Untersuchungen zu einem tumorrelevanten, FGF-bindenden Protein (FGF-BP)
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Philipps-Universität Marburg
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Abstract
The nearly ubiquitous growth factors FGF-1 and
FGF-2 play next to their physiological functions also a
important role in the growth of many neoplastic diseases. Upon
secretion though, FGF-1 and FGF-2 are immobilized in the
extracellular matrix (ECM) and are thus kept from activation of
their high-affinity FGF receptors.
A secreted FGF-binding
protein (FGF-BP) binds non-covalently and reversible to FGF-1
and FGF-2, releases them from the ECM and makes thus an
interaction with their receptors possible. This process of
growth factor bioactivation seems to play a pivotal role in the
growth of certain neoplastic diseases especially through
induction of tumor angiogenesis. This central regulative role
of FGF-BP in malignant diseases makes it a promising aim of
therapeutic and diagnostic means.
In the first part of this
thesis the biologic activity of exogenous applied recombinant
FGF-BP on tumor and endothelial cell lines was defined more
closely.
To accomplish this recombinant purified FGF-BP was
produced through a baculovirus expression system in insect
cells and a suspension culture for this system was
established.
The paracrine, FGF-2-dependend bioactivity of
the recombinant Bv-(FGF-BP) was shown using a softagar assay
with SW-13 and DU-145 cells. By adding (FGF-BP) a significant
enhancement in growth was induced which was completely
blockable by FGF-2 antibodies.
The growhts of HUVECs in
proliferation assays was also sped up by Bv-(FGF-BP). These
results indicate a dual growth-supporting role of FGF-BP in
tumors: Direct by stimulation of tumor cells and indirect by
induction of angiogenesis.
In the second part of this
thesis a previously detected pattern of specific
FGF-BP-immunoreactive high molecular weight forms, which
presumably represent stable covalent complexes of FGF-BP, were
examined.
After ruling out a possible glycation as a reason
for the occurence of these high molecular bands, FGF-BP and
FGF-2 were coexpressed in insect cells to gain clues about
intracellular complex formation. Despite succesful coexpression
a complex formation was not seen under the chosen conditions.
In the third part for the first time endogenous expressed
FGF-BP was shown through immunhistochemistry in prostate
carcinomas. In all 129 samples of 88 patients a positive
immunhistochemical reaction was seen.
These findings give
further insight about the biological effect of FGF-BP, show its
FGF-2-mediated, dual growth inducing action on tumors and its
expression in prostate cancer. These results emphasize the
possible relevance of this protein as a therapeutic target
molecule.The nearly ubiquitous growth factors FGF-1 and
FGF-2 play next to their physiological functions also a
important role in the growth of many neoplastic diseases. Upon
secretion though, FGF-1 and FGF-2 are immobilized in the
extracellular matrix (ECM) and are thus kept from activation of
their high-affinity FGF receptors.
A secreted FGF-binding
protein (FGF-BP) binds non-covalently and reversible to FGF-1
and FGF-2, releases them from the ECM and makes thus an
interaction with their receptors possible. This process of
growth factor bioactivation seems to play a pivotal role in the
growth of certain neoplastic diseases especially through
induction of tumor angiogenesis. This central regulative role
of FGF-BP in malignant diseases makes it a promising aim of
therapeutic and diagnostic means.
In the first part of this
thesis the biologic activity of exogenous applied recombinant
FGF-BP on tumor and endothelial cell lines was defined more
closely.
To accomplish this recombinant purified FGF-BP was
produced through a baculovirus expression system in insect
cells and a suspension culture for this system was
established.
The paracrine, FGF-2-dependend bioactivity of
the recombinant Bv-(FGF-BP) was shown using a softagar assay
with SW-13 and DU-145 cells. By adding (FGF-BP) a significant
enhancement in growth was induced which was completely
blockable by FGF-2 antibodies.
The growhts of HUVECs in
proliferation assays was also sped up by Bv-(FGF-BP). These
results indicate a dual growth-supporting role of FGF-BP in
tumors: Direct by stimulation of tumor cells and indirect by
induction of angiogenesis.
In the second part of this
thesis a previously detected pattern of specific
FGF-BP-immunoreactive high molecular weight forms, which
presumably represent stable covalent complexes of FGF-BP, were
examined.
After ruling out a possible glycation as a reason
for the occurence of these high molecular bands, FGF-BP and
FGF-2 were coexpressed in insect cells to gain clues about
intracellular complex formation. Despite succesful coexpression
a complex formation was not seen under the chosen conditions.
In the third part for the first time endogenous expressed
FGF-BP was shown through immunhistochemistry in prostate
carcinomas. In all 129 samples of 88 patients a positive
immunhistochemical reaction was seen.
These findings give
further insight about the biological effect of FGF-BP, show its
FGF-2-mediated, dual growth inducing action on tumors and its
expression in prostate cancer. These results emphasize the
possible relevance of this protein as a therapeutic target
molecule.
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Dates
Created: 2003Issued: 2003-12-22Updated: 2021-07-16
Faculty
Medizin
Publisher
Philipps-Universität Marburg
Language
ger
Data types
DoctoralThesis
Keywords
FGF-2FGF-BPFGF-2FGF-BP, angiogenesis, cancerfibroblast growth factor
DFG-subjects
AngiogeneseFibroblastenwachstumsfaktorKrebs
DDC-Numbers
610
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Butscheid, Moritz (128639857): Untersuchungen zu einem tumorrelevanten, FGF-bindenden Protein (FGF-BP). : Philipps-Universität Marburg 2003-12-22. DOI: https://doi.org/10.17192/z2003.0746.
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This item has been published with the following license: In Copyright