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282
Thymidine Phosphorylase in Human Esophageal
Squamous Cell Carcinoma
Yuji Takebayashi, M.D.1
Shoji Natsugoe, M.D.1
Masamichi Baba, M.D.1
Suminori Akiba, M.D.2
Toshitaka Fukumoto, M.D.1
Kazutaka Miyadera, Ph.D.3
Yuji Yamada, Ph.D.3
Sonshin Takao, M.D.1
Shin-ichi Akiyama, M.D.4
Takashi Aikou, M.D.1
1
First Department of Surgery, Faculty of Medicine,
Kagoshima University, Kagoshima, Japan.
2
Department of Public Health, Faculty of Medicine,
Kagoshima University, Kagoshima, Japan.
3
Taiho Pharmaceutical Company Ltd., Saitama,
Japan.
4
Department of Cancer Chemotherapy, Institute
for Cancer Research, Faculty of Medicine, Kagoshima University, Kagoshima, Japan.
BACKGROUND. Experimental evidence has shown that thymidine phosphorylase
(dThdPase) is identical to platelet-derived endothelial cell growth factor (PDECGF) and has angiogenic activity. The enzymatic activity of dThdPase was needed
for the angiogenesis by the enzyme. These observations were catalysts for the
current study.
METHODS. The authors examined retrospectively the expression of the angiogenic
factor dThdPase in 163 primary esophageal squamous cell carcinomas and its
association with angiogenesis and clinicopathologic findings. To determine
whether dThdPase expression was a prognostic factor after adjustment for the
established prognostic factors and microvessel count, the authors conducted a
survival analysis using the Cox proportional hazards model.
RESULTS. dThdPase was expressed significantly more frequently (P ⬍ 0.001) in
esophageal carcinomas (83 of 163, 50.9%) than in adjacent nonneoplastic esophageal tissue samples (20 of 163, 12.3%). Microvessel counts were significantly
higher (P ⬍ 0.001) in dThdPase positive carcinomas (18.3 ⫾ 6.2) than in dThdPase
negative carcinomas (8.2 ⫾ 7.5). Significant correlations were observed between
dThdPase expression and numerous clinicopathologic findings, including pT, pN,
pM categories; lymphatic invasion; venous invasion; and residual tumors. Prognostic variables studied using a Cox hazard regression model confirmed that
dThdPase expression was an independent prognostic factor in esophageal squamous cell carcinoma, although pN category was the best predictor of patient
survival.
CONCLUSIONS. This study indicated that in esophageal squamous cell carcinoma,
dThdPase expression is associated with angiogenesis and is an unfavorable prognostic factor. These findings implied that the inhibition of dThdPase would improve the prognoses of some patients with dThdPase positive esophageal tumors.
Cancer 1999;85:282–9. © 1999 American Cancer Society.
KEYWORDS: thymidine phosphorylase, angiogenesis, esophageal carcinoma, metastasis.
T
Address for reprints: Shin-ichi Akiyama, M.D., Department of Cancer Chemotherapy, Institute for
Cancer Research, Faculty of Medicine, Kagoshima
University, Sakuragaoka 8-35-1, Kagoshima 890,
Japan.
Received March 9, 1998; revision received July 1,
1998; accepted July 2, 1998.
© 1999 American Cancer Society
hymidine phosphorylase (dThdPase; EC 2.4.2.4) catalyzes the reversible phosphorolysis of thymidine, deoxyuridine, and their analogs to their respective bases and 2-deoxyribose-1-phosphate.1–3
dThdPase also catalyzes the transfer of deoxyribose from one deoxynucleoside to another base to form a second deoxynucleoside.4 – 6
In mammals, dThdPase consists of two identical subunits with a
molecular weight of 55 kilodaltons (kD).7 dThdPase is identical to
platelet-derived endothelial cell growth factor (PD-ECGF).8,9 PDECGF stimulates chemotaxis and [3H] thymidine incorporation by
endothelial cells in vitro and has angiogenic activity in vivo.10 –12
Recently, we demonstrated that the enzymatic activity of dThdPase
is indispensable for its angiogenic activity.12,13 Among the degradation
Thymidine Phosphorylase in Esophageal Carcinoma/Takebayashi et al.
