Glioblastoma and cerebral microvascular
endothelial cell migration in response to tumor-associated growth factors
Brockmann MA, Ulbricht U, Gruner K, Fillbrandt R, Westphal M, Lamszus K
Hans-Dietrich Herrmann Laboratory for Brain Tumor Biology,
Department of Neurosurgery, University Hospital Hamburg-Eppendorf,
Martinistrasse 52, 20246 Hamburg, Germany.
Objective. Glioma cell migration is determined by a complex interplay
between soluble motogens and extracellular matrix components.
Several growth factors are thought to be involved in glioma cell migration;
however, little is known about their motogenic potency relative to one
Methods. Using modified Boyden chamber assays, we
compared the chemotactic effects of scatter factor/hepatocyte growth factor
(SF/HGF), transforming growth factor (TGF)-alpha, TGF-beta1, TGF-beta2,
epidermal growth factor (EGF), fibroblast growth factor (FGF)-1, FGF-2,
insulin-like growth factor (IGF)-1, IGF-2, platelet-derived growth factor
(PDGF)-AA, PDGF-BB, vascular endothelial growth factor (VEGF), pleiotrophin
(PTN), and midkine (MK) in concentrations ranging from 1 pmol/L to 50 nmol/L on
three different human glioblastoma cell lines.
Checkerboard analyses distinguished between chemotaxis and chemokinesis.
We further investigated the motogenic effects on human cerebral microvascular
endothelial cells and analyzed receptor expression profiles.
Results. SF/HGF was the most potent chemotactic factor
for all three glioblastoma cell lines, inducing up to 33-fold stimulation of
TGF-alpha showed the second strongest effect (up to 17-fold stimulation), and
FGF-1 was also chemotactic for all three glioblastoma cell lines analyzed
(maximal 4-fold effect).
EGF, FGF-2, IGF-1, IGF-2, TGF-beta1, and TGF-beta2 were chemotactic for one or
two of the cell lines (2- to 4-fold effects), whereas PDGF-AA, PDGF-BB, VEGF,
PTN, and MK had no effect.
In contrast, the most potent stimulators of cerebral microvascular endothelial
cell migration were PDGF-AA (4-fold) and PDGF-BB (6-fold).
Conclusion. The expression levels of SF/HGF and TGF-alpha
as well as their respective receptors, MET and EGFR, are known to correlate with
glioma malignancy grade.
The particularly strong motogenic effects of these two growth factors suggest
that they could be promising targets for an antimigratory component of glioma
therapy, at least in comparison with the 12 other factors that were analyzed.
PMID: 12762884 [PubMed - indexed for MEDLINE]