ARTICLE IN PRESS

Respiratory Medicine (2008) 102, 774–779

Angiogenic molecule Tie-2 and VEGF in the

pathogenesis of pleural effusions
Foteini Economidoua, Katerina M. Antonioua, Nikolaos Tzanakisb,
Katerina Sfiridakic, Nikolaos M. Siafakasa,, Sofia E. Schizaa

a
Department of Thoracic Medicine, University Hospital, Medical School, University of Crete, Heraklion 71110 Crete, Greece
b
Department of Epidemiology and Public Health, Medical School, University of Crete, Heraklion 71110 Crete, Greece
c
Department of Hematology, Venizeleion General Hospital, Heraklion, Greece

Received 3 May 2007; accepted 31 October 2007

Available online 4 March 2008

KEYWORDS Summary
Angiogenesis; Background: The role of angiogenesis in the pathogenesis of pleural effusion (PE) has not
Receptor tyrosine been determined. The expression of angiogenic factors may represent useful markers for
kinase Tie-2; the diagnosis and prediction of disease outcome. To measure the pleural fluid (PF) and
Vascular endothelial serum levels of vascular endothelial growth factor (VEGF), basic fibroblast growth factor
growth factor; (bFGF) and Tie receptor tyrosine kinase (Tie-2) in order to investigate their role in the
Basic fibroblast pathogenesis of PEs.
growth factor; Methods: Sixty-seven, 17 with transudative PEs due to heart failure and 50 with exudative
Exudates; PEs (malignant, 22; inflammatory, 15; undiagnosed, 13) were included in the study. PF and
Transudates serum levels of the growth factors (VEGF, bFGF and Tie-2) were measured using enzyme-
linked immunosorbent assays.
Results: PF and serum VEGF levels but not bFGF and Tie-2 levels were higher (po0.005) in
exudates than in transudates. PF VEGF levels were significantly higher in malignant than
inflammatory and undiagnosed PEs (p ¼ 0.03). In addition, PF Tie-2 levels were not found
different in malignant or in parapneumonic PEs.
Conclusion: Our results showed that VEGF is one of the main mediators in exudative PEs,
but this effect is not mediated through the angiogenetic pathway Ang-1/Tie-2. However,
the role of angiogenesis and its pathways in the pathogenesis of exudative PEs needs
further exploration.
& 2007 Elsevier Ltd. All rights reserved.

Abbreviations: Ang-1, angiopoietin 1; Ang-2, angiopoietin 2; bFGF, basic fibroplast growth factor; IQR, interquartile range, PE, pleural
effusion; PF, pleural fluid; LDH, lactate dehydrogenase, Tie-2, tie receptor tyrosine kinase, VEGF, vascular endothelial growth factor.
Corresponding author.
E-mail address: siafak@med.uoc.gr (N.M. Siafakas).

0954-6111/$ - see front matter & 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.rmed.2007.10.021
 ARTICLE IN PRESS
Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusions 775