products of thymidine by dThdPase, 2-deoxy-D-ribose, a
dephosphorylated product derived from 2-deoxy-D-ribose-1-phosphate, had chemotactic activity in vitro and
angiogenic activity in vivo. These findings suggested that
the enzymatic products may stimulate the chemotaxis of
endothelial and possibly other cells, causing angiogenesis. Transfection of PD-ECGF/dThdPase into transformed fibroblasts in nude mice resulted in increased
tumor vascularization.11 Overexpression of dThdPase in
MCF-7 cells transfected with dThdPase cDNA conferred
a growth advantage to these cells when xenografted into
nude mice, but it did not affect their growth in vitro,
suggesting angiogenic advantage of the dThdPase-expressing cells.14 Increased dThdPase expression in human breast carcinoma cells was shown to correlate with
microvessel density in the tumor.15 Areas of high blood
velocity in ovarian tumors were associated with increased expression of PD-ECGF/dThdPase.16 These observations suggest that dThdPase actually is involved in
angiogenesis in some human tumors. Compared with
adjacent normal tissues, higher levels of dThdPase were
observed in a variety of malignant tumors.15–25
Experimental evidence has shown that tumor
growth is dependent on angiogenesis.26,27 When tumors reach a size of a few millimeters, new capillaries
penetrate, allowing for rapid tumor growth. These new
vessels facilitate the entry of tumor cells into the vasculature and their subsequent metastasis, so that angiogenesis correlates with the probability of metastases.28 –30 Angiogenesis in human solid tumors is a risk
factor for metastasis and recurrence.31–38 The aims of
this study were to examine the expression of dThdPase
in esophageal squamous cell carcinomas and the correlation between dThdPase expression and angiogenesis, clinicopathologic findings, or clinical outcome.
283
TABLE 1
Relation between Thymidne Phosphorylase Expression and
Clinicopathologic Variables in 163 Patients with Esophageal
Carcinoma
dThdPase evaluation (%)
Variables
Sex
Female
Male
Histologic type
Well
Moderate
Poor
Residual tumor
R0
R1
pT category
pT1
pT2
pT3
pT4
pN category
N0
N1
pM category
M0
M1
Lymphatic invasion
Negative
Positive
Venous invasion
Negative
Positive
Stage
I
II
III
IV
Negative (n ⴝ 80)
Positive (n ⴝ 83)
8 (66.7)
72 (47.7)
4 (33.3)
79 (52.3)
33 (45.8)
36 (54.5)
11 (44.0)
39 (54.2)
30 (45.5)
14 (56.0)
69 (54.3)
11 (30.6)
58 (45.7)
25 (69.4)
35 (83.3)
7 (33.3)
30 (40.0)
8 (32.0)
7 (16.7)
14 (66.7)
45 (60.0)
17 (68.0)
49 (72.1)
31 (32.6)
19 (27.9)
64 (67.4)
64 (56.6)
16 (32.0)
49 (43.4)
34 (68.0)
45 (68.2)
35 (36.1)
21 (31.8)
62 (63.9)
68 (54.4)
12 (31.6)
57 (45.6)
26 (68.4)
29 (77.7)
24 (55.8)
12 (31.6)
15 (30.6)
4 (12.3)
19 (44.2)
26 (68.4)
34 (69.4)
P value
0.241
0.394
0.019
⬍0.001
⬍0.001
0.006
⬍0.001
0.023
⬍0.001
dThdPase: thymidine phosphorylase.
MATERIALS AND METHODS
Patients and Tumors
The characteristic features of the 163 patients with
esophageal carcinoma investigated in this study are
summarized in Table 1. We obtained informed consent from all the patients in this study. All patients
who underwent surgical resection in the First Department of Surgery of Kagoshima University Hospital
between January 1987 and December 1991 were evaluated. None had received prior chemotherapy or radiation therapy. Patients received postoperative therapy; however, there was no difference in outcome
among the various treatment modalities. Of the 163
patients, 151 were males, and 12 were females; the
average age was 63.5 years, ranging from 45 to 82
years. Histologic typing and grading of tumors was
performed according to the criteria established by the
World Health Organization.39 pT category, pN cate-
gory, and pM category were determined according to
TNM classification.40 The M category was determined
from clinical data, including intraoperative findings,
chest and bone radiography, ultrasonography, computed tomography, and laboratory tests reflecting
bone and liver metastasis. Tumor specimens were collected after obtaining informed consent in accordance
with institutional guidelines. The deepest invading
sites were selected for immunohistochemistry of factor VIII and dThdPase.
