Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency
Aim: Due to the common etiologic factor, a considerable number of esophagogastric cancer patients suffer from respiratory insufficiency in course of chronic obstructive pulmonary disease, primary to cancer. Systemic hypoxemia may account for poor oxygenation of tumor tissue-a main driving force of t...
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Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України
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irk-123456789-1385522018-06-20T03:04:29Z Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Blachut, K. Kustrzeba-Wojcicka, I. Gamian, A. Original contributions Aim: Due to the common etiologic factor, a considerable number of esophagogastric cancer patients suffer from respiratory insufficiency in course of chronic obstructive pulmonary disease, primary to cancer. Systemic hypoxemia may account for poor oxygenation of tumor tissue-a main driving force of tumor neoangiogenesis. We hypothesized that in cancer patients with respiratory insufficiency, systemic hypoxemia may be related to enhanced aggressiveness of cancer on one side and to the elevation of angiogenic factors on the other. Methods: The levels of vascular endothelial growth factors A and C were determined with immunoenzymatic methods in patients diagnosed with esophagogastric cancer with or without co-existing respiratory insufficiency in course of chronic obstructive pulmonary disease and in healthy controls. Blood gasometry and hemoglobin levels of cancer patients were related to cancer histology and TNM status, and to circulating vascular endothelial growth factors A and C. Results: Patients with systemic hypoxemia had higher incidence rates of locally advanced tumors. Partial oxygen pressure and blood oxygen saturation were significantly lowered in patients with T4 cancers as compared to less advanced onces. Circulating vascular endothelial growth factor A, but not C, was more elevated in esophagogastric cancer patients with co-existing respiratory insufficiency, as compared to those without respiratory insufficiency. Vascular endothelial growth factor A was also strongly related to the extension of primary tumor. Conclusion: Our results show that systemic hypoxemia in esophagogastric cancer patients is associated with the extension of primary tumor and that this effect might be mediated by the up-regulation of circulating vascular endothelial growth factor A. Цель: в связи с общим этиологическим фактором заболевания , значительное количество больных гастроэзофагальным раком страдает от респираторной недостаточности в процессе хронического обструктивного легочного заболевания, кото- рое предшествует раку. Системная гип оксемия может влиять на пониженн ую оксигена цию опухолево й ткани — основной источник опухолевого неоангиогенеза. Авторы предп оложили , что у больных онкологического п рофиля с респираторно й недостаточностью системная гипоксемия может быть связана с повышенной агрессивностью опухолевого процесса, с одной стороны, и повышенным уровнем ангиогенных факторов — с другой. Методы: сод ержание факторов роста эндо- телия сосудов A и C ( VEGF ) опред еляли имму ноферментными мето дами у пациентов с гастроэзофагальным раком на фоне респираторной недостаточности в процессе хронического обструктивного заболевания легких или в отсутствие такового, а также у здоровых доноров. Анализировали д анные газометрии и сод ержания гемоглобина в зависимости от гистологии новообразования, статуса TNM и уровня VEGF A и C. Результаты: у больных с системно й гипоксемие й частота появления новообразований была выше. Парциальное давление кислоро да и насыщение крови кислоро д ом значительно снижено у пациентов с категорией T4. Повышение сод ержания циркулирующего VEGF A, но не C, более выражено у больных с респи- раторной недостаточностью, чем без нее. Содержание VEGF коррелировало с объемом первично й опухоли . Выводы: на результаты показывают, что системная гипоксемия у пациентов с гастроэзофагальным раком связана с увеличением объема первичной опухоли, и такой эффект может быть опосредован повышением содержания циркулирующего VEGF. 2007 Article Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency / M. Krzystek-Korpacka, M. Matusiewicz, D. Diakowska, K. Grabowski, K. Blachut, I. Kustrzeba-Wojcicka, A. Gamian // Experimental Oncology. — 2007. — Т. 29, № 3. — С. 236–242. — Бібліогр.: 29 назв. — англ. 1812-9269 http://dspace.nbuv.gov.ua/handle/123456789/138552 en Experimental Oncology Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
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Original contributions Original contributions Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Blachut, K. Kustrzeba-Wojcicka, I. Gamian, A. Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency Experimental Oncology |
| description |
