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 comprise the majority of nervous system tumors in humans. A strong association 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 evaluated using basic FGF-specific antisense oligonucleotides. These studies indicated that human glioblastoma cell growth in vitro, can be inhibited by suppressing basic FGF expression. Human astrocytomas also exhibited changes in FGF receptor (FGFR) expression during the course of their progression from a benign to a malignant phenotype. FGFR2 (bek) expression was abundant in normal white matter and in all low grade astrocytomas, but was not observed in glioblastomas. Conversely, FGFR1 (flg) expression was absent or barely detectable in normal white matter, but was significantly elevated in glioblastomas. Glioblastomas also expressed an alternatively spliced form of FGFR1 containing two immunoglobulin-like disulfide loops (FGFR1 beta), whereas normal human adult and fetal brain expressed a form of the receptor containing three immunoglobulin-like disulfide loops (FGFR1 alpha). Intermediate grades of astrocytic tumors exhibited a gradual loss of FGFR2 and a shift in expression from FGFR1 alpha to FGFR1 beta as they progressed from a benign to a malignant phenotype. The underlying cytogenetic changes that contribute to these alterations are not entirely understood, but abnormalities in the p53 tumor suppressor gene may influence expression of bFGF as well as the FGFR. These results suggest that alterations in FGFR signal transduction pathways may play a critical role in the malignant progression of astrocytic tumors.
Department of Neurosurgery, University of Texas M.D. Anderson Cancer Center, Houston 77030.
R S
RS
Morrison
F
F
Yamaguchi
H
H
Saya
J M
JM
Bruner
A M
AM
Yahanda
L A
LA
Donehower
M
M
Berger
D001253:Astrocytes / Q000378:metabolism; D001254:Astrocytoma / Q000473:pathology*; D001921:Brain / Q000378:metabolism / Q000473:pathology; D001932:Brain Neoplasms / Q000473:pathology*; D002455:Cell Division; D016222:Fibroblast Growth Factor 2 / Q000502:physiology*; D000091344:Filaggrin Proteins; D005786:Gene Expression Regulation; D016158:Genes, p53; D006801:Humans; D012333:RNA, Messenger / Q000378:metabolism; D017468:Receptors, Fibroblast Growth Factor / Q000235:genetics / Q000502:physiology*
C000717249:FLG protein, human; D000091344:Filaggrin Proteins; D012333:RNA, Messenger; D017468:Receptors, Fibroblast Growth Factor; D016222:Fibroblast Growth Factor 2