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Human
cortical glial tumors contain neural stem-like cells expressing
astroglial and neuronal markers in vitro
Ignatova TN, Kukekov VG, Laywell ED, Suslov ON, Vrionis FD,
Steindler DA
Departments of Neuroscience and Neurosurgery, McKnight Brain
Institute and Shands Cancer Center, University of Florida,
Gainesville, Florida 32610, USA.
Neural stem cells from neurogenic regions of mammalian CNS are
clonogenic in an in vitro culture system exploiting serum and
anchorage withdrawal in medium supplemented with methyl cellulose and
the pleiotropic growth factors EGF, FGF2, and insulin.
The
aim of this study was to test whether cortical glial tumors contain
stem-like cells capable, under this culture system, of forming clones
showing intraclonal heterogeneity in the expression of neural
lineage-specific proteins.
The
high frequencies of clone-forming cells (about 0.1-10 x 10(-3)) in
clinical tumor specimens with mutated p53, and in neurogenic regions
of normal human CNS, suggest that the ability to form clones in this
culture system is induced epigenetically.
RT-PCR
analyses of populations of normal brain- and tumor-derived sister
clones revealed transcripts for nestin, neuron-specific enolase, and
glial fibrillary acidic protein (GFAP).
However,
the tumor-derived clones were different from clones derived from
neurogenic regions of normal brain in the expression of transcripts
specific for genes associated with neural cell fate determination via
the Notch-signaling pathway (Delta and Jagged), and cell survival at
G2 or mitotic phases (Survivin).
Moreover,
the individual glioma-derived clones contain cells immunopositive
separately for GFAP or neuronal beta-III tubulin, as well as single
cells coexpressing both glial and neuronal markers.
The
data suggest that the latent critical stem cell characteristics can be
epigenetically induced by growth conditions not only in cells from
neurogenic regions of normal CNS but also in cells from cortical glial
tumors.
Moreover,
tumor stem-like cells with genetically defective responses to
epigenetic stimuli may contribute to gliomagenesis and the
developmental pathological heterogeneity of glial tumors.
Copyright
2002 Wiley-Liss, Inc.
PMID: 12203386 [PubMed - indexed for MEDLINE]
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