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Uterine-specific loss of Tsc2 leads to myometrial tumors in both the uterus and lungs.
[lymphangioleiomyomatosis]
Lymphangioleiomyomatosis
(
LAM
)
is
a
rare
disease
characterized
by
proliferation
of
abnormal
smooth-
muscle
cells
in
the
lungs
,
leading
to
functional
loss
and
sometimes
lung
transplantation
.
Although
the
origin
of
LAM
cells
is
unknown
,
several
features
of
LAM
provide
clues
.
First
,
LAM
cells
contain
inactivating
mutations
in
genes
encoding
Tsc
1
or
Tsc
2
,
proteins
that
limit
mTORC
1
activity
.
Second
,
LAM
tumors
recur
after
lung
transplantation
,
suggesting
a
metastatic
pathogenesis
.
Third
,
LAM
is
found
almost
exclusively
in
women
.
Finally
,
LAM
shares
features
with
uterine
leiomyomas
,
benign
tumors
of
myometrial
cells
.
From
these
observations
,
we
proposed
that
LAM
cells
might
originate
from
uterine
leiomyomas
containing
Tsc
mutations
.
To
test
our
hypothesis
,
and
to
develop
mouse
models
for
leiomyoma
and
LAM
,
we
targeted
Tsc
2
deletion
primarily
in
uterine
cells
.
In
fact
,
nearly
100
%
of
uteri
from
uterine
-
specific
Tsc
2
knockout
mice
developed
myometrial
proliferation
and
uterine
leiomyomas
by
12
and
24
weeks
,
respectively
.
Myometrial
proliferation
and
mTORC
1
/
S
6
activity
were
abrogated
by
the
mTORC
1
inhibitor
rapamycin
or
by
elimination
of
sex
steroid
production
through
ovariectomy
or
aromatase
inhibition
.
In
ovariectomized
Tsc
2
null
mice
,
mTORC
1
/
S
6
activity
and
myometrial
growth
were
restored
by
estrogen
but
not
progesterone
.
Thus
,
even
without
Tsc
2
,
estrogen
appears
to
be
required
for
myometrial
mTORC
1
/
S
6
signaling
and
proliferation
.
Finally
,
we
found
Tsc
2
null
myometrial
tumors
in
lungs
of
older
Tsc
2
uterine
-
specific
knockout
females
,
suggesting
that
lung
LAM
-like
myometrial
lesions
may
indeed
originate
from
the
uterus
.
This
mouse
model
may
improve
our
understanding
of
LAM
and
leiomyomas
and
might
lead
to
novel
therapeutic
strategies
for
both
diseases
.
Diseases
Validation
Diseases presenting
"uterine cells"
symptom
lymphangioleiomyomatosis
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