显著增加。此外，定量实时PCR显示在DCE-MRI观察到变化之前，血管生成信号分子相应增加。
DCE-MRI显示的原位胶质瘤血管通透性的体内变化与血管密度和血管口径的组织学定量以及血管生成因子的分子表达相关。DCE-MRI是临床前肿瘤模型中用于无创体内监测血管生成的有用工具。
