Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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Demash, D.V. Bazas, V.M. Lukianova, N.Yu Rozumiy, D.O. Chekhun, V.F. 2018-06-19T10:51:05Z 2018-06-19T10:51:05Z 2011 Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome / D.V. Demash, V.M. Bazas, N.Yu. Lukianova, D.O. Rozumiy, V.F. Chekhun // Experimental Oncology. — 2011. — Т. 33, № 3. — С. 182-185. — Бібліогр.: 7 назв. — англ. 1812-9269 https://nasplib.isofts.kiev.ua/handle/123456789/138646 en Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України Experimental Oncology Short communications Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome Article published earlier |
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Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome |
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Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome Demash, D.V. Bazas, V.M. Lukianova, N.Yu Rozumiy, D.O. Chekhun, V.F. Short communications |
| title_short |
Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome |
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Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome |
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Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome |
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Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome |
| title_sort |
molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome |
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Demash, D.V. Bazas, V.M. Lukianova, N.Yu Rozumiy, D.O. Chekhun, V.F. |
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Demash, D.V. Bazas, V.M. Lukianova, N.Yu Rozumiy, D.O. Chekhun, V.F. |
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Short communications |
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Short communications |
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2011 |
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English |
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Experimental Oncology |
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Article |
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1812-9269 |
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https://nasplib.isofts.kiev.ua/handle/123456789/138646 |
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Molecular profile of gastric cancer as a basis of individualized treatment and prognosis of disease outcome / D.V. Demash, V.M. Bazas, N.Yu. Lukianova, D.O. Rozumiy, V.F. Chekhun // Experimental Oncology. — 2011. — Т. 33, № 3. — С. 182-185. — Бібліогр.: 7 назв. — англ. |
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| fulltext |
182 Experimental Oncology 33, 182–185, 2011 (September)
MOLECULAR PROFILE OF GASTRIC CANCER AS A BASIS
OF INDIVIDUALIZED TREATMENT AND PROGNOSIS OF DISEASE
OUTCOME
D.V. Demash1,*, V.M. Bazas2,, N.Yu. Lukianova1, D.O. Rozumiy3, V.F. Chekhun1
1R.E. Kavetsky Institute of Experimental Pathology, Oncology and Radiobiology, NAS of Ukraine, Kyiv
03022, Ukraine
2P.L. Shupik National Medical Academy of Post-Garduate Education, Kyiv 04112, Ukraine
3National Cancer Institute, Ministry of Health of Ukraine, Kyiv 03022, Ukraine
Gastric cancer (GC) was the most frequent type
of malignant neoplasm worldwide in the 1980s. Although
its incidence has gradually declined in recent years, today
GC still is on the fourth place after lung, breast and
bowel cancers (14.9 new cases per 100,000 in 2010) [1].
In Ukraine GC is third after lung and skin cancer among
men and sixth after breast, skin, endometrial, intestinal
and cervical cancer among women.
GC still has a very high mortality rate (second af-
ter lung cancer) with 11,4 deaths per 100,000, which
continuously declines during last decades. Such high
mortality rate is caused by the fact that GC is often
diagnosed during late (ІІІ–ІV) stages, when tumor
becomes resistant to chemo- and radiotherapy [2, 3].
It is known that patients with tumors of the same
stage and histological type show totally different re-
sponse to therapy. That is why it is important to find
molecular markers which are associated with different
aspects of tumor growth and differentiation that would
help to predict the disease outcome [1, 4].
Changes in apoptosis and activation of signal
cascades are vitally important for tumors. Wild type
р53 is able to activate DNA repair proteins when DNA
has sustained damage, induce growth arrest by hold-
ing the cell cycle at the G1/S regulation point on DNA
damage recognition or initiate apoptosis if DNA damage
proves to be irreparable. The mutant form of this protein
(tp53) is unable to carry out its functions. Such changes
in p53 structure are observed in more than 50% of tu-
mors of different origin. Another important regulator
of apoptosis is BCL-2 protein which has an ability to in-
activate different proapoptotic proteins [1, 2].
EGFR and HER-2/neu are tyrosine kinase receptors
from the ErbB family which are often overexpressed
on the tumor cell membrane. These receptors are
activated by different ligands by homo- or heterodi-
merisation. The signal from intracellular tyrosine kinase
domain is then transduced to the NF-κB, AKT and
ERK signal pathways, phosphatydilinositol-3-kinase
or phospholipase C, what causes changes in apop-
tosis, cell division and differentiation [5].
