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Journal of Neuro-Oncology (2006) 78: 1929 Springer 2006
DOI 10.1007/s11060-005-9068-yLaboratory InvestigationReduced glioma inltration in Src-decient miceCaren V. Lund1,2, Mai T.N. Nguyen1,2, Georey C. Owens1,2, Andrew J. Pakchoian1,2, Ashkaun Shaterian1,2
Carol A. Kruse1,2 and Brian P. Eliceiri11Division of Cancer Biology La Jolla Institute for Molecular Medicine, San Diego, CA, 92121, USA;2 The
Neurosciences Institute, 92121, San Diego, CA, USAKey words: glioblastoma multiforme, glioma invasion, mouse model, vascular permeability, VEGFSummaryMalignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the
blood-brain barrier (BBB). The inltration of glioma cells away from the primary tumor mass is a pathological
characteristic of glial tumors. The inltrating tumor cells represent a signicant factor in tumor recurrence following
surgical debulking, radiation, and chemotherapy treatments. Vascular endothelial growth factor (VEGF)-mediated
vascular permeability (VP) has been associated with the progression of glioma tumor growth and inltration into
surrounding normal brain parenchyma. While VEGF induces a robust VP response in control mice (src+/+ or src+/)),
the VP response is blocked in src)/) mice that demonstrate a leakage-resistant phenotype in the brain. We used the Srcdecient mouse model to determine the role of Src in the maintenance of the BBB following orthotopic implantation
and growth of glioma cells in the brain. Although solid tumor growth was the same in control and src)/) mice, the
inltrating component of glioma growth was reduced in src)/) mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein brinogen was evaluated to determine the eect of a Src-mediated VP
defect in the host compartment. These studies indicate that the reduced VP of host brain blood vessels of src)/) mice
mediates a reduction in glioma cell invasion in a mouse brain tumor xenograft model.Abbreviations: VEGF vascular endothelial growth factor; VP vascular permeability; BBB blood-brain barrier;
VEGFR-2 VEGF receptor 2; WHO World Health Organization; ECM extracellular matrixIntroductionThe blood brain barrier (BBB) is characterized by specialized endothelial cells that form a continuous barrier
with low paracellular permeability, ultimately controlling the accessibility of molecules to the brain [13].
Tight junctions are a hallmark of the BBB and are
formed between endothelial cells in association with
other cell types including astrocytes, perivascular macrophages, pericytes, and with the basement membrane
[4,5]. Growth of World Health Organization (WHO)
grade IV malignant...