Immunohistochemical Detection and Evaluation of
dThdPase and Factor VIII
The sections were deparaffinized with xylene and dehydrated with 98% ethanol. Endogenous peroxidase
was blocked by immersing the slides in 0.3% hydrogen
284
CANCER January 15, 1999 / Volume 85 / Number 2
peroxide in absolute methanol for 20 minutes at room
temperature. After washing three times with phosphate-buffered saline (PBS) for 5 minutes, the sections
were blocked by soaking in PBS containing 1% bovine
serum albumin for 20 minutes at room temperature.
The blocked sections were incubated overnight at 4°C
with 0.5 mg/mL monoclonal antibody against dThdPase, which has been described previously.22,23,25 This
antibody was specific for detecting dThdPase in human esophageal carcinoma tissues.25 After 12 hours,
the slides were incubated for 30 minutes with biotinylated antimouse immunoglobulin (Ig) G diluted 100fold with PBS at room temperature, washed three
times in PBS for 15 minutes, and incubated with avidin-biotin-peroxidase complex diluted with PBS for 30
minutes.40 After three washes with PBS for 15 minutes,
the sections were incubated with 0.5 mg/mL diaminobenzidine and 0.03% (volume/volume) H2O2 in PBS
for 7 minutes and finally counterstained with hematoxylin prior to mounting. Serial sections also were
incubated with rabbit antiserum against human von
Willebrand factor (DAKO Corporation, Santa Barbara,
CA) diluted 1:200 with PBS containing 5% goat serum.
Antibody binding was detected by sequential incubation with biotinylated goat antirabbit serum. Other
procedures were the same as those described for dThdPase immunohistochemical staining. Representative
sections were made from nonneoplastic tissues and
carcinoma tissues, including the most invasive portions of carcinoma cells. For microscopic analysis, we
examined the whole field of each section whether or
not it was stained with the monoclonal antibody
against dThdPase. Tumor samples were considered to
be dThdPase positive when more than 5% of the carcinoma cells were stained, because less than 5% of
cells were stained in 85.9% of normal tissues (Figs. 1,
2A,B).
For microvessel counts, we screened areas of
intense neovascularization at low power magnification (⫻40 and ⫻100), then areas with the highest
number of factor VIII positive microvessels were
examined at higher power magnification (⫻400) to
obtain accurate microvessel counts (Fig. 2C,D). Both
the evaluation of dThdPase expression and the microvessel count were assessed by two investigators
(Y.T. and S.N.) without their knowledge of the clinicopathologic findings.
Statistical Analysis
Demographic and clinicopathologic characteristics
were compared between patients with dThdPase positive and negative tumors by using the chi-square test
or Student‘s t test.41 The Cox proportional hazards
model was used for the multivariate survival analy-
FIGURE 1. Percent of cells expressing thymidine phosphorylase (dThdPase)
in normal esophageal tissues and in esophageal carcinomas obtained from 163
patients on study.
sis.42 Maximum likelihood parameter estimates and
likelihood ratio statistics (LRS) in Cox proportional
hazards models were obtained by using a statistical
package, EPICURE (HiroSoft International Corporation, Seattle, WA).43 We calculated Wald-type confidence intervals. Tests for statistical interaction were
conducted by including a cross-product term of the
two variables of interest in a model. All P values presented are two-sided.
RESULTS
Expression of dThdPase in Normal Mucosa or
Esophageal Carcinoma
Most normal esophageal mucosal cells were not
stained with the anti-dThdPase antibody (Fig. 2A).
When nonneoplastic esophageal squamous cell epithelium was reacted with this antibody, positive dThdPase immunostaining usually was not detected, but
it was detected sometimes in the basal cells. In contrast, the cytoplasm of many esophageal carcinoma
cells was strongly stained (Fig. 2B). The percentage of
cells expressing dThdPase was less than 5% in 85.9%
of nonneoplastic tissues. The positivity of dThdPase in
esophageal carcinomas (83 of 163, 50.9%) was significantly higher (P ⬍ 0.001) than that of dThdPase in
normal tissues (23 of 163, 14.1%).
Thymidine Phosphorylase in Esophageal Carcinoma/Takebayashi et al.
285
FIGURE 2. Immunostaining for dThdPase in normal esophageal mucosal cells (A) and in esophageal carcinoma cells (B). Microvessel staining with antifactor VIII
antibody on a ⫻100 field (C) and on a ⫻400 field (D).
⫻400 field, 84.6% of samples were dThdPase positive.
Figure 4 shows that the mean microvessel count in
dThdPase positive esophageal carcinomas (18.3 ⫾ 6.2)
was significantly higher (P ⬍ 0.001) than that in dThdPase negative tumors (8.2 ⫾ 7.5).
