title: Invasion precedes tumor mass formation in a malignant brain tumor model of genetically modified neural stem cells.
abstract: Invasiveness, cellular atypia, and proliferation are hallmarks of malignant gliomas. To effectively target each of these characteristics, it is important to understand their sequence during tumorigenesis. However, because most gliomas are diagnosed at an advanced stage, the chronology of gliomagenesis milestones is not well understood. The aim of the present study was to determine the onset of these characteristics during tumor development. Brain tumor-initiating cells (BTICs) were established by overexpressing H-Ras(V12) in normal neural stem/progenitor cells isolated from the subventricular zone of adult mice harboring a homozygous deletion of the Ink4a/Arf locus. High-grade malignant brain tumors were then created by orthotopic implantation of 10(5) BTICs into the forebrain of 6-week-old wild-type mice. Micewere killed every week for 5 weeks, and tumors were assessed for cellular atypia, proliferation, hemorrhage, necrosis, and invasion. All mice developed highly invasive, hypervascular glioblastoma-like tumors. A 100% penetrance rate and a 4-week median survival were achieved. Tumor cell migration along fiber tracts started within days after implantation and was followed by perivascular infiltration of tumor cells with marked recruitment of reactive host cells. Next, cellular atypia became prominent. Finally, mass proliferation and necrosis were observed in the last stage of the disease. Video monitoring of BTICs in live brain slices confirmed the early onset of migration, as well as the main cell migration patterns. Our results showed that perivascular and intraparenchymal tumor cell migration precede tumor mass formation in the adult brain, suggesting the need for an early and sustained anti-invasion therapy.
authors.affiliation: Division of Gene Regulation, School of Medicine, Keio University, Tokyo, Japan.
authors.forename: Oltea
authors.initials: O
authors.lastname: Sampetrean
authors.forename: Isako
authors.initials: I
authors.lastname: Saga
authors.forename: Masaya
authors.initials: M
authors.lastname: Nakanishi
authors.forename: Eiji
authors.initials: E
authors.lastname: Sugihara
authors.forename: Raita
authors.initials: R
authors.lastname: Fukaya
authors.forename: Nobuyuki
authors.initials: N
authors.lastname: Onishi
authors.forename: Satoru
authors.initials: S
authors.lastname: Osuka
authors.forename: Masaki
authors.initials: M
authors.lastname: Akahata
authors.forename: Kazuharu
authors.initials: K
authors.lastname: Kai
authors.forename: Hachiro
authors.initials: H
authors.lastname: Sugimoto
authors.forename: Atsushi
authors.initials: A
authors.lastname: Hirao
authors.forename: Hideyuki
authors.initials: H
authors.lastname: Saya
mesh_terms: D000818:Animals; D001932:Brain Neoplasms / Q000473:pathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D005909:Glioblastoma / Q000473:pathology*; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009336:Necrosis; D009361:Neoplasm Invasiveness / Q000473:pathology; D009368:Neoplasm Transplantation; D058953:Neural Stem Cells; D016283:Proto-Oncogene Proteins p21(ras) / Q000096:biosynthesis; D025803:Tumor Suppressor Protein p14ARF / Q000235:genetics
chemical_list: D019941:Cyclin-Dependent Kinase Inhibitor p16; D025803:Tumor Suppressor Protein p14ARF; D016283:Proto-Oncogene Proteins p21(ras)