Identification of tumor-initiating cells in a highly aggressive brain tumor using promoter activity of nucleostemin.
Controversy remains over whether the cancer stem cell (CSC) theory applies to all tumors. To determine whether cells within a highly aggressive solid tumor are stochastically or hierarchically organized, we combined a reporter system where the nucleostemin (NS) promoter drives GFP expression (termed NS-GFP) with a mouse brain tumor model induced by retroviral Ras expression on a p16(Ink4a)/p19(Arf)-deficient background. The NS-GFP system allowed us to monitor the differentiation process of normal neural stem/precursor cells by analyzing GFP fluorescence intensity. In tumor-bearing mice, despite the very high frequency of tumorigenic cells, we successfully identified the NS-GFP(+) cells as tumor-initiating cells (T-ICs). The clonal studies conclusively established that phenotypical heterogeneity can exist among the cells comprising a genetically homogeneous tumor, suggesting that this aggressive brain tumor follows the CSC model. Detailed analyses of the NS-GFP(+) brain tumor cells revealed that T-ICs showed activation of the receptor tyrosine kinase c-Met, which functions in tumor invasiveness. Thus, the NS-GFP system provides a powerful tool to elucidate stem cell biology in normal and malignant tissues.
Tamase
Akira
A
Division of Molecular Genetics, Center for Cancer and Stem Cell Research, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-0934, Japan.
Muraguchi
Teruyuki
T
Naka
Kazuhito
K
Tanaka
Shingo
S
Kinoshita
Masashi
M
Hoshii
Takayuki
T
Ohmura
Masako
M
Shugo
Haruhiko
H
Ooshio
Takako
T
Nakada
Mitsutoshi
M
Sawamoto
Kazunobu
K
Onodera
Masafumi
M
Matsumoto
Kunio
K
Oshima
Masanobu
M
Asano
Masahide
M
Saya
Hideyuki
H
Okano
Hideyuki
H
Suda
Toshio
T
Hamada
Jun-ichiro
J
Hirao
Atsushi
A
D000071916:AC133 Antigen; D000818:Animals; D000831:Animals, Newborn; D015703:Antigens, CD / Q000378:metabolism; D001932:Brain Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000235:genetics*; D002454:Cell Differentiation; D002999:Clone Cells / Q000378:metabolism / Q000473:pathology; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics / Q000378:metabolism; D005434:Flow Cytometry; D019204:GTP-Binding Proteins; D006023:Glycoproteins / Q000378:metabolism; D049452:Green Fluorescent Proteins / Q000235:genetics / Q000378:metabolism; D007150:Immunohistochemistry; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D008822:Mice, Transgenic; D018613:Microscopy, Confocal; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009474:Neurons / Q000378:metabolism / Q000473:pathology; D009687:Nuclear Proteins / Q000235:genetics*; D010455:Peptides / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000235:genetics*; D019859:Proto-Oncogene Proteins c-met / Q000378:metabolism; D016601:RNA-Binding Proteins
D000071916:AC133 Antigen; D015703:Antigens, CD; D002352:Carrier Proteins; C417743:Cdkn2a protein, mouse; D019941:Cyclin-Dependent Kinase Inhibitor p16; D006023:Glycoproteins; D009687:Nuclear Proteins; D010455:Peptides; D016601:RNA-Binding Proteins; C470311:nucleostemin protein, mouse; D049452:Green Fluorescent Proteins; D019859:Proto-Oncogene Proteins c-met; D019204:GTP-Binding Proteins