|
|
Autocrine pathways of the vascular endothelial
growth factor (VEGF) in glioblastoma multiforme: clinical relevance of
radiation-induced increase of VEGF levels
Steiner HH, Karcher S, Mueller MM, Nalbantis E, Kunze S, Herold-Mende C
Molecular Biology Laboratory, Department of Neurosurgery,
University of Heidelberg, INF 400, Germany. hsteiner@med.uni-heidelberg.de
In tumour-induced angiogenesis of gliomas, vascular endothelial growth factor
(VEGF) and its receptors fms-like tyrosine kinase (Flt-1) and
kinase-insert-domain-containing receptor (KDR) play a major role and are
promising targets for tumour therapy.
Nevertheless, preliminary results of such therapies could not prove clinical
efficacy and thus make a profound knowledge of VEGF regulation essential.
Based on earlier results, which demonstrated an inhibitory influence of VEGF on
Flt-1-expressing glioblastoma cells, in the present study we focused on the
extent of VEGF and VEGF receptor coexpression and possible therapeutical
consequences.
Protein expression of VEGF, Flt-1 and KDR was analysed by immunohistochemistry
in native tumour tissues of 63 glioblastomas.
VEGF could be detected in all glioblastomas.
Additionally and independently to the expected Flt-1 and KDR expression in
tumour endothelia, we found a coexpression of VEGF with Flt-1 in tumour cells of
46 and with KDR in 45 glioblastomas.
After exposure of glioblastoma cells to X-ray radiation we observed a strong
dose-dependent increase of VEGF secretion in two glioblastoma cell cultures by
up to 46% and 96%, respectively that originated from an increased VEGF mRNA
expression.
In contrast, under the same conditions secretion of HGF/SF was only slightly
elevated and bFGF despite being strongly increased remained at very low overall
amounts compared to VEGF.
Based on previous data on an autocrine function of VEGF in Flt-1-expressing
glioblastoma cells we hypothesise that the X-ray radiation induced upregulation
of VEGF might result in a downregulation of tumour cell proliferation and thus
lead to a reduced sensitivity to radiation therapy.
Therefore our results support the idea that a combination of anti-VEGF and
radiation therapy might prove a promising new option in fighting against one of
the most fatal tumour types.
PMID: 15015778 [PubMed - indexed for MEDLINE]
Source: http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?cmd=Retrieve&db=pubmed&dopt=Abstract&list_uids=15015778
|
