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Originally published online as doi:10.2353/ajpath.2008.080043 on November 13, 2008

Published online before print November 13, 2008
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(American Journal of Pathology. 2008;173:1828-1838.)
© 2008 American Society for Investigative Pathology
DOI: 10.2353/ajpath.2008.080043

The Guanine Nucleotide Exchange Factors Trio, Ect2, and Vav3 Mediate the Invasive Behavior of Glioblastoma

Bodour Salhia*{dagger}, Nhan L. Tran{dagger}, Amanda Chan{ddagger}, Amparo Wolf*, Mitsutoshi Nakada§, Fiona Rutka*, Matthew Ennis{dagger}, Wendy S. McDonough{dagger}, Michael E. Berens{dagger}, Marc Symons{ddagger} and James T. Rutka*

From the Arthur and Sonia Labatt Brain Tumor Research Centre,* Cancer and Cell Biology Division, The Hospital for Sick Children, the University of Toronto, Toronto, Canada; the Translational Genomics Research Institute,{dagger} Phoenix, Arizona; the Department of Cancer and Cell Biology,{ddagger} The Feinstein Institute for Medical Research at North Shore–Long Island Jewish Health System, Manhasset, New York; and the Division of Neurosurgery,§ Kanazawa University Graduate School of Medicine, Kanazawa, Japan

Malignant gliomas are characterized by their ability to invade normal brain tissue. We have previously shown that the small GTPase Rac1 plays a role in both migration and invasion in gliomas. Here, we aim to identify Rac-activating guanine nucleotide exchange factors (GEFs) that mediate glioblastoma invasiveness. Using a brain tumor expression database, we identified three GEFs, Trio, Ect2, and Vav3, that are expressed at higher levels in glioblastoma versus low-grade glioma. The expression of these GEFs is also associated with poor patient survival. Quantitative real-time polymerase chain reaction and immunohistochemical analyses on an independent set of tumors confirmed that these GEFs are overexpressed in glioblastoma as compared with either nonneoplastic brain or low-grade gliomas. In addition, depletion of Trio, Ect2, and Vav3 by siRNA oligonucleotides suppresses glioblastoma cell migration and invasion. Depletion of either Ect2 or Trio also reduces the rate of cell proliferation. These results suggest that targeting GEFs may present novel strategies for anti-invasive therapy for malignant gliomas.






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