Cancerous stem cells can arise from pediatric brain tumors.
Pediatric brain tumors are significant causes of morbidity and mortality. It has been hypothesized that they derive from self-renewing multipotent neural stem cells. Here, we tested whether different pediatric brain tumors, including medulloblastomas and gliomas, contain cells with properties similar to neural stem cells. We find that tumor-derived progenitors form neurospheres that can be passaged at clonal density and are able to self-renew. Under conditions promoting differentiation, individual cells are multipotent, giving rise to both neurons and glia, in proportions that reflect the tumor of origin. Unlike normal neural stem cells, however, tumor-derived progenitors have an unusual capacity to proliferate and sometimes differentiate into abnormal cells with multiple differentiation markers. Gene expression analysis reveals that both whole tumors and tumor-derived neurospheres express many genes characteristic of neural and other stem cells, including CD133, Sox2, musashi-1, bmi-1, maternal embryonic leucine zipper kinase, and phosphoserine phosphatase, with variation from tumor to tumor. After grafting to neonatal rat brains, tumor-derived neurosphere cells migrate, produce neurons and glia, and continue to proliferate for more than 4 weeks. The results show that pediatric brain tumors contain neural stem-like cells with altered characteristics that may contribute to tumorigenesis. This finding may have important implications for treatment by means of specific targeting of stem-like cells within brain tumors.
Hemmati
Houman D
HD
Division of Biology 139-74, California Institute of Technology, Pasadena, CA 91125, USA.
Nakano
Ichiro
I
Lazareff
Jorge A
JA
Masterman-Smith
Michael
M
Geschwind
Daniel H
DH
Bronner-Fraser
Marianne
M
Kornblum
Harley I
HI
D000071916:AC133 Antigen; D000818:Animals; D015703:Antigens, CD; D001921:Brain / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology*; D001973:Bromodeoxyuridine / Q000494:pharmacology; D002454:Cell Differentiation; D002648:Child; D004396:Coloring Agents / Q000494:pharmacology; D004268:DNA-Binding Proteins / Q000096:biosynthesis; D015972:Gene Expression Regulation, Neoplastic; D006023:Glycoproteins / Q000096:biosynthesis; D024002:HMGB Proteins; D006801:Humans; D007150:Immunohistochemistry; D007223:Infant; D009368:Neoplasm Transplantation; D009419:Nerve Tissue Proteins / Q000096:biosynthesis; D009457:Neuroglia / Q000473:pathology*; D009474:Neurons / Q000473:pathology*; D009687:Nuclear Proteins / Q000096:biosynthesis; D010455:Peptides; D010744:Phosphoric Monoester Hydrolases / Q000096:biosynthesis; D016601:RNA-Binding Proteins / Q000096:biosynthesis; D051381:Rats; D020133:Reverse Transcriptase Polymerase Chain Reaction; D055748:SOXB1 Transcription Factors; D013234:Stem Cells / Q000473:pathology*; D014157:Transcription Factors
D000071916:AC133 Antigen; D015703:Antigens, CD; D004396:Coloring Agents; D004268:DNA-Binding Proteins; D006023:Glycoproteins; D024002:HMGB Proteins; C491297:MSI1 protein, human; C491296:Msi1 protein, rat; D009419:Nerve Tissue Proteins; D009687:Nuclear Proteins; C000606023:PROM1 protein, human; D010455:Peptides; C000606025:Prom1 protein, rat; D016601:RNA-Binding Proteins; C527782:SOX2 protein, human; D055748:SOXB1 Transcription Factors; C527784:Sox2 protein, rat; D014157:Transcription Factors; D010744:Phosphoric Monoester Hydrolases; C022394:phosphoserine phosphatase; D001973:Bromodeoxyuridine