THE POTENTIAL ROLE OF BASIC FIBROBLAST, GROWTH-FACTOR IN THE TRANSFORMATION OF CULTURED PRIMARY HUMAN FETAL ASTROCYTES AND THE PROLIFERATION OF HUMAN GLIOMA (U-87) CELLS

BASIC FIBROBLAST GROWTH factor (bFGF) is a potent stimulator of angiogenesis, proliferation, and invasion in human gliomas. To test the hypothesis that bFGF is important in the development of the malignant phenotype of human gliomas, bFGF expression was prospectively modulated in primary human fetal astrocytes and in an established human glioma cell line. Fetal astrocytes were transfected with a vector expressing bFGF modified by the addition of a secretory signal peptide sequence. Two of these bFGF astrocyte clones examined in vitro demonstrated anchorage-independent growth, loss of contact inhibition, and decreased glial fibrillary acidic protein immunoreactivity, changes consistent with cellular transformation. To analyze the inhibition of bFGF expression, phosphore-thioated bFGF antisense oligodeoxynucleotides were added to cultures of the U-87 human glioma cell line. The U-87 cell proliferation was inhibited to 70.6 +/- 0.4% of control at 10 mu Lmol/L and to 53.2 +/- 5.6% of control at 20 mu mol/L (P < 0.05). Both the 7.0- and 4.0-kilobase bFGF messenger ribonucleic acid transcripts were reduced after exposure to the antisense oligodeoxynucleotide, and cell-associated bFGF protein was reduced by 44%. The sense oligodeoxynucleotide, a negative control, failed to inhibit U-87 proliferation. These data support the concept that bFGF expression could be a key event in glial tumorigenesis that may be necessary for the sustained growth of human gliomas.