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Downloaded 09/27/21 07:54 AM UTC H Neurosurg Focus 8 (4):Article 1, 2000, Click here to return to Table of Contents A review of astrocytoma models HAO DING, M.D., PH.D., ANDRAS NAGY, PH.D., DAVID H. GUTMANN, M.D., PH.D., AND ABHIJIT GUHA, M.D., F.R.C.S.C. Samuel Lunenfeld Research Institute, Mt. Sinai Hospital; Department of Molecular and Medical Genetics; Labatts Brain Tumor Center, Hospital for Sick Childrens; Division of Neurosurgery, University Hospital Network, University of Toronto, Toronto,Ontario Canada; Department of Neurology, Washington University School of Medicine, St. Louis, Missouri Despite tremendous technical improvements in neuroimaging and neurosurgery, the prognosis for patients with malignant astrocytoma remains devastating because of the underlying biology and growth characteristics of the tumor. However, our understanding of the molecular bases of these tumors has greatly increased due to study findings involv- ing operative specimens, astrocytoma predisposing human syndromes, teratogen-induced animal and established human astrocytoma cell lines, and more recently transgenic mouse models. Appropriate small-animal models of spon- taneously occurring astrocytomas, which replicate the growth and molecular characteristics found in human tumors, are essential to test the relevance and interactions of these molecular aberrations. In addition, it is hoped that relevant molecular targets will eventually be therapeutically exploited to improve patient outcomes. Appropriate animal mod- els are also essential for testing these novel biological therapies, before they are brought to the clinic, requiring a large investment of time and money. In this paper, various astrocytoma models are discussed, with emphasis on transgenic mouse models that are of great interest to laboratory investigators. KEY WORDS • astrocytoma • glioblastoma multiforme • mouse • gene therapy Malignant astrocytoma represents one of the most dev- increasing understanding of the molecular pathogenesis astating tumors affecting children and adults. Surgery and and development of novel biological therapies of malig- adjuvant conventional radio- and chemotherapy have had nant astrocytomas, there is a need to develop appropriate minimal effect on changing the poor prognosis, which re- models in which to test these novel therapies. Indeed, mains at a median range of only 9 to 12 months.35 Malig- many adjuvant therapies, in which promise in various nant astrocytomas are composed of pleomorphic, hyper- existing in vitro and in vivo models of astrocytomas has proliferative infiltrative astrocytes, with areas of necrosis, been demonstrated, have been applied with little success increased tumor angiogenesis and regions of blood–brain in patients; however, there has been a significant cost in barrier breakdown. These heterogeneous pathological terms of time, patient psychological and occasional phys- characteristics pose major obstacles to the effective man- ical morbidity, and economic issues. These failures are agement of gliomas.11,35 In addition to pathological het- partly based on the fact that we sometimes short-circuit erogeneity, there is associated molecular heterogeneity, the rigors of the scientific investigational process because the expression, interactions, and functional importance of of the terminal nature of the disease and because of our which we have just begun to decipher.16,39,50 It is hoped own enthusiasm to obtain a cure. This has contributed to that this increased understanding of the molecular patho- cynicism and nihilism expressed by the public and clini- genesis of astrocytomas will lead to novel therapeutic tar- cians regarding the management of malignant astrocy- gets, which can be exploited in combination with a variety tomas. Hence, it is important that we expend the time and of genetic, pharmacological, and other approaches to effort to develop and test our novel therapies in appropri- improve the overall clinical prognosis. In tandem with our ate preclinical models that most accurately reproduce the clinical, histological, and molecular characteristics found in human astrocytomas; it is hoped that this will translate Abbreviations used in this paper: CDK = cyclin dependent kinase; into improved success in subsequent clinical trials. EFGR = epidermal growth factor receptors; ES = embryonic stem; GBM = glioblastoma multiforme; GFAP = glial fibrillary acid Currently available models of astrocytomas include in protein; NF = neurofibromatosis; PDGFR = platelet-derived growth vitro cell lines derived from human malignant astrocyto- factor receptor; TSC = tuberous sclerosis complex; VEGF = vascu- mas as well as chemically or virally induced rat or mouse lar endothelial growth factor. astrocytomas. These cell lines have certainly served