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Reduced Glioma Infiltration in Src-deficient Mice

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Summary

Malignant brain tumors, such as glioblastoma, are characterized by extensive angiogenesis and permeability of the blood-brain barrier (BBB). The infiltration of glioma cells away from the primary tumor mass is a pathological characteristic of glial tumors. The infiltrating tumor cells represent a significant 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 infiltration 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 Src-deficient 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 infiltrating component of glioma growth was reduced in src−/− mice. Characterization of the expression and localization of the extracellular matrix (ECM) protein fibrinogen was evaluated to determine the effect 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.

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Abbreviations

VEGF:

vascular endothelial growth factor

VP:

vascular permeability

BBB:

blood-brain barrier

VEGFR-2:

VEGF receptor 2

WHO:

World Health Organization

ECM:

extracellular matrix

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Acknowledgements

We thank Mario A. Bourdon and Carole A. Banka for critical reading of this manuscript. Grant support from the NHLBI (B.P.E) and the NINDS (C.A.K.)

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Authors and Affiliations

  1. Division of Cancer Biology , La Jolla Institute for Molecular Medicine, San Diego, CA, 92121, USA

    Caren V. Lund, Mai T. N. Nguyen, Geoffrey C. Owens, Andrew J. Pakchoian, Ashkaun Shaterian, Carol A. Kruse & Brian P. Eliceiri

  2. The Neurosciences Institute, 92121, San Diego, CA, USA

    Caren V. Lund, Mai T. N. Nguyen, Geoffrey C. Owens, Andrew J. Pakchoian, Ashkaun Shaterian & Carol A. Kruse

  3. Division of Cancer Biology, La Jolla Institute for Molecular Medicine, 4570 Executive Drive, Suite 100, San Diego, CA, 92121, USA

    Brian P. Eliceiri

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  1. Caren V. Lund
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  2. Mai T. N. Nguyen
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Correspondence to Brian P. Eliceiri.

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These authors contributed equally to these studies

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Lund, C.V., Nguyen, M.T.N., Owens, G.C. et al. Reduced Glioma Infiltration in Src-deficient Mice. J Neurooncol 78, 19–29 (2006). https://doi.org/10.1007/s11060-005-9068-y

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