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ELMO1 and Dock180, a Bipartite Rac1 Guanine Nucleotide Exchange Factor, Promote Human Glioma Cell Invasion

¹ Cancer Institute and Departments of ² Pathology and ³ Medicine, University of Pittsburgh, Pittsburgh, Pennsylvania; ⁴ Ohio Supercomputer Center-Springfield, Springfield, Ohio; Departments of ⁵ Pathology and ⁶ Neurosurgery, Saitama Medical University, Moroyama-machi, Iruma-gun, Saitama, Japan; and ⁷ Beirne Carter Center for Immunology Research and Department of Microbiology, University of Virginia, Charlottesville, Virginia

Requests for reprints: Shi-Yuan Cheng, Cancer Institute and Department of Pathology, University of Pittsburgh, HCCLB, 2.26f, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-3261; Fax: 412-623-4840; E-mail: chengs{at}upmc.edu or Bo Hu, Cancer Institute and Department of Medicine, University of Pittsburgh, HCCLB, 2.19f, 5117 Centre Avenue, Pittsburgh, PA 15213. Phone: 412-623-7791; Fax: 412-623-4840; E-mail: hub{at}upmc.edu.

A distinct feature of malignant gliomas is the intrinsic ability of single tumor cells to disperse throughout the brain, contributing to the failure of existing therapies to alter the progression and recurrence of these deadly brain tumors. Regrettably, the mechanisms underlying the inherent invasiveness of glioma cells are poorly understood. Here, we report for the first time that engulfment and cell motility 1 (ELMO1) and dedicator of cytokinesis 1 (Dock180), a bipartite Rac1 guanine nucleotide exchange factor (GEF), are evidently linked to the invasive phenotype of glioma cells. Immunohistochemical analysis of primary human glioma specimens showed high expression levels of ELMO1 and Dock180 in actively invading tumor cells in the invasive areas, but not in the central regions of these tumors. Elevated expression of ELMO1 and Dock180 was also found in various human glioma cell lines compared with normal human astrocytes. Inhibition of endogenous ELMO1 and Dock180 expression significantly impeded glioma cell invasion in vitro and in brain tissue slices with a concomitant reduction in Rac1 activation. Conversely, exogenous expression of ELMO1 and Dock180 in glioma cells with low level endogenous expression increased their migratory and invasive capacity in vitro and in brain tissue. These data suggest that the bipartite GEF, ELMO1 and Dock180, play an important role in promoting cancer cell invasion and could be potential therapeutic targets for the treatment of diffuse malignant gliomas. [Cancer Res 2007;67(15):7203–11]

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