Aim: Due to the common etiologic factor, a considerable number of esophagogastric cancer patients suffer from respiratory insufficiency in course of chronic obstructive pulmonary disease, primary to cancer. Systemic hypoxemia may account for poor oxygenation of tumor tissue-a main driving force of tumor neoangiogenesis. We hypothesized that in cancer patients with respiratory insufficiency, systemic hypoxemia may be related to enhanced aggressiveness of cancer on one side and to the elevation of angiogenic factors on the other. Methods: The levels of vascular endothelial growth factors A and C were determined with immunoenzymatic methods in patients diagnosed with esophagogastric cancer with or without co-existing respiratory insufficiency in course of chronic obstructive pulmonary disease and in healthy controls. Blood gasometry and hemoglobin levels of cancer patients were related to cancer histology and TNM status, and to circulating vascular endothelial growth factors A and C. Results: Patients with systemic hypoxemia had higher incidence rates of locally advanced tumors. Partial oxygen pressure and blood oxygen saturation were significantly lowered in patients with T4 cancers as compared to less advanced onces. Circulating vascular endothelial growth factor A, but not C, was more elevated in esophagogastric cancer patients with co-existing respiratory insufficiency, as compared to those without respiratory insufficiency. Vascular endothelial growth factor A was also strongly related to the extension of primary tumor. Conclusion: Our results show that systemic hypoxemia in esophagogastric cancer patients is associated with the extension of primary tumor and that this effect might be mediated by the up-regulation of circulating vascular endothelial growth factor A. |
| format |
Article |
| author |
Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Blachut, K. Kustrzeba-Wojcicka, I. Gamian, A. |
| author_facet |
Krzystek-Korpacka, M. Matusiewicz, M. Diakowska, D. Grabowski, K. Blachut, K. Kustrzeba-Wojcicka, I. Gamian, A. |
| author_sort |
Krzystek-Korpacka, M. |
| title |
Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency |
| title_short |
Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency |
| title_full |
Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency |
| title_fullStr |
Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency |
| title_full_unstemmed |
Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency |
| title_sort |
impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors a and c in gastroesophaeal cancer patients with chronic respiratory insufficiency |
| publisher |
Інститут експериментальної патології, онкології і радіобіології ім. Р.Є. Кавецького НАН України |
| publishDate |
2007 |
| topic_facet |
Original contributions |
| url |
http://dspace.nbuv.gov.ua/handle/123456789/138552 |
| citation_txt |
Impact of systemic hypoxemia on cancer aggressiveness and circulating vascular endothelial growth factors A and C in gastroesophaeal cancer patients with chronic respiratory insufficiency / M. Krzystek-Korpacka, M. Matusiewicz, D. Diakowska, K. Grabowski, K. Blachut, I. Kustrzeba-Wojcicka, A. Gamian // Experimental Oncology. — 2007. — Т. 29, № 3. — С. 236–242. — Бібліогр.: 29 назв. — англ. |
| series |
Experimental Oncology |
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2025-07-10T06:02:24Z |
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2025-07-10T06:02:24Z |
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| fulltext |
236 Experimental Oncology 29, 236–242, 2007 (September)
Tumor hypoxia is considered an important thera
peutic problem since hypoxic tumors are resistant to
some forms of radiochemotherapy as well as pho
todynamic therapy. Therefore, studies on hypoxia in
solid tumors have been included in the mainstream of
cancer research. Current knowledge on the subject is
pointing out at another alarming aspect of tumor hypo
xia. Hypoxia has been found to induce genomic and
proteomic changes in transformed cells, consequently
contributing to the development of more aggressive
tumor phenotypes [28].
The imbalance between oxygen delivery and
consumption, present in majority of locally advanced
solid tumors, is believed to result mainly from ischemic
and diffusional hypoxia. However, a growing body
of evidence has accumulated, suggesting that also
a reduced oxygen transport capability of blood and de
creased oxygen pressure may significantly contribute
to the adverse effects of tumor hypoxia [5, 27–28].
Angiogenesis is one of the most important mani
festations of the aggressiveness of hypoxic tumors,
while hypoxia is considered a main driving force of
neoangiogenesis [27, 28]. Still, the details of mo
lecular basis of this relationship remain unknown and
are intensively investigated [5]. Data on the impact of
systemic hypoxemia on expression and secretion of
factors involved in the induction and sustain of angio
genesis are scanty and so far confusing.
A considerable number of patients diagnosed with
esophagogastric cancer suffer from chronic obstruc
tive pulmonary disease (COPD) due to the common
etiologic factor — smoking. Smoking is a recognized
risk factor of esophageal cancers, which, in associa
tion with an alcohol abuse, accounts for more than
90% of esophageal squamous cell carcinoma cases
in the developed world [3]. Similarly, up to 90% of
COPD cases results from smoking. COPD is defined
as a disease state with airflow limitation that is not fully
reversible. Respiratory insufficiency, which may occur
in COPD patients is mainly a result of ventilation/perfu
sion mismatching [17]. In addition to common etiologic
factor, the involvement of vascular endothelial growth
factor A (VEGFA), a key regulator of angiogenesis,
has been described in pathogenesis of both cancer
[21] and COPD [8, 16].