Correlationship between Clinicopathologic Findings and
dThdPase Expression
FIGURE 3. Microvessel count in a ⫻400 field as a function of the percent of
cells expressing dThdPase. Overlap accounts for less than 166 points appearing on the graph.
Correlation between dThdPase Expression and
Microvessel Count
Figure 3 shows that the percentage of dThdPase positive cells increased with increasing microvessel count.
In tumors with microvessel counts of more than 20 per
Figure 4 and Table 1 summarize the relation between
clinicopathologic features and dThdPase expression in
esophageal carcinomas. Although no significant correlation was found between dThdPase expression and
age (Fig. 4A), sex, and histologic subtype (Table 1),
significant correlations with other clinicopathologic
findings were observed. Table 1 demonstrates that
dThdPase positive tumors invaded deeper and had a
higher frequency of lymph node metastasis than negative tumors (P ⬍ 0.001 and P ⬍ 0.01, respectively).
Expression of dThdPase was significantly higher in
carcinomas with lymphatic invasion (P ⬍ 0.001) and
venous invasion (P ⬍ 0.001), and patients with dThd-
286
CANCER January 15, 1999 / Volume 85 / Number 2
FIGURE 4. Distribution of age, tumor size, and microvessel count as a function of dThdPase expression. In both graphs, the box corresponds to the interquartile
ranges, with the lower boundary of the box representing the 25th percentile and the upper boundary representing the 75th percentile. The dotted line inside the
box represents the median value. The vertical lines represent the 5th and 95th percentiles, and the open circles represent the outliers. P values were calculated
by using Student’s t test.
Pase positive carcinomas had more advanced stages
than those with negative tumors (P ⬍ 0.001).
Prognostic Relevance and Proportional Hazards Analysis
To determine independent prognostic values on patient survival, a Cox regression model was constructed using dThdPase positivity, microvessel
count, and several clinicopathologic findings. The
analysis using model 1, which included microvessel
count but not dThdPase positivity, showed that pT
category, pN category, pM category, and residual
tumor were independent prognostic factors. Microvessel count was not an independent prognostic
factor (hazard ratio, 1.03; 95% confidence interval
[CI], 1.00 –1.06; P ⫽ 0.084). The analysis using model
2, which included dThdPase positivity in addition to
all of the covariables in model 1, showed that
dThdPase was an independent prognostic factor
(hazard ratio, 2.07; 95% CI, 1.04 – 4.10; P ⫽ 0.033),
although pN category was the best predictor of survival for patients with esophageal carcinomas (hazard ratio, 3.60; 95% CI, 1.82– 6.97; P ⬍ 0.001).
DISCUSSION
We found complete sequence identity between 120
amino acids of human dThdPase and the sequence
of PD-ECGF, and we also demonstrated that rPDECGF has dThdPase activity.8,9 These observations
and similar reports from other laboratories suggest
that human dThdPase is identical to PD-ECGF.44 – 46
PD-ECGF reportedly stimulated chemotaxis of endothelial cells in vitro and angiogenesis in vivo.10 In
accordance with this, we have demonstrated that
dThdPase has angiogenic activity and that its enzymatic activity is needed for angiogenesis.10 –13 In
human tissues, several investigators reported the
correlation between dThdPase expression and angiogenesis. In ovarian tumors, areas of increased
blood flows as a measure of angiogenesis were associated with elevated dThdPase expression.16 Expression of thrombomodulin, a marker protein for
an endothelial cell, was significantly correlated with
dThdPase activity in colorectal carcinomas, suggesting that this enzyme may be important in angiogenesis in human colorectal carcinomas.20 Similar findings were reported in breast,15 gastric,23,24 and
colorectal carcinomas.25 In this study, the correlation between dThdPase expression and microvessel
count as an indicator of angiogenesis also was observed in esophageal squamous cell carcinoma.
Retrospective study demonstrated significant
correlations between dThdPase expression and sev-
Thymidine Phosphorylase in Esophageal Carcinoma/Takebayashi et al.