to in- Neurosurg. Focus / Volume 8 / April, 2000 1 Unauthenticated | Downloaded 09/27/21 07:54 AM UTC H. Ding, et al. crease our knowledge of the genetic aberrations in astro- nant Brain Tumor-1 gene46), amplification of EGFR and/ cytomas, permitting a variety of molecular biological ma- or EGFRvIII, and overexpression of VEGF. A second, nipulations to test the functional significance of these younger group progresses through increasing grades of alterations. However, it is well recognized that cell lines astrocytomas, and in these GBMs there are also earlier harbor different genetic profiles that are not representative genetic aberrations such as loss of the p53, p16, and renti- of the parent tumor, a fact that is even more important in noblastoma cell cycle regulatory genes in combination heterogeneous tumors such as malignant astrocytomas. with overexpression of PDGFR.1,5,18,20,21,23,28,33,45,48,56,57,63 Current in vivo astrocytoma models include growth of Chromosomal and loss of heterozygosity analyses of these cell lines in heterotopic or orthotopic locations in GBMs demonstrate amplification and loss of several ge- immunocompromised or syngenic hosts; however, most netic loci. Amplifications most commonly involve chro- fail to recapitulate the infiltrative nature of human malig- mosomes 7 containing EGFR and 12q containing the nant astrocytomas. Human tumor explant xenograft mod- CDK4, MDM2, and Rap1B loci.37,51,68 Loss of the entire els also suffer from these deficiencies, even when chromosome or several regions on chromosome 10 is also attempts have been made to implant them into the brain prevalent in GBMs as discussed previously, with PTEN/ and additionally they are plagued by an extremely low and MMAC1 expression lost in a majority of GBMs, although variable tumor formation rate. Although chemically or the actual rate of mutations is much lower.61,64,65 Mutations virally induced animal models exist, they unfortunately and loss of heterorzygosity at the p53 loci (17p) are ob- also suffer from their low incidence of tumor formation, served in two thirds of lower-grade (World Health Or- and possess significant molecular and pathological differ- ganization Grades I and II) astrocytomas but in only ap- ences from human astrocytomas. Another group of poten- proximately one third of GBMs.18,56 Last, loss of CDK tial in vivo astrocytoma models are found in familial can- inhibitors (p16 and p15) and the loss of retinoblastoma are cer predisposition syndromes that are associated with an also frequently detected, such that aberrations of the p53 or increased incidence of astrocytomas and their correspond- retinoblastoma-regulated cell cycle pathways at one level ing gene knockout mouse models. These include NF1 or another are prevalent in most astrocytomas.1,28,33,48,57,63 and NF2, TSC, and the Li–Fraumeni cancer syndrome. Unfortunately, the corresponding knockout mice do not develop astrocytomas, perhaps reflecting a combination of CANCER PREDISPOSITION SYNDROMES the low incidence of astrocytomas in these familial syn- ASSOCIATED WITH ASTROCYTOMAS AND dromes, the requirement of additional genetic aberrations CORRESPONDING MOUSE MODELS for developing astrocytomas, and the limitations and dif- ferences in mouse models as compared with humans. Examination of cancer predisposition syndromes, Despite the limitations, ongoing research is still re- which have at least one well-characterized genetic alter- quired to develop spontaneously occurring small-animal ation, and their corresponding mouse knockout models is models of astrocytomas that mimic the pathological and potentially informative. The genetic alterations demon- molecular profile of human astrocytomas; additionally, strated in the predisposition syndromes are usually found research in these animal models has the potential to ad- in the more common sporadic human counterparts; there- vance our ability to treat and investigate this disease. Ideal fore, what we learn from studying these well-defined pa- animal models of human astrocytomas should fulfill the tient cohorts and the corresponding mouse models may be following criteria: 1) tumors should arise from astrocytes; extrapolated to the sporadic tumors. 2) tumors should be transformed as characterized by im- mortalization in vitro and the ability to be transplanted Neurofibromatosis Type 1 into syngeneic or immunocompromised hosts in vivo; 3) Neurofibromatosis Type 1 is a common autosomal tumors should develop in small inexpensive animals in dominant cancer predisposition neurocutaneous syndrome which there are relatively short and predictable induction in which 15 to 20% of affected individuals develop astro- times; 4) tumors should share similar molecular profiles cytomas, commonly involving the optic pathway.13 with
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