Adhesion cell contacts formed by cadherin-catenin
complex (Е-cadherin, α- β- and γ-catenins) play
important role in GC growth. Intracellular domains
of E-cadherin are bound to β-catenin, γ-catenin and
p120ctn protein forming a cytoplasm cell adhesion
complex, which is necessary for formation of adhesive
cellular junctions. β-catenin and γ-catenin are also
bound to α-catenin, which connects cadherin-catenin
complex with actin cytoskeleton. Loss of any of these
proteins increases the risk of appearance of local
or distant metastases [2, 6].
Vascular endothelial growth factor (VEGF) induces
formation of protrusions in vascular walls, through
which proteins could move out of the blood vessels.
As a result, extravascular fibrin gel which mediates
growth of endothelial cells, is formed. This causes
blood vessels to grow into the tumor body, thus pro-
moting its growth. On the other hand, tumor which
has high microvessel density could be more sensitive
to chemotherapy [1–3].
So, the aim of the study was to perform complex
study of relations between clinico-morphological prog-
nostic factors and expression of regulators of apop-
tosis (p53, bcl-2), tyrosinkinase receptors (EGFR,
HER-2/neu), adhesion molecules (E-cadherin, α- and
β-catenins) and VEGF.
We have analyzed tumor samples from 150 GC pa-
tients using classic immunohistochemical method. Sex,
age of Gc patients and GC stage distribution correspond-
ed to the statistical data for the Ukrainian population.
Differences between groups were studied using Stu-
dent’s t-test, correlations were studied with computing
Pierson’s (r) and Chuprov’s (K) correlation coefficients.
On the first stage of the study we have analyzed
an expression of regulators of apoptosis, tyrosine
kinase receptors, markers of cell adhesion and
neoangiogenesis in relation to generally accepted
clinico-morphological tumor features (stage, depth
of invasion, local and distant metastases).
We revealed that 75.4 ± 4.0% of stage IV GC pa-
tients showed positive nuclear reaction with mAb spe-
cific to tp53, while only 24.1 ± 5.6 and 31.5 ± 4.4%
of patients with stage II and stage III GC, respectively,
had tp53-positive tumors (Table 1). In the meantime
Bcl-2 expression was predominantly found in tumors
of stage II patients (72.4 ± 5.8 vs. 14.8 ± 3.4 % and
*E-mail: oncom@onconet.kiev.ua
Abbreviations: EGFR – epidermal growth factor receptor; GC –
gastric cancer; mAb – monoclonal antibody; VEGF – vascular
endothelial growth factor.
Exp Oncol 2011
33, 3, 182–185
Experimental Oncology 33, 182–185, 2011 (September) 183
15.8 ± 3.4% for stage III and IV, respectively). Also
we have found moderate correlation between the stage
of the disease according to TNM and tp53 (K=0.34,
p<0.01) and Bcl-2 (K=0.32, p<0.01) expression.
Another interesting finding was moderate correlation
(r=0.32, p<0.01) between the presence of Bcl-2 pro-
tein and absence of tp53 in the tumor.
Table 1. Correlations between expression of molecular markers of apop-
tosis, angiogenesis, cell adhesion and tyrosine kinase receptors in GC tu-
mors and TNM stage of the disease
Marker
Stage
K Р% of positive tumors
II III IV
p53 24.1 ± 5.6 31.5 ± 4.4 75.4 ± 4.0 0.34 <0.01
Bcl-2 72.4 ± 5.8 14.8 ± 3.4 15.8 ± 3.4 0.32 <0.01
E-cadherin 79.3 ± 5.3 40.7 ± 4.7 36.8 ± 4.5 0.31 <0.01
α-catenin 51.7 ± 6.5 31.4 ± 4.4 29.8 ± 4.2 0.15 >0.05
β-catenin 37.9 ± 6.3 27.7 ± 4.3 24.5 ± 4.0 0.08 >0.05
EGFR 34.4 ± 6.2 29.6 ± 4.3 33.3 ± 4.4 0.06 >0.05
Her-2/neu 17.2 ± 4.9 27.7 ± 4.3 49.1 ± 4.6 0.30 <0.01
VEGF 24.1 ± 5.6 29.6 ± 4.3 71.9 ± 4.2 0.34 <0.01
We also found that Е-cadherin, α- and β-catenin
expression in GC tumors was often associated with
earlier stages of the disease. Particularly, 79.3 ± 5.3 %
of stage II tumors were E-cadherin-positive (K=0.31),
51.7 ± 6.5% — α-catenin-positive and 37.9 ± 6.3% —
β-catenin-positive. Statistical analysis showed sig-
nificant correlations only between the GC stage and
E-cadherin expression (K=0.31, p<0.01).
