title: A mouse model of human primitive neuroectodermal tumors resulting from microenvironmentally-driven malignant transformation of orthotopically transplanted radial glial cells.
abstract: There is growing evidence and a consensus in the field that most pediatric brain tumors originate from stem cells, of which radial glial cells constitute a subtype. Here we show that orthotopic transplantation of human radial glial (RG) cells to the subventricular zone of the 3rd ventricle--but not to other transplantation sites--of the brain in immunocompromised NOD-SCID mice, gives rise to tumors that have the hallmarks of CNS primitive neuroectodermal tumors (PNETs). The resulting mouse model strikingly recapitulates the phenotype of PNETs. Importantly, the observed tumorigenic transformation was accompanied by aspects of an epithelial to mesenchymal transition (EMT)-like process. It is also noteworthy that the tumors are highly invasive, and that they effectively recruit mouse endothelial cells for angiogenesis. These results are significant for several reasons. First, they show that malignant transformation of radial glial cells can occur in the absence of specific mutations or inherited genomic alterations. Second, they demonstrate that the same radial glial cells may either give rise to brain tumors or differentiate normally depending upon the microenvironment of the specific region of the brain to which the cells are transplanted. In addition to providing a prospect for drug screening and development of new therapeutic strategies, the resulting mouse model of PNETs offers an unprecedented opportunity to identify the cancer driving molecular alterations and the microenvironmental factors that are responsible for committing otherwise normal radial glial cells to a malignant phenotype.
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Sergey
authors.initials: S
authors.lastname: Malchenko
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Division of Pediatric Neurosurgery, Department of Surgery, Ann & Robert H. Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Simone Treiger
authors.initials: ST
authors.lastname: Sredni
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan; iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan; Molecular Research Center for Children's Mental Development, United Graduate School of Child Development, Osaka University, Kanazawa University, Hamamatsu University School of Medicine, Chiba University and University of Fukui, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Hitoshi
authors.initials: H
authors.lastname: Hashimoto
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan; Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, 1-1 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kasai
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan; iPS Cell-based Research Project on Brain Neuropharmacology and Toxicology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Kazuki
authors.initials: K
authors.lastname: Nagayasu
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America.
authors.forename: Jianping
authors.initials: J
authors.lastname: Xie
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America.
authors.forename: Naira V
authors.initials: NV
authors.lastname: Margaryan
authors.affiliation: Laboratory of Molecular Neuropharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka, Japan; Interdisciplinary Program for Biomedical Sciences, Institute for Academic Initiatives, Osaka University, 1-1 Yamadaoka, Suita, Osaka, Japan.
authors.forename: Kaoru
authors.initials: K
authors.lastname: Seiriki
authors.affiliation: Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Division of Hematology/Oncology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Rishi R
authors.initials: RR
authors.lastname: Lulla
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Richard E B
authors.initials: RE
authors.lastname: Seftor
authors.affiliation: Cure-Juvenile Myositis Program of Excellence, Division of Pediatric Rheumatology, Ann & Robert H. Lurie Children's Hospital of Chicago and Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Lauren M
authors.initials: LM
authors.lastname: Pachman
authors.affiliation: Psychiatry & Behavioral Sciences at the Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Herbert Y
authors.initials: HY
authors.lastname: Meltzer
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Mary J C
authors.initials: MJ
authors.lastname: Hendrix
authors.affiliation: Cancer Biology and Epigenomics Program, Stanley Manne Children's Research Institute, Ann & Robert H. Lurie Children's Hospital of Chicago, Chicago, Illinois, United States of America; Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Robert H. Lurie Comprehensive Cancer Center, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America; Division of Hematology/Oncology, Department of Pediatrics, Feinberg School of Medicine, Northwestern University, Chicago, Illinois, United States of America.
authors.forename: Marcelo B
authors.initials: MB
authors.lastname: Soares
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D017690:Cell Transplantation; D004195:Disease Models, Animal; D006801:Humans; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D018242:Neuroectodermal Tumors, Primitive / Q000473:pathology*; D009457:Neuroglia / Q000166:cytology*; D059016:Tumor Microenvironment
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