We designed our studies to test the hypothesis
that respiratory insufficiency present in a number of
patients with esophagogastric cancers due to the
background chronic pulmonary diseases may be as
Impact of systemIc hypoxemIa on cancer
aggressIveness and cIrculatIng vascular endothelIal
growth factors a and c In gastroesophaeal cancer
patIents wIth chronIc respIratory InsuffIcIency
M. Krzystek-Korpacka1, *, M. Matusiewicz1, D. Diakowska2,
K. Grabowski2, K. Blachut3, I. Kustrzeba-Wojcicka1, A. Gamian1, 4
1Department of Medical Biochemistry, Silesian Piasts University of Medicine, Wroclaw, Poland
2Department of Gastrointestinal and General Surgery, Silesian Piasts University of Medicine, Wroclaw, Poland
3Department of Gastroenterology and Hepatology, Silesian Piasts University of Medicine, Poland
4Institute of Immunology and Experimental Therapy, Polish Academy of Sciences, Wroclaw, Poland
Aim: Due to the common etiologic factor, a considerable number of esophagogastric cancer patients suffer from respiratory insuffi-
ciency in course of chronic obstructive pulmonary disease, primary to cancer. Systemic hypoxemia may account for poor oxygenation
of tumor tissue-a main driving force of tumor neoangiogenesis. We hypothesized that in cancer patients with respiratory insufficiency,
systemic hypoxemia may be related to enhanced aggressiveness of cancer on one side and to the elevation of angiogenic factors on
the other. Methods: The levels of vascular endothelial growth factors A and C were determined with immunoenzymatic methods in
patients diagnosed with esophagogastric cancer with or without co-existing respiratory insufficiency in course of chronic obstructive
pulmonary disease and in healthy controls. Blood gasometry and hemoglobin levels of cancer patients were related to cancer histolo-
gy and TNM status, and to circulating vascular endothelial growth factors A and C. Results: Patients with systemic hypoxemia had
higher incidence rates of locally advanced tumors. Partial oxygen pressure and blood oxygen saturation were significantly lowered
in patients with T4 cancers as compared to less advanced onces. Circulating vascular endothelial growth factor A, but not C, was
more elevated in esophagogastric cancer patients with co-existing respiratory insufficiency, as compared to those without respira-
tory insufficiency. Vascular endothelial growth factor A was also strongly related to the extension of primary tumor. Conclusion:
Our results show that systemic hypoxemia in esophagogastric cancer patients is associated with the extension of primary tumor
and that this effect might be mediated by the up-regulation of circulating vascular endothelial growth factor A.
Key Words: hypoxemia, esophagogastric cancer, angiogenesis, VEGF-A, VEGF-C, COPD, respiratory insufficiency.
Received: May 21, 2007.
*Correspondence: Fax: + 48 71 784 00 85
E-mail: krzystek@bioch.am.wroc.pl
Abbreviations used: ADC – adenocarcinoma; COPD — chronic
obstructive pulmonary disease; SCC — squamous cell carcinoma;
VEGF-A — vascular endothelial growth factor A; VEGF-C — vascu-
lar endothelial growth factor C.
Exp Oncol 2007
29, 3, 236–242
Experimental Oncology 29, 236–242, 2007 (September) 23729, 236–242, 2007 (September) 237September) 237) 237 237
sociated with more aggressive tumors on one side and
upregulation of angiogenic factors on the other.
materIals and methods
Patients. A study group included 81 subjects:
34 patients diagnosed with esophagogastric cancer
and 47 healthy individuals. Sera from blood donors
(six females and 41 males; mean age 44.5 years)
acknowledged healthy on the basis of routine labora
tory tests served as controls and were obtained from
Regional Center of Blood Donation and Therapeutics,
Wroclaw, Poland. Cancer patients (seven females and
27 males; mean age 60 years) were treated in the De
partment of Gastrointestinal and General Surgery of our
institution. All patients were informed about the study.
The stady was approved with local ethic committec.
They were staged clinically according to the guide
lines of UICC TNM [20] system on the basis of upper
digestive tract (udt) endoscopy with the biopsy and
pathologic examination, contrast radiographic studies
of the udt with barium or gastrografin, posteroanterior
and lateral chest radiography, ultrasound examination
of the abdominal cavity and cervical nodes, thorax
and abdominal cavity CT, diagnostic laparotomy and
thoracotomy. We examined 25 cases of squamous cell
carcinomas (SCC) and nine cases of adenocarcinomas
(ADC). Seven patients were presenting with disease
stage II, 14 with stage III and 13 with stage IV. The
recruited cancer patients had a long history of heavy
smoking. The analysis of blood gases was performed
as a part of the routine, pretreatment assessment of
patients’ general condition. Gasometric studies were
conducted on patients at rest, breathing room air. Partial
respiratory insufficiency (hypoxemia without hypercap
nia) was recognized in 19 out of 34 cancer patients and
was related to the coexistence of chronic pulmonary
disorders (COPD). Mean pO2 level in cancer patients
was 61.4 mmHg, SaO2 — 91.6%, pCO2 — 37.4 mmHg.
