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Antiangiogenic activity of trabectedin in myxoid liposarcoma: Involvement of host TIMP-1 and TIMP-2 and tumor thrombospondin-1.
[liposarcoma]
Trabectedin
is
a
marine
natural
product
,
approved
in
Europe
for
the
treatment
of
soft
tissue
sarcoma
and
relapsed
ovarian
cancer
.
Clinical
and
experimental
evidence
indicates
that
trabectedin
is
particularly
effective
against
myxoid
liposarcomas
where
response
is
associated
to
regression
of
capillary
networks
.
Here
,
we
investigated
the
mechanism
of
the
antiangiogenic
activity
of
trabectedin
in
myxoid
liposarcomas
.
Trabectedin
directly
targeted
endothelial
cells
,
impairing
functions
relying
on
extracellular
matrix
remodeling
(
invasion
and
branching
morphogenesis
)
through
the
upregulation
of
the
inhibitors
of
matrix
metalloproteinases
TIMP-
1
and
TIMP-
2
.
Increased
TIMPs
synthesis
by
the
tumor
microenvironment
following
trabectedin
treatment
was
confirmed
in
xenograft
models
of
myxoid
liposarcoma
.
In
addition
,
trabectedin
upregulated
tumor
cell
expression
of
the
endogenous
inhibitor
thrombospondin-
1
(
TSP
-
1
,
a
key
regulator
of
angiogenesis-dependent
dormancy
in
sarcoma
)
,
in
in
vivo
models
of
myxoid
liposarcomas
,
in
vitro
cell
lines
and
primary
cell
cultures
from
patients
'
myxoid
liposarcomas
.
Chromatin
Immunoprecipitation
analysis
showed
that
trabectedin
displaced
the
master
regulator
of
adipogenesis
C
/
EBP
β
from
the
TSP
-
1
promoter
,
indicating
an
association
between
the
up-regulation
of
TSP
-
1
and
induction
of
adipocytic
differentiation
program
by
trabectedin
.
We
conclude
that
trabectedin
inhibits
angiogenesis
through
multiple
mechanisms
,
including
directly
affecting
endothelial
cells
in
the
tumor
microenvironment-with
a
potentially
widespread
activity-and
targeting
tumor
cells
'
angiogenic
activity
,
linked
to
a
tumor
-
specific
molecular
alteration
.
Diseases
Validation
Diseases presenting
"primary cell cultures"
symptom
liposarcoma
pendred syndrome
well-differentiated liposarcoma
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