Brain Tumor Vascularization Research Articles

Hemorrhage in brain tumor – An unresolved issue

Intratumoral hemorrhage (ITH) as a variant of intracranial hemorrhage (ICH) is a known, albeit rare, clinical entity. Hemorrhages within brain neoplasms seem to remain underreported, including angiomatous meningioma and pilocytic astrocytoma as well as sarcoma spread to CNS in pediatric cases. Neuropathological studies remain a valuable part of ITH assessment. New experimental therapies for brain tumors, including combinations with hyperbaric oxygen or treatment with kinase inhibitors need to be evaluated for their effect on brain tumor vascularization. A growing body of scientific evidence points towards the need to strengthen the significance of vascular component in brain tumor classification.

NG2 Proteoglycan-Dependent Contributions of Pericytes and Macrophages to Brain Tumor Vascularization and Progression.

The NG2 proteoglycan promotes tumor growth as a component of both tumor and stromal cells. Using intracranial, NG2-negative B16F10 melanomas, we have investigated the importance of PC and Mac NG2 in brain tumor progression. Reduced melanoma growth in Mac-NG2ko and PC-NG2ko mice demonstrates the importance of NG2 in both stromal compartments. In each genotype, the loss of PC-endothelial cell interaction diminishes the formation of endothelial junctions and assembly of the basal lamina. Tumor vessels in Mac-NG2ko mice have smaller diameters, reduced patency, and increased leakiness compared to PC-NG2ko mice, thus decreasing tumor blood supply and increasing hypoxia. While the reduced PC interaction with endothelial cells in PC-NG2ko mice results from the loss of PC activation of β1 integrin signaling in endothelial cells, reduced PC-endothelial cell interaction in Mac-NG2ko mice results from 90% reduced Mac recruitment. The absence of Mac-derived signals in Mac-NG2ko mice causes the loss of PC association with endothelial cells. Reduced Mac recruitment may be due to diminished activation of integrins in the absence of NG2, causing decreased Mac interaction with endothelial adhesion molecules that are needed for extravasation. These results reflect the complex interplay that occurs between Mac, PC, and endothelial cells during tumor vascularization.

Abstract IA19: Modeling blood-CNS barriers in zebrafish

Abstract The blood-brain barrier (BBB) plays an important role in the treatment of brain tumors. Yet, a comprehensive understanding of brain tumor vasculaturization has been hampered by difficulties in observing this process in vivo. Recently, we have generated several models of brain tumors in zebrafish. To visualize the vascularization of these tumors, we generated transgenic zebrafish lines to serve as in vivo reporters of brain tumor vasculature. We show that our BBB transgenic line drives expression specifically in brain endothelial cells and not in the vasculature of peripheral tissues or circumventricular organs. Using time-lapse confocal microscopy, we find that barriergenesis (i.e. the initiation of BBB development) occurs immediately as new vessels sprout into the brain parenchyma. Using a combination of genetic and chemical tools, we demonstrate that canonical Wnt signaling, but not VEGF signaling, is essential for barriergenesis. These results indicate that CNS angiogenesis and barriergenesis occur simultaneously, but require distinct signals for proper formation. Furthermore, we created a complementary transgenic line that drives expression in fenestrated endothelium, a hallmark of brain tumor vasculature. The combination of these transgenic lines along with our newly developed tumor models will allow us to visualize the complexities of brain tumor vascularization in a live animal model. Citation Format: Robyn A. Umans, Hannah E. Henson, Chaithanyarani Parupalli, Bensheng Ju, Michael R. Taylor. Modeling blood-CNS barriers in zebrafish. [abstract]. In: Proceedings of the AACR Special Conference: Advances in Brain Cancer Research; May 27-30, 2015; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2015;75(23 Suppl):Abstract nr IA19.

NG2 proteoglycan-dependent recruitment of tumor macrophages promotes pericyte-endothelial cell interactions required for brain tumor vascularization

Early stage growth of intracranial B16F10 tumors is reduced by 87% in myeloid-specific NG2 null (Mac-NG2ko) mice and by 77% in pericyte-specific NG2 null (PC-NG2ko) mice, demonstrating the importance of the NG2 proteoglycan in each of these stromal compartments. In both genotypes, loss of pericyte-endothelial cell interaction results in numerous structural defects in tumor blood vessels, including decreased formation of endothelial cell junctions and decreased assembly of the vascular basal lamina. All vascular deficits are larger in Mac-NG2ko mice than in PC-NG2ko mice, correlating with the greater decrease in pericyte-endothelial cell interaction in Mac-NG2ko animals. Accordingly, tumor vessels in Mac-NG2ko mice have a smaller diameter, lower degree of patency, and higher degree of leakiness than tumor vessels in PC-NG2ko mice, leading to less efficient tumor blood flow and to increased intratumoral hypoxia. While reduced pericyte interaction with endothelial cells in PC-NG2ko mice is caused by loss of NG2-dependent pericyte activation of β1 integrin signaling in endothelial cells, reduced pericyte-endothelial cell interaction in Mac-NG2ko mice is due to a 90% reduction in NG2-dependent macrophage recruitment to tumors. The absence of a macrophage-derived signal(s) in Mac-NG2ko mice results in the loss of pericyte ability to associate with endothelial cells, possibly due to reduced expression of N-cadherin by both pericytes and endothelial cells.