Presence of mildgrade anemia was recognized in
19 cancer patients. The following diagnostic criteria
were applied: systemic hypoxemia — pO2 < 60 mmHg
or SaO2 < 90%; anemia — hemoglobin (Hb) < 13 g/dL or
< 12 g/dL in male and female patients, respectively.
Analytical methods. VEGFC and VEGFA con
centrations were assayed according to the manufac
turer instructions by commercially available double
antibody indirect enzymelinked immunosorbent tests
(DASIELISA) provided by IBLHamburg, Germany.
Factors’ levels were determined in sera obtained from
blood by its clotting for 15 minutes at room tempera
ture and subsequent centrifugation for 15 minutes at
3000 rpm. All measurements were duplicated.
Statistical analyses. Data distribution was ana
lyzed with D’AgostinoPearson test for normality. Levels
of pO2, SaO2 and Hb were distributed normally but nei
ther raw data nor logtransformed data on VEGFA and
VEGFC levels had Gaussian distribution. Therefore,
pO2, SaO2 and Hb levels are presented as mean values
with standard error (SE), while VEGFA and VEGFC
results are presented as median values with interquar
tile range (25–75%). The significance of differences
between groups was examined with nonparametric
Mann — Whitney U test (twogroup comparisons) or
Kruskal — Wallis ANOVA rank test (multigroup com
parisons). Correlation analysis was conducted with
Spearman or Pearson’s test in respect to data type
and distribution. Differences in incidence rates were
analyzed with Fisher’s exact test. Kendal tau (in 2 x 2
tables) or Spearman rho coefficients were calculated
for evaluation of the strength of studied relation. All tests
were twosided and p values ≤0.05 were considered
significant. Statistical analysis was conducted with
MedCalc® version 9.2.1.0 statistical software.
results
Patients with systemic hypoxemia had higher
incidence rates of locally advanced tumors. We
evaluated whether and which (if any) of clinicopatho
logical factors were associated with the presence
of systemic hypoxemia in a number of patients with
esophagogastric cancers. The incidence rates of sys
temic hypoxemia in respect to tumor histology, disease
TNM stage and coexistence of anemia, together with
the strength of the association are presented in Table 1
(systemic hypoxemia in terms of pO2) and Table 2
(systemic hypoxemia in terms of SaO2).
Table 1. Evaluation of association between cancer-related variables and
respiratory insufficiency determined in terms of decreased oxygen partial
pressure (pO2) in esophagogastric cancer
Parameter
Incidence of hypoxemia Correlation analysis
Normox-
emic
Hypox-
emic
p value Coef-
ficient
p value
Histology:
SCC
ADC
Disease stage:
II–III
IV
Tumor extension:
T2/T3
T4
Regional metastasis:
N0
N1
Distant metastasis:
M0
M1
Anemia presence:
Non-anemic
Anemic
10
5
10
5
10
5
8
7
11
4
8
7
15
4
11
8
4
15
3
16
13
6
7
12
0.462
0.728
0.013*
0.030*
1.000
0.488
–0.138K
0.009K
(0.263S)
0.460K
(0.466S)
0.398K
0.054K
0.165K
0.237
0.474
(0.131)
<0.001*
(0.007)*
0.001*
0.679
0.179
SCC — squamous cell carcinoma; ADC — adenocarcinoma; KKendall cor-
relation coefficient; SSpearman correlation coefficient; *statistically signifi-
cant at p ≤ 0.05.
We found that regardless of the criteria of systemic
hypoxemia, the strongest association was observed
with the extension of primary tumor, followed by regional
metastasis. Also mean levels of pO2 and SaO2 differed
significantly in groups of cancer patients stratified ac
cording to the extension of primary tumor. The differ
ences in pO2 and SaO2 levels in respect to other cancer
related features were found insignificant (Table 3).
