BASIC FIBROBLAST GROWTH-FACTOR AND FIBROBLAST GROWTH-FACTOR RECEPTOR-I ARE IMPLICATED IN THE GROWTH OF HUMAN ASTROCYTOMAS

Malignant astrocytomas are highly invasive, vascular neoplasms that co mprise the majority of nervous system tumors in humans. A strong assoc iation has previously been made between malignancy in human astrocytic tumors and increased expression of certain fibroblast growth factor ( FGF) family members, including basic and acidic FGF. The influence of endogenous basic FGF on glioblastoma cell growth in vitro was evaluate d using basic FGF-specific antisense oligonucleotides. These studies i ndicated that human glioblastoma cell growth in vitro, can be inhibite d by suppressing basic FGF expression. Human astrocytomas also exhibit ed changes in FGF receptor (FGFR) expression during the course of thei r progression from a benign to a malignant phenotype. FGFR2 (bek) expr ession was abundant in normal white matter and in all low grade astroc ytomas, but was not observed in glioblastomas. Conversely, FGFR1 (flg) expression was absent or barely detectable in normal white matter, bu t was significantly elevated in glioblastomas. Glioblastomas also expr essed an alternatively spliced form of FGFR1 containing two immunoglob ulin-like disulfide loops (FGFR1 beta), whereas normal human adult and fetal brain expressed a form of the receptor containing three immunog lobulin-like disulfide loops (FGFR1 alpha). Intermediate grades of ast rocytic tumors exhibited a gradual loss of FGFR2 and a shift in expres sion from FGFR1 alpha to FGFR1 beta as they progressed from a benigh t o a malignant phenotype. The underlying cytogenetic changes that contr ibute to these alterations are not entirely understood, but abnormalit ies in the p53 tumor suppressor gene may influence expression of bFGF as well as the FGFR. These results suggest that alterations in FGFR si gnal transduction pathways may play a critical role in the malignant p rogression of astrocytic tumors.