Introduction results indicate that VEGF does not act through the Tie-2
receptor pathway in exudative PEs.
Pleural effusion (PE) is common finding in clinical practice.
Increased vascular permeability and leakage play a principal Methods and materials
role in the development of exudative PEs.1 However, the
role of angiogenesis in the pathogenesis of PE has not been
Between January 1, 2004 and August 30, 2005, we
determined. Angiogenesis is controlled by a balance of
prospectively studied 67 consecutive patients with PEs.
positive and negative regulators involved in multiple path-
The study was approved by the Ethics Committee of our
ways that result in endothelial cell proliferation, differ-
hospital, and before the thoracentesis all patients signed an
entiation and organization into a functional network of
informed consent.
vascular channels.2,3 These regulatory factors have a potent
PEs were categorized as exudates or transudates accord-
angiogenic effect, and their precise coordination is essential
ing to Light’s criteria.25–27 A PE was attributed to heart
for vascular development. Angiogenic cytokines, such as
failure when it was transudative, the patient had symptoms
vascular endothelial growth factor (VEGF) and basic fibro-
and signs of left ventricular failure, a heart ultrasound study
blast growth factor (bFGF) are candidates for the induction
revealed systolic or diastolic dysfunction of the left
of PEs because they have been implicated in the induction of
ventricle, and the PE responded to the appropriate therapy.
neovascularization, vascular permeability, and hemorrhage
A malignant PE was diagnosed if the PF cytology or pleural
both in the inflammatory process and in tumor progres-
biopsy findings were positive for malignant cells, (i.e.,
sion.2–7 Thus, the expression of angiogenic factors may
proven malignant PE), or if the patient had a persistent PE
represent useful markers for diagnosis and prediction of
with a known malignancy and alternative diagnoses were
disease outcome.
excluded (i.e., probable malignant PE). A parapneumonic PE
VEGF has been reported to play an important role in the
was defined as one associated with bacterial pneumonia,
development of certain types of effusion.6,8–11 Several
including empyema. A PE was categorized as tuberculous if
studies indicate that VEGF is consistently higher in exuda-
Mycobacteria tuberculosis were found in PF, sputum,
tive than in transudative PEs.12–14 Effusions associated with
bronchial lavage fluid, or pleural biopsy specimen (positive
malignancies seem to have higher levels of VEGF than benign
smear or culture) [i.e., proven tuberculous PE] or if pleural
effusions.8,9,13,15,17–19 It has been suggested that increased
biopsy revealed granuloma and other granulomatous dis-
VEGF levels in the malignant PEs increase vascular perme-
eases were excluded (i.e., probable tuberculous PE). A
ability and contribute to fluid accumulation.9,16 Despite
specific diagnosis could not be made even after open pleural
the statistically significant differences in pleural fluid (PF)
biopsy, and they were included in the ‘‘undiagnosed’’ group.
VEGF levels between malignant and non-malignant effu-
The PF was aspirated and blood was drawn immediately
sions, substantial overlap exists, suggesting that VEGF
after the thoracentesis, and the specimens were collected
levels are unlikely to be useful diagnostically as a single
in plain sterile tubes. PF and blood samples were centri-
marker.20
fuged at 1000g at 4 1C for 10 min. PF supernatants and serum
Recently, another endothelial cell-specific receptor tyr-
samples were stored at 80 1C. The following characteristics
osine kinase (Tie-2) and its ligand family, angiopoietin-1
were recorded: PF and serum total protein levels; lactate
(Ang-1) and angiopoietin-2 (Ang-2), have been shown to
dehydrogenase (LDH) concentration (upper limit for serum
mediate different functions of angiogenesis.20–23 Identified
LDH, 480 IU/L); glucose levels; PF pH; PF nucleated cell
on the basis of homology screening, Ang-2 acts as an
counts; and differential cell counts.
alternative ligand for Tie-220,21 and binds to Tie-2 with
The levels of VEGF, bFGF Tie-2 in PE and serum were
similar affinity, but competitively antagonizes Ang-1 effects
measured by enzyme-linked immunosorbent assay using a
with blockage of Tie-2 phosphorylation and activation.
duoset methodology (R&D Systems; Minneapolis, MN).
Functionally, transgenic mice over-expressing Ang-2 show
Briefly, after standard procedures, the cell-free samples
similar defects as the Ang-1 or Tie-2 deficient mice,
were pipetted into the wells of the microtitre plates,
suggesting that Ang-2 acts as a natural antagonist to Ang-
specific horseradish peroxidase-linked polyclonal antibodies
1/Tie-2 action.20–23 In line with this notion, it has been
were added and immunoreactive levels of VEGF, bFGF and
recently reported that Ang-2 levels but not Ang-1 levels are
Tie-2 were determined. Values below the detection limit
elevated in exudative PEs suggesting that Ang-2 along with
were assumed as zero.
VEFG participate in pleural inflammation and the pathogen-
esis of exudative PEs.17 On the contrary, it was suggested
that Ang-2 may have a direct role in stimulating Tie-2 Statistical analysis
receptor signaling and inducing in vitro angiogenesis.24
These findings indicate that the physiological role of Ang-2 Values were reported as the median (interquartile range
is more complex than previously recognized: acting alter- [IQR]) for non-normally and as mean (SD) for normally
nately to promote or blunt Tie-2 receptor signaling in distributed variables. Mann–Whitney, Kruskal–Wallis, and
endothelial cells, depending on local conditions.24 Wilcoxon ranked sum tests were used to assess the
To the best of our knowledge, the role of Tie-2 in the difference between different groups, as appropriate. The
pathogenesis of PEs has not been investigated. The aim of Spearman test was used to assess the correlation between
the present study was to determine the levels of VEGF, bFGF, variables. Values below the detection limit were assumed to
and Tie-2 in PF and corresponding serum samples of patients be zero for statistical analysis. For statistical analysis, a
with PEs, in order to further evaluate the signaling pathway statistical software package SPSS, version 11.0; SPSS Inc.,
of VEGF through the angiopoietins’ receptor, Tie-2. Our Chicago, IL was used.
 ARTICLE IN PRESS
776 F. Economidou et al.