Anemia did not account for the observed as-
sociation between systemic hypoxemia and the
extension of primary tumor. Anemia is one of the
conditions, which may account for the occurrence
of systemic hypoxemia. But we did not observe sig
238 Experimental Oncology 29, 236–242, 2007 (September)
nificantly higher incidence rates of anemia in cancer
patients with respiratory insufficiency (see Table 1
and Table 2). Moreover, mean pO2 and SaO2 levels
did not differ in nonanemic vs. anemic cancer pa
tients (Table 3). Yet, in order to fully exclude possible
impact of anemia on hypoxemia relation to the ex
tension of primary tumor, we determined whether a
direct correlation between levels of pO2 or SaO2 and
Hb concentration exists. We also examined whether
anemia presence was related to the aggressive be
havior of disease, analyzed in terms of local invasion
(T), regional (N) or distant (M) metastasis. We found
no direct correlation between Hb and pO2 level (r =
0.074, p = 0.676), as well as Hb with SaO2 level (r =
0.104, p = 0.557). Anemia was not related to clinical
evaluation of cancer T stage (rho = 0.072, p = 0.679)
and M stage (r = 0.054, p = 0.679), but was correlated
with N stage (r = 0.525, p < 0.0001).
Table 2. Evaluation of association between cancer-related variables and
respiratory insufficiency determined in terms of decreased oxygen satura-
tion (SaO2) in esophagogastric cancer.
Parameter
Incidence of hypoxemia Correlation analysis
Normo-
xemic
Hypo-
xemic p value Coef-
ficient p value
Histology:
SCC
ADC
Disease stage:
II–III
IV
Tumor extension:
T2/T3
T4
Regional metastasis:
N0
N1
Distant metastasis:
M0
M1
Anemia presence:
Non-anemic
Anemic
18
6
16
8
13
11
10
14
17
7
10
14
7
3
5
5
1
9
1
9
7
3
5
5
1.000
0.450
0.024*
0.113
1.000
0.717
0.052K
0.156K
(0.191S)
0.409K
(0.362S)
0.308K
0.008K
–0.076K
0.694
0.205
(0.273)
<0.001*
0.037*
0.011*
0.972
0.504
SCC — squamous cell carcinoma; ADC — adenocarcinoma; KKendall cor-
relation coefficient; SSpearman correlation coefficient; *statistically signifi-
cant at p ≤0.05.
Table 3. Relation of mean levels of oxygen partial pressure (pO2) and
oxygen saturation (SaO2) to cancer-related features in esophagogastric
cancers
Parameters pO2 level
mmHg p value SaO2 level
% p value
Histology:
SCC
ADC
Disease stage:
II/III
IV
Tumor extension:
T2/T3
T4
Regional metastasis:
N0
N1
Distant metastasis:
M0
M1
Anemia presence:
Non-anemic
Anemic
60.6 ± 2.0
63.6 ± 4.4
63.2 ± 2.3
58.4 ± 2.9
66.6 ± 2.6
57.7 ± 2.3
64.5 ± 2.8
59.9 ± 2.4
62.0 ± 2.1
59.8 ± 3.6
60.6 ± 2.5
62.0 ± 2.6
0.479
0.204
0.015*
0.243
0.592
0.713
91.5 ± 0.6
91.6 ± 1.7
92.2 ± 0.7
90.6 + 1.1
93.5 ± 0.6
90.2 ± 0.9
93.2 ± 1.0
90.8 ± 0.8
91.6 ± 0.8
91.4 ± 1.2
91.5 ± 1.1
91.6 ± 0.8
0.952
0.244
0.011*
0.071
0.892
0.913
SCC — squamous cell carcinoma; ADC — adenocarcinoma; *statistically
significant at p ≤ 0.05.
VEGF-A, but not VEGF-C, was more elevated in
esophagogastric cancer patients with systemic
hypoxemia. We found that differences in circulating
VEGFA levels between healthy subjects and cancer
patients with and without systemic hypoxemia, both
when determined in terms of pO2 (p < 0.0001) or SaO2
(p < 0.0001), were significant. A strong tendency to
wards higher VEGFA concentrations in hypoxemic vs.
normoxemic cancer patients could be observed (Fig. 1).
The strength of the relation between VEGFA levels and
the presence of hypoxemia was: rho = 0.335, p = 0.054,
when pO2 was applied as the criterion, and rho = 0.270,
p = 0.121 in case of SaO2. The tendency towards direct
correlation between VEGFA concentration and pO2 or
SaO2 levels was rather weak: rho = –0.203, p = 0.243
and rho = –0.206, p = 0.237, respectively.
fig. 1. Comparison of serum levels of vascular endothelial
growth factor A (VEGFA) in healthy individuals and cancer pa
tients without and with systemic hypoxemia. A. respiratory
insufficiency in terms of oxygen partial pressure. B. respiratory
insufficiency in terms of oxygen saturation
Boxes represent interquartile range, bars inside boxes — me
dians, whiskers — 5 and 95 percentil; *statistically significant
at p ≤0.05; **statistically significant at p ≤ 0.1; CP — cancer
patients.
The differences between serum levels of VEGFC
between controls and cancer patients with and with
out systemic hypoxemia were found significant (p <
0.0001 for both pO2 and SaO2) as well. However, there
was no difference in circulating VEGFC between non
hypoxemic and hypoxemic cancer patients (Fig. 2).
