| Abstract |
Genetic alterations in astrocytic tumors have frequently been examined to
determine areas of possible intervention. Adult and pediatric tumor
samples as well as cell lines established from adult tumors have provided
the substrate for these analyses. Many adult cell lines have been
characterized and used as model systems to study brain tumor progression.
However, limited numbers of pediatric astrocytic cell lines have been
established for these purposes. Three new cell lines have been established
from pediatric glioblastoma multiforme (GBM) patients and two from
pediatric anaplastic astrocytoma (AA) patients. The cell lines were first
characterized for the most common genetic alterations observed in
astrocytic tumors and then were assessed for the potential to
differentiate in response to neurotrophins or retinoids. One cell line
expressed glial fibrillary acidic protein transcript. The transcripts for
EGFR, c-myc, N-myc, and basic fibroblast growth factor were examined for
alterations or overexpression of these genes. All five cell lines
expressed elevated levels of the EGFR transcript when compared to the
normal brain controls. One of the GBM cell lines expressed the c-myc
transcript at high levels as a result of an amplified c-myc gene.
Mutations in the p53 gene were found in all five cell lines. Three of the
cell lines had dominant negative p53 mutations in codons 273 or 248. One
cell line carried a mutation in codon 72 and the other had a loss of
function mutation. The primary tumors from which the cell lines were
derived also contained the same mutations. The expression of genes
required for a potential response to differentiating agents were assessed.
All five cell lines expressed transcripts for trkB and retinoic acid
receptor alpha, beta, and gamma; three expressed retinoic acid X receptor
alpha, and one expressed transcripts for gp75NGFR and trkC. However, none
of the cell lines differentiated after exposure to neurotrophins, retinoic
acids, or retinols. Treatment with retinaldehydes had a cytotoxic effect.
These in vitro findings may help to identify specific genes and compounds
of interest when evaluating new treatment strategies.
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