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Designing new therapy by blocking brain tumor invasion and metastasis

Brain tumors are devastating and among those most recalcitrant to treatment (Katzenstein and Conn, 1998). A critical issue is tumor cell invasion, leading to diffuse infiltration of tumor into the surrounding brain tissues and making it difficult to carry out clean removal of brain tumors by surgery. This is a major cause of treatment failure (Bjerkvig et al.. 1997). To overcome this problem and improve the therapeutic efficacy, we are developing a new strategy to control the invasion and metastasis of brain tumor cells. This strategy is based on results from our previous and ongoing studies on molecular mechanisms of cancer cell migration and brain tumor invasion. Our studies have demonstrated that the secreted protein Slit repels neurons (Wu et ai., 1999; Zhu et ai., 1999). inhibits leukocyte chemotaxis (Wu et ai.. 2001), reduces endothelial cell migration (Park et ai.. 2003) and suppresses tumor cell invasion and metastasis (wu et a), unpublished; Werbowetski-Ogiivie et ai, 2006). Recent genetic studies show that Slit is frequently inactivated in cancer, including brain tumors, suggesting Slit as a tumor suppressor gene. The potent activity of Slit in inhibiting the migration of different types of cells suggests a fundamentally conserved mechanism that controls the migration of different cells, ranging from neurons to leukocytes and from normal cells to tumor cells (Rao et al., 2002; Rao and Wu, 2003). Here we propose to study the role of Slit in inhibiting invasion and metastasis of brain tumor cells and to develop new strategy for treating brain tumors.

Previous studies of molecular mechanisms of brain tumor metastasis have largely focused on cell adhesion molecules and integrins. Recent data indicate that extracellular secreted proteins play an important role in tumor invasion and metastasis. Our studies in the past decade led to the identification of critical guidance molecules for neuronal migration and of downstream signal transduction pathways. We have discovered that secreted neuronal repellent molecule Slit also inhibits tumor cell migration, including brain tumor cells such as medulloblastoma and glioma cells (Wu et al, 1999; Wu et al., 2001; Wu et al. unpublished; Werbowetski-Ogiivie et al. 2006). Several lines of evidence support that Slit may inhibit brain tumor metastasis. First, previous studies have shown that brain tumor cells are similar to normal fetal neurons in their migratory behaviors (Bernstein et ai.. 1989; Pedersen et al., 1993). Second, our preliminary study has shown that brain tumor cells express Robo genes that encode receptors for Slit. For example. UW3 medulloblastoma and glioma cells expressed Robol. These cells will therefore allow us to test the idea of using Slit to control medulloblastoma and glioma cell invasion and metastasis. Third, our recent experiments indicate that Slit can inhibit brain tumor invasion and metastasis in animal models (Wu et ai. unpublished; Werbowetski-Ogiivie et at. 2006).

As a newly discovered gene family involved in tumor suppression, Slit genes encode secreted proteins that guide neuronal migration, inhibit leukocyte chemotaxis and suppress tumor cell migration (seeansnoim* TesswLangne. 1999. Raoetai 2001. wu«ai, 2001 Guan & Rao, 2003, Prasad, 2004. wu et ai, pfefcninary studios). Slit proteins bind to and signal through single-pass transmembrane receptors named Roundabout (Robo). Recent genetic and biochemical studies have begun to reveal the intracellular signal transduction pathways mediating Slit-Robo activities (Fig.1). However, the molecular mechanisms underlying Slit inhibition of brain tumor cell invasion and metastasis remain to be elucidated. Our recent experiments demonstrate that similar to neurons, Slit effect in brain tumor cells is also mediated by Robo receptor and downstream srGAP protein. Furthermore, the small GTPase downstream of srGAP, cdc42, plays an important role in mediating Slit inhibitory activity in brain tumor cells. These findings strongly suggest that srGAP and Cdc42 can be tested as drug target molecules for screening chemical compounds for treating brain tumor by inhibiting tumor cell migration and metastasis. To this end, we have begun to develop high-throughput screening assays for identifying chemicals that suppress brain tumor cell migration and/or enhance the tumor inhibitory activity of possible tumor suppressor gene Slit. Together, These results provide a solid foundation for developing new therapeutic strategies for brain tumors by screening chemicals inhibiting brain tumor migration and by enhancing Slit inhibitory activity of tumor cell migration/metastasis.

Fig 1 A schematic of Slit-Robo signal transduction In call migration, a critical regulatory pathway tor inhibiting tumor call Invasion and metastasis (Adapted from Rao «t al. 2002)

Brain tumor remains a devastating health problem. Our biochemical, cell biology and molecular studies in the past decade have advanced our understanding of neuronal migration and axon guidance. Our experiments also show that molecular mechanisms controlling the migration of different cell types share similarities. For example, neuronal repellent molecule Slit also acts on tumor cells, inhibiting brain tumor cell invasion and migration. Recent experiments provide promising leads for developing a new strategy for brain tumor by inhibiting tumor cell migration and metastasis. We propose to use a combined approach to investigate brain tumor cell migration/metastasis in vitro, to understand the underlying molecular mechanism, to develop high through-put screening approaches for identifying chemical compounds that inhibit brain tumor cell invasion and metastasis in vitro and to test identified candidate chemicals in brain tumor inhibition in animal models. Our proposed study will not only help us understand how brain tumor cells invade to adjacent tissues and metastasize to distant organs but not provide new information useful for developing therapeutic approaches based on blocking tumor metastasis.

These studies will not only help us understand molecular mechanisms regulating tumor suppressor genes but also provide useful information for designing new therapies based on inhibiting cancer metastasis. If successful, our study combining basic research with translational studies will have significant implications for brain tumor patients, both for identifying new biomarkers for diagnostics and for developing new therapy to improve the life quality of cancer patients.
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The James S. McDonnell Foundation
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Saint Louis, MO 63117
Phone: 314-721-1532