Accordingly, no tendency towards direct correlation
between circulating VEGFC and the presence of hy
poxemia was found: rho = –0.118, p = 0.496 (for pO2
as hypoxemia criterion) and rho = –0.018, p = 0.917
(for SaO2 as hypoxemia criterion). Similarly, concen
trations of circulating VEGFC were not related to the
Experimental Oncology 29, 236–242, 2007 (September) 23929, 236–242, 2007 (September) 239September) 239) 239 239
levels of pO2 (rho = 0.066, p = 0.704) or SaO2 (rho =
0.061, p = 0.724).
fig. 2. Comparison of serum levels of vascular endothelial
growth factor C (VEGFC) in healthy individuals and cancer pa
tients without and with systemic hypoxemia. A. respiratory
insufficiency in terms of oxygen partial pressure. B. respiratory
insufficiency in terms of oxygen saturation
Boxes represent interquartile range, bars inside boxes — me
dians, whiskers — 5 and 95 percentil; *statistically significant
at p ≤ 0.05; **statistically significant at p ≤ 0.1; CP — cancer
patients.
Circulating VEGF-A and VEGF-C levels are
elevated in locally advanced tumors. We evalua
ted VEGFA and VEGFC relation with the extension
of primary tumor. We found that serum VEGFA level
was significantly higher in T4 cancers as compared
with less advanced ones (Fig. 3) and that circulating
VEGFA concentration also directly correlated with
tumor extension: rho = 0.648, p < 0.001. Similarly,
serum VEGFC concentration was higher in locally
more advanced tumors (see Fig. 3), but no direct cor
relation between parameters was found: rho = 0.227,
p = 0.191.
Circulating VEGFA exhibited tendency to be up
regulated also in cancers metastasizing to regional
lymph nodes. Median serum VEGFA levels in N0 can
cers was 327 pg/ml (97–356) vs. 372 pg/ml (198–652)
in N1 cancers (p = 0.066). Median serum concen
tration of VEGFC in N0 cancers was 15.96 ng/ml
(13.79–18.17) vs. 20.05 ng/ml (13.83–25.72) in N1
cancers (p = 0.167).
The levels of circulating VEGFA were correlated
neither with Hb concentration (r = 0.052, p = 0.767)
nor with anemia presence (r = 0.151, p = 0.385). In
turn, serum VEGFC levels tended to be related with
anemia presence (r = 0.341, p = 0.050), but there
was no direct correlation between VEGFC and Hb
(r = –0.164, p = 0.347).
fig. 3. Relation of serum levels of vascular endothelial growth
factors with the extension of primary tumor (T). A. vascular
endothelial growth factor A (VEGFA). B. vascular endothelial
growth factor C (VEGFC)
Boxes represent interquartile range, bars inside boxes — me
dians, whiskers — 5 and 95 percentil; *statistically significant at
p ≤ 0.05; **statistically significant at p ≤ 0.1.
dIscussIon
We hypothesized that esophagogastric tumors
from patients suffering from respiratory insufficiency in
course of background chronic obstructive pulmonary
disease may behave more aggressively than those
from patients with cancer disease alone. The proba
bility of enhanced aggressiveness in this subgroup of
cancer patients together with possible involvement
of angiogenesis mediators have not been addressed
yet. Indeed, our results demonstrated that COPDre
lated hypoxemia in esophagogastric cancer patients
was associated with higher incidence rates of locally
advanced tumors and lymph node metastasis. The
mean levels of pO2 and SaO2 were significantly lower
in T4 cancer patients than in those with less advanced
tumors as well. We also showed that a key regulator
of angiogenesis, vascular endothelial growth factor A
(VEGFA), might be involved.
Our findings seem to be important from clinical point
of view. Tumor hypoxia favors cancer aggressiveness,
angiogenesis and metastasis, and consequently is as
sociated with poorer prognosis regardless of treatment
strategy [28]. Yet, the current methods of measuring the
oxygenation status in tumor tissue are invasive and not
applicable in clinical practice, while reliable surrogate
markers are still being searched [22]. We showed that
presence of systemic hypoxemia in cancer patients was
associated with increased extension of primary tumors
as well as with higher rates of regional metastasis. On
240 Experimental Oncology 29, 236–242, 2007 (September)
this basis, it can be suggested that coexistence of
systemic hypoxemia may guide the selection of patients
with more aggressive tumors, who probably would
not benefit from oxygenbased treatment strategies
and may help in directing their further management. It
may also facilitate the selection of patients who are at
higher risk of disease recurrence also when treated with
surgery alone. This seems to be especially important in
esophageal cancers characterized by reduced overall
survival rates in comparison with other solid tumors and
distinguished by high recurrence rates (up to 79% after
curative resection) with lymph node metastasis being a
common pattern [11, 26].
