306 Current Stem Cell Research & Therapy, 2009, 4, 306-313 1574-888X/09 $55.00+.00 © 2009 Bentham Science Publishers Ltd. Cancer Stem Cells and the Biology of Brain Tumors Debora Gazzana Flores 1 , Pitia Flores Ledur 2 , Ana Lucia Abujamra 1,3,4 , Algemir Lunardi Brunetto 1,3,4 , Gilberto Schwartsmann 1,4,5 , Guido Lenz* ,2 and Rafael Roesler* ,1,4,6 1 Cancer Research Laboratory, University Hospital Research Center (CPE-HCPA), Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil; 2 Laboratory of Cellular Signaling and Plasticity, Department of Biophysics, Institute of Biosciences, Federal University of Rio Grande do Sul, 91501-970 Porto Alegre, RS, Brazil; 3 Children’s Cancer Institute (ICI-RS) and Pediatric Oncology Service, 90035-003 Porto Alegre, RS, Brazil; 4 National Institute for Translational Medicine (INCT-TM), 90035-003 Porto Alegre, RS, Brazil; 5 Department of Internal Medicine, Faculty of Medicine, Federal University of Rio Grande do Sul, 90035-003 Porto Alegre, RS, Brazil; 6 Laboratory of Molecular Neuropharmacology, Department of Pharmacology, Institute for Basic Health Sciences, Federal University of Rio Grande do Sul, 90046-900 Porto Alegre, RS, Brazil Abstract: There is now compelling evidence that brain tumors harbor a small population of cells characterized by their ability to undergo self-renewal and initiate tumors, termed cancer stem cells (CSCs). The development of therapeutic strategies targeted towards CSC signaling may improve the treatment of brain tumors such as malignant gliomas and me- dulloblastomas. Here we review the role of cancer stem cells in glioma and medulloblastoma and some of the signaling mechanisms involved in brain tumor stem cell (BTSC) biology, and discuss how these signaling pathways may represent new stem cell targets for the treatment of brain tumors. In addition, we provide illustrative immunohistochemical data on the presence of BTSCs in human gliomas and medulloblastomas, and show preliminary findings suggesting the involve- ment of a GPCR, the gastrin-releasing peptide receptor (GRPR), in the expansion of BTSCs in vitro. Keywords: Cell signaling, neural stem cells, cancer stem cells, glioma, medulloblastoma, brain tumors. INTRODUCTION Gliomas and medulloblastoma are the most frequent ma- lignant brain tumors in adults and children, respectively. The most prevalent and aggressive form of glioma is grade IV glioma (glioblastoma multiforme, GBM), which is highly malignant and resistant to standard chemotherapy. The prog- nosis of this tumor type remains poor despite optimal clinical treatment, with overall survival of less than 20% after one year and less than 5% after two years [1-3]. Medulloblas- toma is a primitive neuroectodermal tumor that represents the most common pediatric primary malignant intracranial neoplasm. In spite of significant advances in chemo- and radiation therapy, about 30% of patients still have a low chance of being cured and survivors experience long-term neurocognitive and/or neuroendocrine sequelae [4, 5]. The development of novel therapies based on the understanding of the basic biology of brain tumors is clearly needed to im- prove the treatment of both gliomas and medulloblastoma. In recent years, several studies have reported the pres- ence of a subpopulation of tumor cells with stem-cell like properties, termed cancer stem cells (CSCs), in both gliomas and medulloblastoma. These brain tumor stem cells (BTSCs) display self-renewal properties, unlimited growth, a high migration rate, resistance to chemotherapy, and are capable *Address correspondence to these authors at the Department of Biophysics, IB, Federal University of Rio Grande do Sul (Campus do Vale/UFRGS), 91501-970 Porto Alegre, RS, Brazil and Department of Pharmacology, ICBS, Federal University of Rio Grande do Sul (Campus Centro/UFRGS), 90046-900 Porto Alegre, RS, Brazil; E-mail: lenz@ufrgs.br and rroesler@terra.com.br of recapitulating the whole tumor cell population [6-8]. BTSCs provide a target for the treatment of malignant brain tumors, and understanding the signaling pathways involved in BTSC proliferation may contribute to the development of novel therapies. In this review, we discuss the role of BTSCs in the initiation and progression of brain tumors. We summa- rize some of the signaling pathways critically implicated in the proliferation of BTSCs, including G-protein coupled re- ceptors (GPCRs) as emerging targets to inhibit BTSC propa- gation and reduce brain tumor progression. Finally, we pre- sent original data illustrating the presence of BTSCs in glioma and medulloblastoma samples from patients and the possible role of a GPCR in stimulating the expansion of BTSCs in culture. STEM CELLS IN THE CENTRAL NERVOUS SYS- TEM Our understanding of BTSC biology has been enhanced by studies of normal stem cells in the central nervous system (CNS). Almost every known mammalian tissue contains a population of stem cells, which play a crucial role in tissue development and repair. Stem cells are defined as cells capa- ble of undergoing self renewal and generating all major cell types found in the host tissue, coordinating tissue generation, maintenance, and regeneration. In the adult CNS, stem cells differentiate into distinctive mature cell types. Thus, mul- tipotent neural stem cells (NSCs) can originate neurons, as- trocytes and oligodendrocytes via the generation of lineage- committed progenitor cell populations. Astrocytes may be derived from either oligodendrocyte type 2 astrocyte (O-2A) cells (which in turn derive from glial-restricted precursor cells) or astrocyte precursor cells, whereas oligodendrocytes