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Differential effects of targeting Notch receptors in a mouse model of liver cancer.
[cholangiocarcinoma]
Primary
liver
cancer
encompasses
both
hepatocellular
carcinoma
(
HCC
)
and
cholangiocarcinoma
(
CC
)
.
The
Notch
signaling
pathway
,
known
to
be
important
for
the
proper
development
of
liver
architecture
,
is
also
a
potential
driver
of
primary
liver
cancer
.
However
,
with
four
known
Notch
receptors
and
several
Notch
ligands
,
it
is
not
clear
which
Notch
pathway
members
play
the
predominant
role
in
liver
cancer
.
To
address
this
question
we
utilized
antibodies
to
specifically
target
Notch
1
,
Notch
2
,
Notch
3
or
Jag
1
in
a
mouse
model
of
primary
liver
cancer
driven
by
AKT
and
NRas
.
We
show
that
inhibition
of
Notch
2
reduces
tumor
burden
by
eliminating
highly
malignant
hepatocellular
carcinoma
-
and
cholangiocarcinoma
-like
tumors
.
Inhibition
of
the
Notch
ligand
Jag
1
had
a
similar
effect
,
consistent
with
Jag
1
acting
in
cooperation
with
Notch
2
.
This
effect
was
specific
to
Notch
2
,
as
Notch
3
inhibition
did
not
decrease
tumor
burden
.
Unexpectedly
,
Notch
1
inhibition
altered
the
relative
proportion
of
tumor
types
,
reducing
HCC-like
tumors
but
dramatically
increasing
CC-like
tumors
.
Finally
,
we
show
that
Notch
2
and
Jag
1
are
expressed
in
,
and
Notch
2
signaling
is
activated
in
,
a
subset
of
human
HCC
samples
.
Conclusions
:
These
findings
underscore
the
distinct
roles
of
different
Notch
receptors
in
the
liver
and
suggest
that
inhibition
of
Notch
2
signaling
represents
a
novel
therapeutic
option
in
the
treatment
of
liver
cancer
.
(
Hepatology
2014
;
)
.
Diseases
Validation
Diseases presenting
"relative proportion"
symptom
cholangiocarcinoma
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