Other markers that showed significant differences
between different GC stages were Her-2/neu and
VEGF. Presence of both of these proteins in tumors
were associated with the stage IV of the disease (49.1 ±
4.6 and 71.9 ± 4.2% of positive tumors, respectively).
We also showed moderate correlation between VEGF
expression and tumor stage (К=0.34, p<0.05).
Next, we have studied the expression of mentioned
proteins in relation to parameters on which TNM
classification is based: T (depth of gastric wall inva-
sion), N (local metastases), M (distant metastases).
We didn’t observe any significant differences in expres-
sion of studied proteins in relation to M status because
of very small group of M-positive patients (n = 16).
We found that both studied regulators of apoptosis
(tp53 and Bcl-2) and VEGF were expressed mostly
in lymph-node positive GC tumors (55.2 ± 2.6%, 48.4 ±
2.4% and 51.3 ± 2.4%, respectively). Also, we ob-
served increase of Her-2/neu expression from 28.5 ±
1.7% in N0 tumors to 40.5 ± 2.1% in tumors with N2.
On the other hand, E-cadherin, α- and β-catenin–posi-
tive tumors were present in patients without regional
lymph node metastases (74.6 ± 3.1% for E-cadherin
and 61.9 ± 2.5% for α-catenin). We found moderate
correlations between E-cadherin (K=0.45, p<0.05),
α-catenin (K=0.41, p<0.05), and VEGF (K=0.41,
p<0.01) expression and lymph node status.
The only protein, which expression significantly dif-
fered between groups of patients with different T-stage
tumors was VEGF. Its expression correlated (K=0.32,
p<0.01) with T4 stage of gastric wall invasion (68.9 ±
3.2% of positive tumors).
Another significant criterion in diagnostics of neo-
plasms of any localization is their morphological inves-
tigation. Today Lauren’s GC classification [7] is often
used in clinical practice, according to which two types
of the disease are diagnosed: intestinal (slow growth,
high degree of differentiation) and diffuse (faster
growth, lower degree of differentiation).
We have found (Table 2) that E-cadherin and
β-catenin were associated with GC of intestinal type
(78.7 ± 5.0 and 63.6 ± 5.9%, respectively) which
is thought to be more favorable in prognosis because
of higher sensitivity to chemotherapy. Also positive
expression of both studied tyrosine kinase receptors
was related to this histological type of GC (69.7 ± 5.6%
for EGFR and 72.7 ± 5.4% for Her-2/neu). Statistical
analysis showed moderate correlations between E-
cadherin (r=0.36, p<0.01), β-catenin (r=0.39, p<0.01),
EGFR (r=0.42, p<0.01) and Her-2/neu (0.50, p<0.01)
expression and histological type of tumor. On the other
hand, tp53 and VEGF positive expression were markers
of diffuse GC type (r=0.48 and r=0.19, respectively).
Table 2. Correlations between expression of molecular markers of apop-
tosis, angiogenesis, cell adhesion and tyrosinkinase receptors in GC tu-
mors and histological type of the disease
Marker
Histological type of tumor
r р% of positive tumors
Intestinal type Diffuse type
р53 17.9 ± 2.5 72.7 ± 5.4 0.48 <0.01
Bcl-2 54.5 ± 6.1 46.1 ± 3.2 0.05 <0.01
E-cadherin 78.7 ± 5.0 34.1 ± 3.1 0.36 <0.01
α-catenin 42.4 ± 3.0 31.6 ± 6.0 0.08 <0.01
β-catenin 63.6 ± 5.9 18.8 ± 2.5 0.39 <0.01
EGFR 69.7 ± 5.6 20.5 ± 2.6 0.42 <0.01
Her-2/neu 72.7 ± 5.4 22.2 ± 2.7 0.50 <0.01
VEGF 39.3 ± 5.9 63.6 ± 3.1 0.19 <0.01
One of the main prognostic criteria of treatment
efficiency is the duration of the survival period.
We divided tumor samples into three groups according
to the length of patient survival period (Group 1 — less
than 12 months, Group 2 — 12–36 months and Group
3 — more than 36 months).
We showed that tumors from the patients from the
Group 1 expressed VEGF (64.9 ± 3.9 %), Bcl-2 (41.5 ±
3.9%) and tp53 (67.5 ± 3.7%) and were mostly E-
cadherin and α-catenin negative (16.8 ± 3.0% and
19.4 ± 3.1% of positive tumors, respectively). Patients
from the Group 2 were characterized by increased
number of Е-cadherin-positive (up to 66.6 ± 4.9%) and
α-catenin-positive (31.1 ± 4.8%) tumors, while number
of VEGF-positive tumors decreased (24.4 ± 4.5%).
