© Copyright 2008 by the Society for Neuro-Oncology
Received April 7, 2008
Accepted July 28, 2008
Basic and Translational Investigations
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AMPA receptors promote perivascular glioma invasion via 
1 integrin-dependent adhesion to the extracellular matrix
John de Groot 1*,
Yuji Piao 2,
Li Lu 3
1 M. D. Anderson Cancer Center, 1515 Holcombe Blvd., Unit 431, Houston, TX 77030, USA
2 Brain Tumor Center, University of Texas, M. D. Anderson Cancer Center, Houston, TX
3 Brain Tumor Center, University of Texas, M. D. Anderson Cancer Center, Houston, TX
* To whom correspondence should be addressed. E-mail: jdegroot{at}mdanderson.org.
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Abstract |
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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 expression and stimulation promote glioma cell migration and invasion. Overexpression of GluR1, the most abundant AMPA receptor subunit in gliomas, positively correlated with glioma cell adhesion to types I and IV collagen which was decreased in cells with knockdown of GluR1 and with blocking antibodies to 
1 integrin. Furthermore, stimulation of the AMPA receptor led to detachment of cells from the 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 1 integrin, increased phosphorylation of focal adhesion kinase (FAK-Y397) and enhanced the number of focal adhesion (FA) complexes. Cells overexpressing GluR1 had increased co-localization 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 AMPA receptors 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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