title: A novel, diffusely infiltrative xenograft model of human anaplastic oligodendroglioma with mutations in FUBP1, CIC, and IDH1.
abstract: Oligodendroglioma poses a biological conundrum for malignant adult human gliomas: it is a tumor type that is universally incurable for patients, and yet, only a few of the human tumors have been established as cell populations in vitro or as intracranial xenografts in vivo. Their survival, thus, may emerge only within a specific environmental context. To determine the fate of human oligodendroglioma in an experimental model, we studied the development of an anaplastic tumor after intracranial implantation into enhanced green fluorescent protein (eGFP) positive NOD/SCID mice. Remarkably after nearly nine months, the tumor not only engrafted, but it also retained classic histological and genetic features of human oligodendroglioma, in particular cells with a clear cytoplasm, showing an infiltrative growth pattern, and harboring mutations of IDH1 (R132H) and of the tumor suppressor genes, FUBP1 and CIC. The xenografts were highly invasive, exhibiting a distinct migration and growth pattern around neurons, especially in the hippocampus, and following white matter tracts of the corpus callosum with tumor cells accumulating around established vasculature. Although tumors exhibited a high growth fraction in vivo, neither cells from the original patient tumor nor the xenograft exhibited significant growth in vitro over a six-month period. This glioma xenograft is the first to display a pure oligodendroglioma histology and expression of R132H. The unexpected property, that the cells fail to grow in vitro even after passage through the mouse, allows us to uniquely investigate the relationship of this oligodendroglioma with the in vivo microenvironment.
authors.affiliation: Institut für Klinische Genetik, Medizinische Fakultät Carl Gustav Carus, Technische Universität Dresden, Dresden, Germany.
authors.forename: Barbara
authors.initials: B
authors.lastname: Klink
authors.forename: Hrvoje
authors.initials: H
authors.lastname: Miletic
authors.forename: Daniel
authors.initials: D
authors.lastname: Stieber
authors.forename: Peter C
authors.initials: PC
authors.lastname: Huszthy
authors.forename: Jaime Alberto
authors.initials: JA
authors.lastname: Campos Valenzuela
authors.forename: Jaime Alberto Campos
authors.initials: JA
authors.lastname: Valenzuela
authors.forename: Jörg
authors.initials: J
authors.lastname: Balss
authors.forename: Jian
authors.initials: J
authors.lastname: Wang
authors.forename: Manja
authors.initials: M
authors.lastname: Schubert
authors.forename: Per Øystein
authors.initials: PØ
authors.lastname: Sakariassen
authors.forename: Terje
authors.initials: T
authors.lastname: Sundstrøm
authors.forename: Anja
authors.initials: A
authors.lastname: Torsvik
authors.forename: Mads
authors.initials: M
authors.lastname: Aarhus
authors.forename: Rupavathana
authors.initials: R
authors.lastname: Mahesparan
authors.forename: Andreas
authors.initials: A
authors.lastname: von Deimling
authors.forename: Lars
authors.initials: L
authors.lastname: Kaderali
authors.forename: Simone P
authors.initials: SP
authors.lastname: Niclou
authors.forename: Evelin
authors.initials: E
authors.lastname: Schröck
authors.forename: Rolf
authors.initials: R
authors.lastname: Bjerkvig
authors.forename: Janice M
authors.initials: JM
authors.lastname: Nigro
mesh_terms: D000818:Animals; D001483:Base Sequence; D016172:DNA Fingerprinting; D004265:DNA Helicases / Q000235:genetics*; D017931:DNA Primers / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics*; D004195:Disease Models, Animal; D049452:Green Fluorescent Proteins / Q000378:metabolism; D006801:Humans; D007150:Immunohistochemistry; D007521:Isocitrate Dehydrogenase / Q000235:genetics*; D008279:Magnetic Resonance Imaging; D051379:Mice; D016688:Mice, Inbred NOD; D016513:Mice, SCID; D046228:Microarray Analysis; D008969:Molecular Sequence Data; D009837:Oligodendroglioma / Q000235:genetics*; D016601:RNA-Binding Proteins; D012097:Repressor Proteins / Q000235:genetics*; D017422:Sequence Analysis, DNA; D014183:Transplantation, Heterologous
chemical_list: C498610:CIC protein, human; D017931:DNA Primers; D004268:DNA-Binding Proteins; C492258:FUBP1 protein, human; D016601:RNA-Binding Proteins; D012097:Repressor Proteins; C485184:enhanced green fluorescent protein; D049452:Green Fluorescent Proteins; D007521:Isocitrate Dehydrogenase; C543588:IDH1 protein, human; D004265:DNA Helicases