287
TABLE 2
Results from Cox Proportional Hazard Regression Analysis for Survivals of 163 Patients with Esophageal Carcinomas
Model 1
Model 2
Variables (category)a
Hazard ratio
95% CI
P value
Hazard ratio
95% CI
P value
pT category
(T1, T2 ⫽ 0; T3, T4 ⫽ 1
pN category
(N0 ⫽ 0, N1 ⫽ 1
pM category
(M0 ⫽ 0, M1 ⫽ 1
Residual tumor
(R0 ⫽ 0, R1 ⫽ 1
Microvessel count (no.)
dThdPase positivity
Negative ⫽ 0, positive ⫽ 1
1.00
1.02
1.00
4.04
1.00
1.70
1.00
1.95
1.03
Reference
1.18–2.30
Reference
2.10–7.80
Reference
1.17–2.47
Reference
1.06–3.60
1.00–1.06
0.002
1.00
1.65
1.00
3.65
1.00
1.60
1.00
1.86
1.04
1.00
2.07
Reference
1.18–2.30
Reference
1.82–6.97
Reference
1.10–2.31
Reference
1.01–3.42
0.97–1.05
Reference
1.04–4.10
0.002
⬍0.001
0.006
0.035
0.084
⬍0.001
0.015
0.049
0.682
0.033
dThdPase: thymidine phosphorylase; CI: confidence interval.
a
The following codes were used: 0, negative; 1, positive, with the following hazard function at N time: W(t) ⫽ h0(t)exp(¥␤iXi), where h0 was a base line hazard rate, and X1 . . . Xn represented covariable
measurements. i␤1 . . . ␤N were regression parameters to be estimated. In model 1, covariables were age, sex, histologic type, tumor location, lymphatic invasion, venous invasion, pT category, pN category, pM
category, residual tumor, and microvessel count. Model 2 included dThdPase positivity in addition to the covariables in model 1.
eral clinicopathologic findings as well as clinical
outcome in primary esophageal carcinomas. The
proportion of dThdPase positive cells was higher in
carcinomas with deep invasion and/or lymph node
metastases. Angiogenesis is needed for rapid tumor
growth, and the vascularized tumor extends vertically into the deep tissues beneath the basement
membrane. The new proliferating capillaries disrupt
the basement membrane and are more penetrable
by tumor cells than mature vessels. During the vascular phase, tumor cells may be shed into the circulation.28 The clinical significance of these findings
has been documented in studies of cutaneous melanoma31 and of breast,32,33 prostate,34 lung,35,36 gastric,37 and colorectal39 carcinomas in which microvessel density has been shown to be correlated
significantly with the occurrence of metastases and
recurrence of the diseases. With this observation as
the model, the current study suggests that increased
dThdPase in esophageal carcinomas may enhance
invasiveness and the ability to metastasize of the
tumors by its angiogenic properties. dThdPase, but
not microvessel count, proved to be a significant
prognostic factor according to multivariate analysis
with the Cox hazard regression model (Table 2). We
previously reported that only Dukes stage and dThdPase expression, but not microvessel count, were
statistically significant prognostic factors for mortality of patients with colorectal carcinoma.25 Furthermore, dThdPase expression was not correlated
with microvessel counts in breast tumors and
MCF-7 cells.14,48 Recently, O’Brien et al. reported
that expression of PD-ECGF/dThdPase in invasive
bladder carcinomas was 33-fold higher than in superficial bladder carcinomas and that expression of
vascular endothelial cell growth factor in superficial
bladder carcinomas was higher than in invasive
bladder carcinomas.21 These findings suggest that
dThdPase has capabilities that are concerned with
the progression of carcinomas other than angiogenic activity.
dThdPase expression in esophageal squamous cell
carcinomas was higher than that in adjacent nonneoplastic tissues. dThdPase expression in esophageal
squamous cell carcinomas also was higher than that in
gastric and colorectal adenocarcinomas in the current
study.24,25 This may explain in part the reason why
patients with esophageal squamous cell carcinoma
showed poorer prognosis than those with adenocarcinomas of the stomach or colorectum.
This study showed that dThdPase expression in
esophageal carcinoma was correlated significantly
with several clinicopathologic findings and was an
independent prognostic factor in a multivariate Cox
proportional hazards regression model. A dThdPase
inhibitor, 6 amino-5-chrolouracil, inhibited the angiogenesis by dThdPase in a CAM assay or a mouse
gelatin sponge implanted assay.12,13 Although further
studies are needed to clarify the mechanism of dThdPase-mediated angiogenesis, invasiveness, and its
ability to metastasize, our current and previous studies10,13 suggest that inhibitors of this enzyme and prodrugs that are activated by this enzyme may suppress
the growth of dThdPase expressing tumors and may
be valuable in the therapy of patients with esophageal
carcinoma.
288
CANCER January 15, 1999 / Volume 85 / Number 2
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