We also hypothesized that the presence of COPD
related respiratory insufficiency in cancer patients may
be associated with more elevated secretion of pro
angiogenic factors as compared to cancer patients
without hypoxemia. The rationale was that hypoxia
alters gene expression in a way that enables the trans
formed cells to overcome oxygen deprivation mainly by
hypoxiainduced transcription factor HIF1α. In turn,
HIF1α activates a plethora of genes, VEGF-A, being
one of the strategic targets [1]. Also VEGF-C has been
reported to be upregulated in response to hypoxia
[18]. Accordingly, we found that serum levels of VEGF
A tended to be more elevated in cancer patients with
respiratory insufficiency as compared to those with
cancer disease alone. Moreover, similarly to systemic
hypoxemia, circulating levels of VEGFA were strongly
related to the extension of primary tumor. Therefore,
it is tempting to speculate that the impact of systemic
hypoxemia on tumor local advancement is realized by
oversecretion of VEGFA.
The impact of systemic hypoxemia on upregula
tion of angiogenesis mediators has been controver
sially discussed in the recent literature. The majority of
limited studies concerned the conditions induced by
exercise and/or highaltitude, or nocturnal episodes
of hypoxemia in course of sleeping disorders. These
reports were entirely focused on VEGFA, but their
results have been exceedingly confusing. While some
authors reported the elevation of circulating VEGFA in
response to altituderelated hypoxemia [29] or the oc
currence of acute mountain sickness [24], yet without
correlation between VEGFA concentration and pO2 or
SaO2 levels, the others observed the adverse effect of
VEGFA downregulation [4]. Similarly to the latter find
ing, the reduction of oxygen saturation in healthy men
under experimental conditions caused the decrease in
VEGFA level, as reported by Oltmanns et al. [14].
Contrary to high altituderelated hypoxemia, night
time hypoxemia in course of obstructive sleep apnea
seems to be associated with the upregulation of cir
culating VEGFA [6, 10, 19, 23] and to be significantly
correlated with the degree of nocturnal desaturation
[19, 23]. Yet, Valipour et al. [25] failed to confirm the
relation of circulating VEGFA to nighttime hypoxemia
in patients with sleep disorder.
Our results in part corroborate the findings of
limited studies on changes in VEGFA concentration
related to systemic hypoxia in cancer. Matsuyama et
al. [13] reported that serum levels of VEGFA were
higher in lung cancer patients with systemic hypoxemia
as compared to patients with normoxemia. Moreover,
the authors observed a direct negative correlation
between VEGFA concentration and the levels of
oxygen partial pressure. In turn, Ono et al. [15] found
that VEGFA is more strongly expressed in colorectal
cancer tissue from hypoxemic patients and that the
level of VEGFA expression adversely correlated with
systemic pO2. These authors reported systemic pO2 to
be an independent factor influencing VEGFA content
in colorectal cancer tissue.
We also evaluated whether VEGFC, regarded as
the most important mediator of lymphangiogenesis,
yet with angiogenic potential as well, was affected by
systemic hypoxemia. Especially that we observed a
tendency towards higher incidence rates of cancers
metastasizing to regional lymph nodes in cancer pa
tients with respiratory insufficiency. The upregulation
of tissue expression [2, 12] and elevation of serum
levels [9] of VEGFC together with factor’s relation to
regional metastasis have previously been reported in
esophageal cancer. Moreover, hypoxia through HIF1α
has recently been linked to lymphatic metastasis in this
cancer type via VEGFC upregulation [7]. Yet, we failed
to show VEGFC overexpression in cancer patients with
respiratory insufficiency. The elevation of factor’s level
in cancers metastasizing to regional lymph nodes was
not significant in this group of patients. It can be a result
of relatively small number of observations. However, it
can not be excluded that the relation of systemic hypox
emia to lymph node metastasis observed here may be
mediated by other lymphangiogenic factors.
Anemia may account for the presence of systemic
hypoxemia on one side and upregulation of angio
genic factors on the other [28]. Our results showed,
however, that at least in population studied here,
the anemia presence did not mediate the observed
relationships between hypoxemia, cancer clinico
pathological variables and angiogenesis mediators.
Lack of correlation between VEGFA and Hb reported
in this paper is in agreement with our previous findings
(manuscript submitted) we have observed a rise
in VEGFA level only when Hb level dropped below
11 g/dL, while anemia in currently studied patients
was of a mild grade.
acknowledgements
The authors would like to thank the Regional Center
of Blood Donation and Therapeutics, Wroclaw, Poland
for supply of control sera.
