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Establishment and characterization of esophageal squamous cell carcinoma patient-derived xenograft mouse models for preclinical drug discovery.
[esophageal carcinoma]
The
purpose
of
this
study
was
to
establish
and
characterize
patient-derived
esophageal
squamous
cell
carcinoma
xenograft
(
PDECX
)
mice
for
utilization
in
antitumor
drug
discovery
.
A
total
of
96
esophageal
squamous
cell
carcinoma
(
ESCC
)
tissues
from
Chinese
patients
were
transplanted
subcutaneously
into
immunodeficient
mice
.
Histology
,
EGFR
,
K-
ras
,
B-
raf
,
and
PIK
3
CA
mutations
,
and
HER
2
gene
amplifications
were
analyzed
in
both
patient
tumors
and
mouse
xenograft
tissues
using
immunohistochemistry
,
mutant-enriched
liquid
chip
sequencing
and
fluorescence
in
situ
hybridization
assays
,
respectively
.
Furthermore
,
in
vivo
efficacy
studies
using
five
PDECX
mice
harboring
a
variety
of
genetic
aberrations
were
performed
using
the
chemotherapy
agents
5
-
fluorouracil
(
5
-
FU
)
and
cisplatin
.
Thirty
-
seven
PDECX
mouse
models
were
successfully
established
in
immunodeficient
mice
.
Pathological
analysis
revealed
similar
histological
architecture
and
degrees
of
differentiation
between
patient
ESCC
and
xenografted
tumors
.
No
mutations
were
identified
in
EGFR
,
K-
ras
,
and
B-
raf
genes
in
either
xenograft
models
or
patient
ESCC
tissues
.
In
contrast
,
PIK
3
CA
gene
mutations
were
detected
in
12
.
5
%
(
12
/
96
)
ESCC
patients
and
18
.
9
%
(
7
/
37
)
PDECX
models
.
Interestingly
,
patient
ESCC
tissues
exhibiting
HER
2
overexpression
or
gene
amplification
were
unable
to
survive
in
immunodeficient
mice
.
Further
analysis
showed
that
PDECX
models
carrying
HER
2
2
+
expression
had
no
response
to
5
-
FU
/
cisplatin
,
compared
with
HER
2
-
negative
models
.
In
conclusion
,
a
panel
of
PDECX
mouse
models
,
which
include
PIK
3
CA
mutant
and
HER
2
-
positive
models
,
was
established
and
characterized
thus
mimicking
the
current
clinical
genetic
setting
of
esophageal
carcinoma
.
The
sensitivity
of
HER
2
-
negative
ESCC
models
to
chemotherapy
supports
stratification
approaches
in
the
treatment
of
esophageal
carcinoma
patients
and
warrants
further
investigation
of
the
impact
of
PI
3
KCA
on
treatment
response
.
Diseases
Validation
Diseases presenting
"pik3ca gene mutations"
symptom
esophageal carcinoma
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