Slit2 inhibits glioma cell invasion in the brain by suppression of Cdc42 activity

¹ University of Pittsburgh Cancer Institute, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA; Department of Neurological Surgery, Tri-Services General Hospital and National Defense Medical Center, Taipei, Taiwan; Veterans Hospital, Taoyuan, Taiwan
² University of Pittsburgh Cancer Institute, Department of Medicine, University of Pittsburgh, Pittsburgh, PA, USA
³ University of Pittsburgh Cancer Institute, Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA
⁴ Department of Neurology, Northwestern University Feinberg Medical School
⁵ Department of Neurological Surgery, Tri-Services General Hospital and National Defense Medical Center, Taipei, Taiwan
⁶ University of Pittsburgh, Cancer Institute and Department of Pathology, HCCLB, 2.26f, 5117 Centre Ave., Pittsburgh, PA 15213, USA

^* To whom correspondence should be addressed. E-mail: chengs{at}upmc.edu.

	Abstract

Acquisition of the insidious invasiveness by malignant glioma cells involves multiple genetic alterations in signaling pathways. Slit2, a chemorepulsive factor, controls cell migration of neuronal and glial cells during development and inhibits chemotaxic migration of various types of cells in vitro. However, the role of Slit2 in vitro remains controversial and the biological significance of Slit2 expression in cancer cell invasion in vivo has not yet been determined. In the present study, we characterized the effects of Slit2 expression on the migration and invasion of invasive glioma cells in vitro and in vivo. By RT-PCR analyses, Slit2 was found to express at lower levels in primary glioma specimens and invasive glioma cells when compared with normal human brains and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuate cell migration and invasion through inhibition of Cdc42 activity in vitro. Cellular depletion of Robo1, a cognate receptor for Slit2 prevented Slit2 inhibition of Cdc42 activity and glioma cell migration. In vivo, expression of Slit2 by invasive SNB19 cells markedly inhibited glioma cell infiltration into the brain of mice. Moreover, impediment of glioma cell invasion by Slit2 did not affect the expression of N-cadherin and -catenin in glioma cells. These results provide the first evidence demonstrating that Slit2–Robo1 inhibits glioma invasion through attenuating Cdc42 activity in vitro and in the brain. Understanding the mechanisms of Slit2–Robo1 inhibition of glioma cell invasion will foster new treatments for malignant gliomas.

Key Words: Cdc42, glioma, invasion, Slit2

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