Abstract
Neoangiogenesis is a pivotal therapeutic target in glioblastoma. Tumor monitoring requires imaging methods to assess treatment effects and disease progression. Until now mapping of the tumor vasculature has been difficult. We have developed a combined magnetic resonance and optical toolkit to study neoangiogenesis in glioma models. We use in vivo magnetic resonance imaging (MRI) and correlative ultramicroscopy (UM) of ex vivo cleared whole brains to track neovascularization. T2* imaging allows the identification of single vessels in glioma development and the quantification of neovessels over time. Pharmacological VEGF inhibition leads to partial vascular normalization with decreased vessel caliber, density, and permeability. To further resolve the tumor microvasculature, we performed correlated UM of fluorescently labeled microvessels in cleared brains. UM resolved typical features of neoangiogenesis and tumor cell invasion with a spatial resolution of ~5 µm. MR-UM can be used as a platform for three-dimensional mapping and high-resolution quantification of tumor angiogenesis.
Highlights
Gliomas are highly malignant brain tumors with poor prognosis (Wen and Kesari, 2008)
New methods are currently developed to better identify those patients who might benefit from antiangiogenic therapies: Next to molecular approaches (Sandmann et al, 2015), magnetic resonance (MR) imaging could be used for patient stratification
The human S24 cell line was derived as a primary glioblastoma culture from a resected glioblastoma and Glioblastoma multiforme (GBM) typical genetic changes were confirmed by comparative genomic hybridization (Lemke et al, 2012; Osswald et al, 2015)
Summary
Gliomas are highly malignant brain tumors with poor prognosis (Wen and Kesari, 2008). Angiogenesis is a hallmark of malignant tumors, and most tumors show an exponential ingrowth of neovessels upon a certain tumor size to accommodate their metabolic needs (Carmeliet and Jain, 2011; Hanahan and Weinberg, 2011) This phenomenon is called ’angiogenic switch’ and is characterized by the upregulation of pro-angiogenic molecules like vascular endothelial growth factor (VEGF) or angiopoietin 2 (Ang-2) that induce fast tumor angiogenesis. Many efforts have been made to develop antiangiogenic therapies to ’starve’ tumors off their resources (Huang et al, 2003) This approach of using anti-VEGF agents like bevacizumab has shown clinical benefit in certain tumor types (Mittal et al, 2014) but, despite significant improvement of progression-free survival, does not prolong overall survival of primary GBM in an unselected patient cohort (Chinot et al, 2014). Improved imaging techniques that faithfully and non-invasively characterize vessel architecture and antiangiogenic treatment effects are needed to facilitate the understanding of biological actions of these therapies, and the development of clinical trials
Sign-in/Register to view highlights & summary Sign-in/Register to access full text options 
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call
