Abstract
BackgroundGlioma cells are exposed to elevated interstitial fluid flow during the onset of angiogenesis, at the tumor periphery while invading normal parenchyma, within white matter tracts, and during vascular normalization therapy. Glioma cell lines that have been exposed to fluid flow forces in vivo have much lower invasive potentials than in vitro cell motility assays without flow would indicate.Methodology/Principal FindingsA 3D Modified Boyden chamber (Darcy flow through collagen/cell suspension) model was designed to mimic the fluid dynamic microenvironment to study the effects of fluid shear stress on the migratory activity of glioma cells. Novel methods for gel compaction and isolation of chemotactic migration from flow stimulation were utilized for three glioma cell lines: U87, CNS-1, and U251. All physiologic levels of fluid shear stress suppressed the migratory activity of U87 and CNS-1 cell lines. U251 motility remained unaltered within the 3D interstitial flow model. Matrix Metalloproteinase (MMP) inhibition experiments and assays demonstrated that the glioma cells depended on MMP activity to invade, and suppression in motility correlated with downregulation of MMP-1 and MMP-2 levels. This was confirmed by RT-PCR and with the aid of MMP-1 and MMP-2 shRNA constructs.Conclusions/SignificanceFluid shear stress in the tumor microenvironment may explain reduced glioma invasion through modulation of cell motility and MMP levels. The flow-induced migration trends were consistent with reported invasive potentials of implanted gliomas. The models developed for this study imply that flow-modulated motility involves mechanotransduction of fluid shear stress affecting MMP activation and expression. These models should be useful for the continued study of interstitial flow effects on processes that affect tumor progression.
Highlights
Developing glioma vasculature is convoluted with temporally and spatially heterogeneous flow and enhanced neovascularization [1,2,3,4,5]
Angiogenesis-induced breakdown of normal vasculature leads to hyperpermeable vessels that are associated with elevated interstitial convection into the parenchyma and elevated fluid shear stress on tumor cell surfaces [6,7,8,9,10,11,12,13]
Solid brain tumors are characterized by elevated fluid flux into the parenchyma at the tumor boundary [13]
Summary
Developing glioma vasculature is convoluted with temporally and spatially heterogeneous flow and enhanced neovascularization [1,2,3,4,5]. Normalization of the tumor vasculature via antiangiogenic interventions decreases the fluid flow heterogeneity to improve fluid drainage through the parenchyma and white matter tracts [1,2,13,14]. There have been no assessments of the effect of fluid shear stress on the migratory activity of glioma cells It has, been theorized that spatial and temporal heterogeneities in flow, elevated fluid flow at the periphery, and fluid shear stress may modulate metastasis, growth, and invasion [1,15,16]. Glioma cells are exposed to elevated interstitial fluid flow during the onset of angiogenesis, at the tumor periphery while invading normal parenchyma, within white matter tracts, and during vascular normalization therapy. Glioma cell lines that have been exposed to fluid flow forces in vivo have much lower invasive potentials than in vitro cell motility assays without flow would indicate
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