[CANCER RESEARCH 63, 3001–3004, June 1, 2003] Meeting Report Mouse Models of Human Cancer Consortium Symposium on Nervous System Tumors 1 David H. Gutmann, 2 Suzanne J. Baker, Marco Giovannini, Joel Garbow, and William Weiss Departments of Neurology [D. H. G.] and Radiology [J. G.], Washington University School of Medicine, St. Louis, Missouri 63110; Department of Developmental Neurobiology, St. Jude Children’s Research Hospital, Memphis, Tennessee 38105 [S. J. B.]; INSERM U343, 75010 Paris, France [M. G.]; and Department of Neurology, University of California-San Francisco, San Francisco, California 94143 [W. W.] Abstract Nervous system tumors represent unique neoplasms that arise within the central and peripheral nervous system. Recent progress in generating genetically engineered mouse models of these tumors has advanced our understanding of the critical molecular and cellular events important for the development of these tumors. Recently, the National Cancer Institute- sponsored Mouse Models of Human Cancer Consortium convened a meeting on Nervous System Tumors to review recent advances and sug- gest directions for future research. Refined and novel approaches to modeling central nervous system tumors, including gliomas, meningio- mas, medulloblastomas, and oligodendrogliomas, as well as peripheral nervous system tumors such as neurofibromas, schwannomas, and malig- nant peripheral nerve sheath tumors, were presented. In this review, we discuss the current status of mouse modeling of human nervous system cancers with a specific focus on unresolved scientific questions pertaining to the molecular genetics and cellular biology of these tumors. Introduction Nervous system tumors represent a unique challenge to clinicians because of the complexity of the brain, the difficulty in identifying precancerous lesions, and the limited effective therapies available (1). These tumors include those that grow within the CNS 3 (glioma, medulloblastoma, ependymoma, and meningioma), as well as those that are associated with peripheral nerves (schwannoma, neurofi- broma, and malignant peripheral nerve sheath tumor). Unlike other organ sites, screening of presymptomatic individuals is not possible, and tumors often grow to a considerable size before detection. In addition, there are very few successful therapeutic options, besides surgery, that have demonstrated effective local control and none, in the case of high-grade gliomas, that alter the long-term clinical out- come. The development and evaluation of effective therapies would be accelerated by the generation of adequate small animal tumor models that accurately recapitulate their human counterparts. The purpose of this meeting summary was to provide a current update of progress in the development, refinement, and application of mouse modeling of nervous system tumors, as well as to outline future directions for scientific investigation. Initial models of human nervous system tumors focused on the use of established tumor cell lines with specific genetic changes or human tumor explants grown in rodents (2), but over the past several years, the focus has shifted to the generation of mice with specific genetic changes that represent the common genetic alterations seen in human tumors (3). This approach has led to the development of GEM for each of the major nervous system tumor types. Within the CNS, four major tumor types have been successfully modeled, including astro- cytoma (glioma), oligodendroglioma, medulloblastoma, and meningi- oma (4). In the PNS, Schwann cell tumors (schwannomas, neurofi- bromas, and MPNSTs) have also been accurately modeled in GEM. Common Themes. On the basis of molecular genetic analyses of human tumors, there are genetic changes that occur commonly in the benign, low-grade tumors (initiating genetic changes), and other ge- netic alterations identified almost exclusively in high-grade tumors (progression-associated, cooperating genetic changes). Some of the specific initiating genetic events chosen for mouse modeling were based on the genes mutated in inherited cancer syndromes where affected individuals are prone to the development of nervous system tumors (5). In recent years, mouse models that use conventional gene targeting (standard knockout mice), conditional tissue-specific knock- out mice, and viral-mediated transgene delivery have been developed. Each of these approaches has its strengths and limitations, but all have proven that robust, accurate, small animal models of human nervous system tumors can be generated. Significant progress in adapting these models for preclinical applications has been made. Small animal imaging, including MRI, computerized tomography, and PET, have been used to detect many of these tumors in the living animal and follow their growth longitudinally. With the development of these mouse models, it has become possible to exploit GEM to address basic questions in cancer biology. In the case of many CNS tumors, the precise cell of origin is un- known. Although it is presumed that gliomas arise from astroglial cells and meningiomas arise from leptomeningeal cells, it is becoming increasingly clear that the consequences of specific genetic alterations have different effects depending on the developmental state of the cell (6). A common theme discussed in this meeting concerned the use of GEM to elucidate the cell of origin for CNS tumors. A second theme important in cancer progression involved the identification and characterization of cooperating, progression-asso- ciated, genetic changes. A number of specific genes have been studied and found to accelerate tumor development or promote malignant progression. These cooperating genetic events represent alterations in growth factor receptors or cell cycle regulatory genes. In addition to known cooperating genetic events, mouse models are now used to identify novel progression-associated events that may represent addi- tional targets for therapeutic drug design and tumor monitoring. In addition to specific genetic events that promote tumorigenesis, there are undoubtedly modifying genes in each of our genetic make-up that attenuate the probability that we will develop cancer. It Received 1/27/03; accepted 3/28/03. The costs of publication of this article were defrayed in part by the payment of page charges. This article must therefore be hereby marked advertisement in accordance with 18 U.S.C. Section 1734 solely to indicate this fact. 1 National Cancer Institute-sponsored symposium held in conjunction with the Society for Neuro-oncology Annual meeting in San Diego, CA on November 21, 2002. 2 To whom requests for reprints should be addressed, at 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@ neuro.wustl.edu. 3 The abbreviations used are: CNS, central nervous system; GEM, genetically engi- neered mice; PNS, peripheral nervous system; MPNST, malignant peripheral nerve sheath tumor; EGFR, epidermal growth factor receptor; GFAP, glial fibrillary acidic protein; MRI, magnetic resonance imaging; PET, positron emission tomography; RB, retinoblas- toma; Hif-1, hypoxia-inducible factor 1; PDGF, platelet-derived growth factor; Shh, Sonic Hedgehog; Nf, neurofibromatosis; RCAS, replication-competent, ALV-LTR, splice acceptor; TOR, target of rapamycin. 3001 Research. on December 4, 2021. © 2003 American Association for Cancer cancerres.aacrjournals.org Downloaded from