Abstract
Glioblastoma (GBM), a highly aggressive form of brain tumor, is a disease marked by extensive invasion into the surrounding brain. Interstitial fluid flow (IFF), or the movement of fluid within the spaces between cells, has been linked to increased invasion of GBM cells. Better characterization of IFF could elucidate underlying mechanisms driving this invasion in vivo. Here, we develop a technique to non-invasively measure interstitial flow velocities in the glioma microenvironment of mice using dynamic contrast-enhanced magnetic resonance imaging (MRI), a common clinical technique. Using our in vitro model as a phantom “tumor” system and in silico models of velocity vector fields, we show we can measure average velocities and accurately reconstruct velocity directions. With our combined MR and analysis method, we show that velocity magnitudes are similar across four human GBM cell line xenograft models and the direction of fluid flow is heterogeneous within and around the tumors, and not always in the outward direction. These values were not linked to the tumor size. Finally, we compare our flow velocity magnitudes and the direction of flow to a classical marker of vessel leakage and bulk fluid drainage, Evans blue. With these data, we validate its use as a marker of high and low IFF rates and IFF in the outward direction from the tumor border in implanted glioma models. These methods show, for the first time, the nature of interstitial fluid flow in models of glioma using a technique that is translatable to clinical and preclinical models currently using contrast-enhanced MRI.
Highlights
The identification and characterization of mediators of tumor cell invasion could aid in the treatment of GBM
With our combined magnetic resonance (MR) and analysis method, we show that velocity magnitudes are similar across four human GBM cell line xenograft models and the direction of fluid flow is heterogeneous within and around the tumors, and not always in the outward direction
Initial influx of intravenous gadobenate dimeglumine (Gd) into the tumor was detected by dynamic contrast-enhanced magnetic resonance imaging (MRI), followed by spin echo MRI (T1-weighted) [Fig. 1(d), supplementary material, Video 2]
Summary
The identification and characterization of mediators of tumor cell invasion could aid in the treatment of GBM. Growing tumors are marked by increased interstitial pressure, due to accumulation of proliferating tumor cells, extracellular matrix, and fluid, which is higher than the pressure in the surrounding tissue.. Growing tumors are marked by increased interstitial pressure, due to accumulation of proliferating tumor cells, extracellular matrix, and fluid, which is higher than the pressure in the surrounding tissue.11 This pressure differentially yields increased IFF across the invasive edges of tumors where tumor meets healthy tissue. Noninvasive attempts to characterize bulk fluid transport in vivo employ magnetic resonance imaging (MRI) These approaches in implanted brain (intradermal/subcutaneous) and breast tumors (orthotopic) have used multi-compartment models to approximate IFF velocities based on the rate of change of the contrast-enhanced ring at the tumor border over time, or identify the fluid drainage volume and pooling rates.. We quantify and map interstitial flow in these models, relating the patterns of flow to a common marker of fluid drainage from tumors, Evans blue dye, to verify that this method is a valid approach for determining regions of interstitial fluid flow in the brain tumor microenvironment
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