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EPHB4 tyrosine-kinase receptor expression and biological significance in soft tissue sarcoma.
[liposarcoma]
Soft
tissue
sarcomas
(
STS
)
are
heterogeneous
malignant
tumors
of
mesenchymal
origin
.
Due
to
low
incidence
and
high
number
of
different
histological
subtypes
,
their
pathogenesis
and
thus
potential
targets
for
their
therapy
remain
barely
investigated
.
Several
studies
revealed
significant
higher
EPHB
4
expression
in
malignancies
such
as
prostate
and
colorectal
cancer
showing
survival
advantages
for
these
tumor
cells
.
Therefore
we
studied
the
expression
of
EPHB
4
in
a
total
of
46
clinical
human
specimens
of
different
STS
and
human
fibroblasts
.
EPHB
4
mRNA
and
protein
expression
were
significantly
increased
in
synovial
sarcoma
.
After
targeting
EPHB
4
in
fibrosarcoma
,
synovial
sarcoma
,
liposarcoma
and
MFH
sarcoma
cell
lines
by
siRNA
or
by
inhibition
of
autophosphorylation
using
the
specific
EPHB
4
kinase
inhibitor
NVP-BHG
712
a
decreased
proliferation
rate
/
vitality
of
synovial-
and
fibrosarcoma
cells
was
observed
.
Silencing
of
EPHB
4
significantly
reduced
the
transmigration
of
synovial
sarcoma
cells
towards
fibroblasts
and
endothelial
cells
.
In
addition
,
we
assessed
the
anti-metastatic
effect
of
EPHB
4
inhibition
in
vivo
by
intraperitoneal
administration
of
the
EPHB
4
inhibitor
in
an
appropriate
sarcoma
lung
metastasis
xenograft
model
.
As
result
43
%
of
NVP-BHG
712
treated
mice
(
n
 
=
 
3
/
7
)
developed
pulmonary
metastases
whereas
all
control
mice
(
n
 
=
 
5
)
revealed
lung
metastases
.
The
residual
57
%
of
mice
(
n
 
=
 
4
/
7
)
showed
only
small
local
tumor
cell
spots
.
Size
measurements
of
the
Vimentin
positive
area
explained
significant
decrease
in
lung
metastasis
formation
(
p
 
<
 
0
.
05
)
after
EPHB
4
kinase
inhibition
.
In
summary
,
these
data
provide
first
evidence
of
the
importance
of
EPHB
4
in
the
tumorigenesis
of
synovial
sarcoma
and
present
EPHB
4
as
a
potential
target
in
the
therapy
of
this
malignancy
.
