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

Abstract

Acquisition of 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 reverse transcriptase polymerase chain reaction (PCR) analyses, Slit2 was found to be expressed at lower levels in primary glioma specimens and invasive glioma cells compared with normal human brain cells and astrocytes. Ectopic expression of Slit2 or treatment with recombinant Slit2 on glioma cells attenuates 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 glioma 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 beta-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.

Roundabout4 Suppresses Glioma-Induced Endothelial Cell Proliferation, Migration and Tube Formation in Vitro by Inhibiting VEGR2-Mediated PI3K/AKT and FAK Signaling Pathways

“…Slit2, whose gene is located at chromosome 4p15.2, was originally identified as a down-regulated gene in gliomas and might act as a tumor suppressor gene [36]. Slit2 inhibits glioma cell migration and invasion by binding to Robo1 receptor and inactivation of Cdc42-GTP [37,38]. These results prove that Slit2, which was produced and secreted by glioma cells, could regulate glioma angiogenesis by binding to Robo4.…”

Slit2/Robo1 signaling in glioma migration and invasion

“…In vivo studies reveal that after implantation of invasive SNB19 glioma cells stably expressing Slit2 into the brain of 8-weekold female mice, glioma cell infiltration into the brain parenchyma is markedly attenuated. Meanwhile, ectopic expression of Slit2 in SNB19 cells could attenuate cell migration and invasion, but has only minimal impacts on cell proliferation and survival, as revealed by cell viability assay [24] . These protein in glioma cells [24] .…”

“…Meanwhile, ectopic expression of Slit2 in SNB19 cells could attenuate cell migration and invasion, but has only minimal impacts on cell proliferation and survival, as revealed by cell viability assay [24] . These protein in glioma cells [24] .…”

A vascular perspective on neuronal migration

“…infiltration (Ohnishi et al, 1997;Ray et al, 2014;Reardon et al, 2008;Serres et al, 2014). In addition, increasing evidences suggest that neurovascular guidance cues, such as Eph/ephrin (Miao et al, 2015;Nakada et al, 2004;Wang et al, 2012), DCC/netrin (Jarjour et al, 2011;Shimizu et al, 2013;Ylivinkka et al, 2013), Robo/slit (Dallol et al, 2003;Mertsch et al, 2008;Yiin et al, 2009), Plexin/semaphorin (Bagci et al, 2009;Sabag et al, 2012;Zhou et al, 2012), are involved in glioma invasion. As an example, EphA2…”