An attempt toward objective assessment of brain tumor vascularization using susceptibility weighted imaging and dedicated computer program – a preliminary study

SummaryBackground:Susceptibility weighted imaging (SWI) is a novel MRI sequence which demonstrates the susceptibility differences between adjacent tissues and it is promising to be a sequence useful in the assessment of brain tumors vascularity. The aim of our study was to demonstrate usefulness of SWI in evaluation of intratumoral vessels in comparison to CET1 sequence in a standardized, objective manner.Material/Methods:10 patients with supratentorial brain tumors were included in the study. All of them underwent conventional MRI examination with a 1,5 T scanner. SWI sequence was additionally performed using the following parameters: TR 49 ms,TE 40 ms. We used authors’ personal computer software – Vessels View, to assess the vessels number.Results:Comparison of SWI and CET1 sequences was performed using our program. Analysis of all 26 ROIs demonstrated predominance of SWI in the amount of white pixels (vessel cross-sectional) and a similar number of elongated structures (blood vessels).Conclusions:To conclude, the results of this study are encouraging; they confirm the added value of SWI as an appropriate and useful sequence in the process of evaluation of intratumoral vascularity. Using our program significantly improved visualization of blood vessels in cerebral tumors. The Vessel View application assists radiologists in demonstrating the vessels and facilitates distinguishing them from adjacent tissues in the image.

Combined multispectral near-infrared optoacoustic tomography and magnetic resonance imaging technique to monitor brain tumor vascularization

Combined multispectral near-infrared optoacoustic tomography and magnetic resonance imaging technique to monitor brain tumor vascularization

Longitudinal brain imaging of five malignant glioma patients treated with bevacizumab using susceptibility-weighted magnetic resonance imaging at 7 T

Malignant glioma is a rare tumor type characterized by prominent vascular proliferation. Antiangiogenic therapy with the monoclonal antibody bevacizumab is considered as a promising therapeutic strategy, although the effect on tumor vascularization is unclear. High-field susceptibility-weighted imaging (SWI) visualizes the microvasculature and may contribute to the investigation of antiangiogenic therapy responses in gliomas. We prospectively studied five adult malignant glioma patients treated with bevacizumab-containing regimens. In each patient, we performed three 7-T SWI and T1-weighted imaging investigations (baseline and 2 and 4 weeks after the start of bevacizumab treatment). In addition, we imaged a postmortem brain of a patient with glioblastoma using 7-T SWI and performed detailed histopathological analysis. We observed almost total resolution of brain edema in three of five patients after initiation of bevacizumab therapy. In one case with rapid increase of the lesion size despite bevacizumab therapy, SWI showed progressive increase of irregular hypointense structures, most likely corresponding to increasing amounts of pathological microvasculature. In one case with progressive neurological decline, 7-T images showed multiple intratumoral microhemorrhages after the first bevacizumab application. Correlation of postmortem neuroimaging with histopathology confirmed that SWI-positive structures correspond to tumor vasculature. The experience from our case series indicates that longitudinal 7-T SWI seems to be an appropriate method for investigation of changes in brain tumor vascularization over time under antiangiogenic therapy.

A noninvasive multimodal technique to monitor brain tumor vascularization

Determination of tumor oxygenation at the microvascular level will provide important insight into tumor growth, angiogenesis, necrosis and therapeutic response and will facilitate to develop protocols for studying tumor behavior. The non-ionizing near infrared spectroscopy (NIRS) technique has the potential to differentiate lesion and hemoglobin dynamics; however, it has a limited spatial resolution. On the other hand, magnetic resonance imaging (MRI) has achieved high spatial resolution with excellent tissue discrimination but is more susceptible to limited ability to monitor the hemoglobin dynamics. In the present work, the vascular status and the pathophysiological changes that occur during tumor vascularization are studied in an orthotopic brain tumor model. A noninvasive multimodal approach based on the NIRS technique, namely steady state diffuse optical spectroscopy (SSDOS) along with MRI, is applied for monitoring the concentrations of oxyhemoglobin, deoxyhemoglobin and water within tumor region. The concentrations of oxyhemoglobin, deoxyhemoglobin and water within tumor vasculature are extracted at 15 discrete wavelengths in a spectral window of 675–780 nm. We found a direct correlation between tumor size, intratumoral microvessel density and tumor oxygenation. The relative decrease in tumor oxygenation with growth indicates that though blood vessels infiltrate and proliferate the tumor region, a hypoxic trend is clearly present.

Microvessel density is not crucial for scintigraphic visualization of brain tumors using 99mTc-MIBI

Functional imaging of brain tumors assists biopsy localization, therapy monitoring, and differentiating tumor recurrence from radiation necrosis. Tumor vascularization is a strong prognostic predictor in solid tumors and also a key factor of tracer uptake. However, the relationship of brain tumor vascularization and functional imaging has not yet been investigated sufficiently so far. In the present study, we correlated histologically assessed microvessel density as an objective parameter for brain tumor vascularization with imaging data. Four male patients were studied. After 99mTc-MIBI scintigraphy, all patients had a MRI within 2 weeks. Histology showed microcystic astrocytoma, glioblastoma ( n = 2), and anaplastic oligodendroglioma, respectively. Microvessel density was lowest in the microcystic astrocytoma, medium in the glioblastomas, and highest in the anaplastic oligodendroglioma. Scintigraphy visualized only the glioblastomas, but not the microcystic astrocytoma or oligodendroglioma. Our data showed no correlation between tumor microvessel density and 99mTc-MIBI scintigraphy. Thus, we conclude that scintigraphic visualization of brain tumors is not strictly dependent on tumor vascularization.