Tumorigenesis in the Brain: Location, Location, Location Richard J. Gilbertson 1 and David H. Gutmann 2 1 Departments of Developmental Neurobiology and Oncology, St. Jude Children’s Research Hospital, Memphis, Tennessee and 2 Department of Neurology, Washington University School of Medicine, St. Louis, Missouri Abstract Emerging evidence from numerous laboratories supports the notion that brain tumors arise from cells with stem cell/ neuroglial progenitor cell properties (‘‘cancer stem cells’’). Two recent studies suggest that histologically similar tumors from different brain regions are molecularly distinct because they arise from distinct populations of site-restricted progen- itor cells. These new findings imply an interaction between the cell of origin, the tumor microenvironment, and specific cancer-causing genetic changes in the evolution of central nervous system tumors. [Cancer Res 2007;67(12):5579–82] Introduction Tumors of the central nervous system (CNS) account for less than 2% of all malignancies, yet brain tumors are the leading cause of cancer-related death in children and the fourth leading cause in adults (1). Glial cell tumors (gliomas and ependymomas) represent the most common CNS neoplasms in all age groups. Gliomas (astrocytomas) and ependymomas are composed of glial fibrillary acidic protein (GFAP)–immunoreactive neoplastic cells. Low-grade astrocytomas (e.g., pilocytic astrocytomas; PA) are more common in children and young adults and are typically located in the cerebellum, brainstem, and optic pathway. In contrast, malignant gliomas predominate in adults and usually arise supratentorially. Ependymomas are slow-growing tumors of children and young adults that originate from the wall of the cerebral ventricles or from the spinal canal, and are most commonly located in the posterior fossa and spinal cord. It has long been recognized that histologically identical brain tumors could exhibit strikingly diverse clinical behaviors; however, the molecular basis for this variability is currently unknown. Some of these differences may be attributable to the effects of specific genetic changes or unique growth-regulatory cues present in the tumor microenvironment. However, it is also possible that these clinical differences reflect the inherent properties of the tumor cell of origin. With the advent of high-density molecular profiling, it is nowpossibletodefinethegeneexpressionpatternsofbraintumors relative to their putative cell of origin. Previous microarray-based studies have identified differentially expressed transcripts that distinguish low-grade gliomas from nonneoplastic tissue as well as histologically identical but molecularly distinct tumor subgroups. Interestingly, many of these differentially expressed genes encode proteins with important roles in brain development and neuroglial progenitor differentiation, including neural cell adhesion molecule and connexin-43 (2), growth-associated protein-43 (3), brain lipid– binding protein (4), doublecortin and semaphorin-3B (5), and archaete-scute complex-1 (6). The relationship between glioma- genesisandbraindevelopmenthasbeenfurtherunderscoredbythe finding that high-grade gliomas can be subclassified according to the expression of gene signatures (neural, proliferating, and mesenchymal-like) characteristic of distinct stages and patterns of differentiation (7). Collectively, these observations raise the possibility that molecularly distinct subgroups of gliomas arise from specific populations of progenitors. This notion has recently been furthered by two groups employ- ing gene expression microarray analyses to define molecular differences between histologically identical glial cell tumors arising in distinct CNS locations (8, 9). Both studies showed that the site- specific tumor gene expression signatures were similar to those seen in normal neuroglial precursor cell populations (e.g., astro- cytes, radial glia, and neural stem cells) from the corresponding regions of the CNS. These findings raise the intriguing possibility that specific populations of progenitor cells within the nervous system give rise to histologically similar tumors with distinct molecular properties. Moreover, these observations underscore the relationship between neuro-oncology and developmental neurobi- ology and reinforce the need to view the process of CNS tumorigenesis in the context of normal brain development. Regional Diversity in Normal Neural Tissues Thediversityofcelltypesinthemammalianbrainisastounding. In the human brain, approximately 10 12 neurons are supported by more than 10 13 glial cells, and each of these two major cell types is composed of multiple distinguishable subtypes. It has been estimated that there are as many as 10,000 different forms of neurons; and numerous morphologic and molecular variants comprise the glial population. One of the most remarkable features oftheCNSisthedegreetowhichthiscellulardiversityisorganized spatiality, resulting in anatomic regions with distinct histologic structures and functions. A variety of cell-autonomous and non– cell-autonomous mechanisms have been shown to shape and maintain regional specification in the developing and mature CNS, and regional differences in neural progenitor cells are evident at the inception of neurogenesis. Progenitor cell populations capable of generating glia and neurons include both radial glia (RG) and neural stem cells (NSC). RG arise from neuroepithelial cells throughout the CNS at the start of neurogenesis, and represent the predominant neuronal progen- itor (10). These cells generally display a radial morphology and mixed primitive cell/glial immunophenotype, but the fate and a function of RG varies markedly from region to region within the CNS. In this regard, studies in which the fate of specific RG populationsaretracedgenetically in vivo (11), ex vivo studiesofRG differentiation (12), and live time-lapse video microscopy studies (13) collectively suggest that dorsal and ventral telencephalic RG Requests for reprints: David H. Gutmann, Department of Neurology, Washington University School of Medicine, Box 8111, 660 South Euclid Avenue, St. Louis, MO 63110. Phone: 314-362-7379; Fax: 314-362-2388; E-mail: gutmannd@wustl.edu or Richard J. Gilbertson, Department of Developmental Neurobiology, St Jude Children’s Research Hospital, Room 2006G, 332 North Lauderdale Street, Memphis TN 38105. Phone: 901-495-3913; Fax: 901-495-2270; E-mail: Richard.Gilbertson@ stjude.org. I2007 American Association for Cancer Research. doi:10.1158/0008-5472.CAN-07-0760 www.aacrjournals.org 5579 Cancer Res 2007; 67: (12). June 15, 2007 Review Downloaded from http://aacrjournals.org/cancerres/article-pdf/67/12/5579/2568347/5579.pdf by guest on 03 November 2022