TY - JOUR
T1 - Invasion precedes tumor mass formation in a malignant brain tumor model of genetically modified neural stem cells
AU - Sampetrean, Oltea
AU - Saga, Isako
AU - Nakanishi, Masaya
AU - Sugihara, Eiji
AU - Fukaya, Raita
AU - Onishi, Nobuyuki
AU - Osuka, Satoru
AU - Akahata, Masaki
AU - Kai, Kazuharu
AU - Sugimoto, Hachiro
AU - Hirao, Atsushi
AU - Saya, Hideyuki
N1 - Funding Information:
Abbreviations: BTIC, brain tumor–initiating cell; NSC/NPCs, neural stem/progenitor cells; Ras-NSC, neural stem cells transduced with H-RasV12; SVZ, subventricular zone Address all correspondence to: Hideyuki Saya, MD, PhD, Division of Gene Regulation, Institute for Advanced Medical Research, Keio University School of Medicine, 35 Shinanomachi, Shinjuku-ku, Tokyo 160-8582, Japan. E-mail: [email protected] 1This study was supported by a Ministry of Education, Culture, Sports, Science, and Technology of Japan grant to H.S. 2This article refers to supplementary materials, which are designated by Videos W1 to W4 and Figure W1 and are available online at www.neoplasia.com. Received 6 May 2011; Revised 31 July 2011; Accepted 3 August 2011 Copyright © 2011 Neoplasia Press, Inc. All rights reserved 1522-8002/11/$25.00 DOI 10.1593/neo.11624
PY - 2011/9
Y1 - 2011/9
N2 - 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-RasV12 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 105 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.
AB - 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-RasV12 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 105 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.
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U2 - 10.1593/neo.11624
DO - 10.1593/neo.11624
M3 - Article
C2 - 21969812
AN - SCOPUS:80053452975
SN - 1522-8002
VL - 13
SP - 784
EP - 791
JO - Neoplasia
JF - Neoplasia
IS - 9
ER -