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First published on October 28, 2008
This version was published on January 1, 2009
Neuro Oncol 2009 11(3):260-273; DOI:10.1215/15228517-2008-094
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Basic and Translational Investigations

AMPA receptors promote perivascular glioma invasion via β1 integrin–dependent adhesion to the extracellular matrix

Yuji Piao, Li Lu and John de Groot

Brain Tumor Center, University of Texas M. D. Anderson Cancer Center, Houston, TX, USA

Address correspondence to John de Groot, M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA (jdegroot{at}mdanderson.org).

High-grade gliomas release excitotoxic concentrations of glutamate, which has been shown to enhance tumor proliferation and migration. {alpha}-Amino-3-hydroxy-5-methylisoxazole-4-propionic acid (AMPA) glutamate receptors are abundantly expressed at the invading edge of glioblastoma specimens, suggesting they may play an important biologic role in tumor invasion. In this study, we examined potential mechanisms by which AMPA receptor (AMPAR) expression and stimulation promote glioma cell migration and invasion. Overexpression of GluR1, the most abundant AMPAR subunit in gliomas, positively correlated with glioma cell adhesion to type I and type IV collagen, which was decreased in cells with knockdown of GluR1 and with blocking antibodies to β1 integrin. Furthermore, stimulation of the AMPAR led to detachment of cells from the extracellular matrix (ECM). Immunoprecipitation studies showed that GluR1 associated with the actin cytoskeleton-linked protein band 4.1B (brain type), which may serve as a link between GluR1 and integrins. Overexpression of GluR1 correlated with increased cell-surface expression of β1 integrin, increased phosphorylation of focal adhesion kinase (FAK-Y397), and enhanced numbers of focal adhesion (FA) complexes. Cells overexpressing GluR1 had increased colocalization of actin and paxillin at FAs and, in several glioma cell lines, significantly increased invasion in an in vitro Matrigel transwell assay. Likewise, in an intracranial xenograft model, overexpression of GluR1 led to perivascular and subependymal glioma cell invasion similar to patterns of tumor dissemination described in human glioblastoma. Together, these results suggest that AMPARs may link signals from the ECM to sites of FA, where signal integration promotes tumor invasion.

Key Words: AMPA receptor • glioblastoma • glutamate • invasion • perivascular


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