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242 Experimental Oncology 29, 236–242, 2007 (September)
Влияние системной гипоксемии на агрессиВность
заболеВания и содержание циркулирующих
фактороВ роста эндотелия сосудоВ а и с у больных
гастроэзофагальным раком с хронической
респираторной недостаточностью
Цель:: �� ������� � ������� ������������������ ��������� �������������, ������������� ������������ �������� ��������������������� ������� � ������� ������������������ ��������� �������������, ������������� ������������ �������� �������������������
������ ����д��� �� ���п���������й ��д������������� �� п��ц���� �������������� �����у���������� ��������� �������������, ����-
��� п��дш�����у�� ���у. ����������� ���п��������� ������ �������� �� п��������у�� ���������ц���� �пу��������й ������ �� ��������й ����������� ���п��������� ������ �������� �� п��������у�� ���������ц���� �пу��������й ������ �� ��������й����������� ���п��������� ������ �������� �� п��������у�� ���������ц���� �пу��������й ������ �� ��������й
���������� �пу���������� ���������������. ������� п��дп���������, ��� у �������� ���������������� п������� � ���п���������й. ������� п��дп���������, ��� у �������� ���������������� п������� � ���п���������йп��дп���������, ��� у �������� ���������������� п������� � ���п���������й
��д�������������� ����������� ���п��������� ������ ���� �������� � п����ш����й ����������������� �пу���������� п��ц����, �
�д��й �������, �� п����ш������ у�������� ������������� ��������� �� � д�у��й.. Методы:: ��д�������� ��������� ����� ��д�-��д�������� ��������� ����� ��д�- ��������� ����� ��д�-��������� ����� ��д�-
������ ���уд��� A �� C �VEGF�� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� ���� A �� C �VEGF�� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� ������ C �VEGF�� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� ���� C �VEGF�� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� �����VEGF�� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� ����VEGF�� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� ���� �п��д������ ������у���������������� �����д����� у п�ц�������� � ������������������� ������ �� ����
���п���������й ��д������������� �� п��ц���� �������������� �����у���������� ������������� �������� ����� �� ���у�������� ���������,
� ����� у �д�������� д�������. ����������������� д����� ������������� �� ��д�������� ������������� �� ���������������� �� �������������. ����������������� д����� ������������� �� ��д�������� ������������� �� ���������������� �� ������������������������������ д����� ������������� �� ��д�������� ������������� �� ���������������� �� �������������
������������������, ����у�� TNM �� у������ VEGF A �� C. TNM �� у������ VEGF A �� C.�� у������ VEGF A �� C. VEGF A �� C.�� C. C. Результаты:: у �������� � ����������й ���п���������й ������� п����������у �������� � ����������й ���п���������й ������� п����������
�����������������й ���� ���ш�. ���ц�������� д��������� ��������д� �� ���������� ������� ��������д��� ������������ �������� у. ���ц�������� д��������� ��������д� �� ���������� ������� ��������д��� ������������ �������� у���ц�������� д��������� ��������д� �� ���������� ������� ��������д��� ������������ �������� у
п�ц�������� � ����������й T4. �����ш����� ��д�������� ц����у����у������ VEGF A, �� �� C, ����� ��������� у �������� � ���п��-T4. �����ш����� ��д�������� ц����у����у������ VEGF A, �� �� C, ����� ��������� у �������� � ���п��-�����ш����� ��д�������� ц����у����у������ VEGF A, �� �� C, ����� ��������� у �������� � ���п��-VEGF A, �� �� C, ����� ��������� у �������� � ���п��-�� �� C, ����� ��������� у �������� � ���п��- C, ����� ��������� у �������� � ���п��- ����� ��������� у �������� � ���п��-
�������й ��д��������������, ���� ��� ���. ��д�������� VEGF ��������������� � ��������� п���������й �пу������.. ��д�������� VEGF ��������������� � ��������� п���������й �пу������.��д�������� VEGF ��������������� � ��������� п���������й �пу������.VEGF ��������������� � ��������� п���������й �пу������.��������������� � ��������� п���������й �пу������.. Выводы:: ��ш����ш��
���у������ п�����������, ��� ����������� ���п��������� у п�ц�������� � ������������������� ������ �������� � у�������������� �������
п���������й �пу������, �� ����й ������ ������ ���� �п����д����� п����ш������� ��д�������� ц����у����у������ VEGF A.VEGF A.
Ключевые слова:: ���п���������, �����������������й ���, �����������, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-���п���������, �����������������й ���, �����������, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-, �����������������й ���, �����������, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-�����������������й ���, �����������, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-, �����������, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-�����������, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-, VEGF-A, VEGF-C, COPD, ���п���������� ��д����-���п���������� ��д����-
��������..
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