The Group 3 of patients was characterized by highest
percent of E-cadherin- and α-catenin-positive tumors
(82.1 ± 5.1 % and 78.5 ± 5.4 %). Also, low and mode-
rate β-catenin, Her-2/neu and EGFR expression were
observed in all three groups of patients.
We found correlations between tp53 (K=0.34,
p<0.01), Bcl-2 (K=0.30, p<0.01), E-cadherin (K=0.48,
p<0.01), α-catenin (K=0.39, p<0.01) and VEGF
(K=0.35, p<0.01) and length of the survival period.
We also built Caplan — Meier survival curves
(Figure) for groups of patients with tumors positive
or negative by each studied marker. Analysis of these
curves confirmed the results mentioned above and
showed that patients with tp53-negative, Bcl-2-neg-
ative, E-cadherin-positive, α-catenin-positive and
184 Experimental Oncology 33, 182–185, 2011 (September)
VEF-negative tumors had significantly longer overall
survival period while we did not observe significant
differences between patients with β-catenin, EGFR
and Her-2/neu-positive and negative tumors.
Multifactor Cox analysis (Table 3) showed that
р53, Bcl-2, Е-cadherin, α-catenin and VEGF positive
expressions could be used as independent prognostic
factors. Particularly, Е-cadherin and α-catenin positive
expression, as well as loss of р53, Bcl-2 and VEGF
expression are markers of favorable disease prognosis
and correlates with longer survival period.
Table 3. Multifactor Cox analysis of studied markers
Marker β Р
р53 -0.33 <0.05
Bcl-2 -0.28 <0.05
E-cadherin 0.46 <0.05
α-catenin 0.51 <0.05
β-catenin -0.10 >0.05
Her-2/neu -0.14 >0.05
EGFR -0.08 >0.05
VEGF -0.36 <0.05
In conclusion, we showed strong correlation be-
tween expression of р53, Bcl-2, Е-cadherin, Her2/
neu and VEGF in tumor cells and the stage of disease
according to TNM classification. We observed the
highest percent of р53, Her-2/neu and VEGF positive
tumors in group of stage IV GC patients, while high
levels of Bcl-2 and E-cadherin were observed in tumors
of stage II GC patients. GC patients with Т4 degree
of gastric wall invasion show tendency to increased
percent of Bcl-2- and VEGF-positive tumors. Also
we showed that E-cadherin expression correlated with
absence of lymph node metastases and is observed
primarily in GC patients with II stage. β-catenin ex-
pression is more often observed in GC tumors without
distant metastases, while VEGF expression correlated
with T-stage and presence of metastases in regional
lymph nodes. Expression of some molecular markers
is associated with histological type and degree of tumor
differentiation. We observed increase of E-cadherin,
α-catenin, EGFR and Her2/neu-positive tumors in the
group of patients with intestinal type of GC. Tumors
of diffuse type often expressed р53 та VEGF. We proved
that the presence of р53, Bcl-2, Е-cadherin, α-catenin
and VEGF could be used as independent prognostic
markers of survival for GC patients: high Е-cadherin,
a b
c d
e f
100
80
60
40
20
0
0 0
%
000 0 0 00 0
0
p = 0,0042
E-cadterin+
E-cadterin–
00 0
100
80
60
40
20
0
0 0
%
000 0 0 00 0
0
p = 0,0217
α-cadterin+
α-cadterin–
00 0
100
80
60
40
20
0
0 0
%
000 0 0 00 0
0
p = 0,0029
p53+
p53–
00 0
100
80
60
40
20
0
0 0
%
000 0 0 00 0
0
p = 0,0008
Bcl-2+
Bcl-2–
00 0
100
80
60
40
20
0
0 0
%
000 0 0 00 0
0
p = 0,0109
VEGF+
VEGF–
00 0
100
80
60
40
20
0
0 0
%
000 0 0 00 0
0
p = 0,0502
EGFR+
EGFR–
00 0
Figure. Caplan — Meier survival curves for GC patients with tumors positive and negative by E-caddherin (A), α-catenin (B), tp53 (C),
Bcl-2 (D), VEGF (E) and EGFR (F) expression. Curves were compared using Wilcoxon U-test
Experimental Oncology 33, 182–185, 2011 (September) 185
α-catenin and low р53, Bcl-2 and VEGF expression
in tumor cells point on favorable prognosis of disease
outcome with significantly longer survival period.
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