Fluid shear stress regulates the invasive potential of glioma cells via modulation of migratory activity and matrix metalloproteinase expression

• Published in: PloS one Vol. 6; no. 5; p. e20348
• Main Authors: Qazi, Henry, Shi, Zhong-Dong, Tarbell, John M
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 26.05.2011; Public Library of Science (PLoS)
• Subjects: Angiogenesis; Animals; Apoptosis; Apoptosis - drug effects; Biology; Biomedical engineering; Biotechnology; Boyden chamber; Brain cancer; Brain research; Brain tumors; Cell culture; Cell Line, Tumor; Cell Movement - drug effects; Cell Survival - drug effects; Central nervous system; Chemotactic Factors - pharmacology; Chemotaxis; Chemotaxis - drug effects; Collagen; Compaction; Computational fluid dynamics; Cosa; Development and progression; Down-Regulation - drug effects; Extracellular matrix; Fluid flow; Fluorescence; Gelatinase A; Gels; Gene expression; Glioma; Glioma - enzymology; Glioma - pathology; Glioma cells; Gliomas; Humans; Hydrodynamics; Interstitial collagenase; Matrix metalloproteinase; Matrix Metalloproteinase 1 - metabolism; Matrix Metalloproteinase 2 - metabolism; Mechanical stimuli; Mechanotransduction; Medical research; Medicine; Metalloproteinase; Metastasis; Modulation; Motility; Neoplasm Invasiveness; Parenchyma; Permeability - drug effects; Physiology; Polymerase chain reaction; Rats; Reproducibility of Results; Rheology - drug effects; Shear stress; Stress, Mechanical; Substantia alba; Surgical implants; Three dimensional flow; Three dimensional models; Transforming Growth Factor beta - pharmacology; Tumors; New York; United States > US
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0020348

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. A 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. Fluid 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.