Results exudates (malignant, inflammatory, and undiagnosed PEs;

Table 3). No significant correlation was found between bFGF
Patient characteristics levels and chemical (LDH ratio, total protein ratio)
parameters.
Sixty-seven patients, 41 men and 26 women were included
in the study. The median age was 73.5 years (IQR, 20–95
years). Seventeen patients had transudative PEs due to Tie-2 levels in patients with PEs
heart failure, and 50 patients had exudative PEs of different
origin: malignant PEs, 22 (lung cancer, 12; metastatic PF and serum Tie-2 levels were not different (p40.05) in
malignancies, 10); inflammatory PEs, 15 (12 parapneumonic, exudates than in transudates (Table 1). In both exudates and
tuberculous PEs, 3); and pleural exudates remained un- transudates PF, Tie-2 levels were not significantly different
diagnosed, 13. The PF and serum concentrations of VEGF, in comparison with serum levels (p40.05) (Table 1). PF
bFGF and Tie-2, were measured in 66, 66, and 62 patients, and serum Tie-2 levels were not significantly different in
respectively. the different exudates (malignant, inflammatory, and
undiagnosed PEs) (Table 4). No significant correlation was
VEGF levels in patients with PEs found between Tie-2 levels and chemical or hematologic
parameters.
PF and serum VEGF levels were higher in exudates (po0.001
and po0.05, respectively) than in transudates (Table 1). Table 2 Pleural fluid and serum VEGF in patients with
No significant differences were detected between inflam- PEs of different etiologies.
matory and malignant VEGF levels, in both serum and
PF. In transudates, the PF VEGF levels were significantly VEGF levels
decreased in comparison with serum levels (p ¼ 0.02) (pg/mL)
(Table 1). PF VEGF levels were significantly higher in
Variables PF Serum p-Valuey
malignant than inflammatory and undiagnosed PEs (p ¼
0.03) (Table 2). VEGF ratio (pleural/serum) statistically Malignancy 657 571 NS
significantly related with LDH ratio (r ¼ 0.449, p ¼ 0.0001) (116–4870) (121–13 575)
(Figure 1) and Total Protein ratio (r ¼ 0.361, p ¼ 0.003) Inflammatory 590 1114 NS
(Figure 2). (66–4560) (125–9759)
Undiagnosed 116 527 NS
bFGF levels in patients with PEs exudates (36–2714) (81–2944)
p-Valuez 0.03 NS
PF and serum bFGF levels were not different (p40.05) in
exudates than in transudates (Table 1). In exudates, the PF NS ¼ non-significant.
 Values are given as the median (IQR).
bFGF levels were significantly increased in comparison with y
Corresponds to the difference in PF and serum levels of
serum levels (po0.0001) (Table 1). No significant differ-
VEGF.
ences were detected between inflammatory and malignant z
Corresponds to the differences among patients with PEs of
bFGF levels, in both serum and PF. PF and serum bFGF levels various etiologies (Kruskal–Wallis test).
were not significantly different in the various types of

Table 1 Pleural fluid and serum levels in patients with pleural exudate and pleural transudate.

Variables Exudates Transudates py

VEGF pg/mL PF 534 (36–4867) 86 (25–4867) o0.001

Serum 616 (81–13 575) 285 (10 592.63–60.1) o0.05
pz NS p ¼ 0.02
bFGF pg/mL PF 3.8 (1.9–16.4) 3.1 (1.7–7.7) NS
Serum 2.1(0.2–16.6) 1.9 (4.3–0.3) NS
pz po0.0001 p ¼ 0.06

Tie-2 pg/mL PF 0.6 (0.2–3.6) 0.5 (0.2–4.1) NS

Serum 1 (0.1–30.5) 0.3 (0.2–5.4) NS
pz NS NS

NS ¼ non-significant.
 Values are given as the median (IQR).
y
Corresponds to the difference in PF or serum levels between exudates and transudates.
z
Corresponds to the difference between PF and serum levels of a growth factor.
 ARTICLE IN PRESS
Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusions 777

6 reported in previous studies,12–14,17 we have found VEGF

n = 66 levels significantly higher in exudates than in transudates.
r = 0.449 Recent studies have demonstrated high levels of VEGF in
5 p = 0.0002
exudative inflammatory and neoplastic PEs, and a possible
aetiological role in the pathogenesis of these types of
LDH ratio (Pleural/Serum)

effusions.12,15,28 We have also found the highest VEGF levels

4
in malignant than parapneumonic PEs. In addition, VEGF
levels were correlated with markers of increased vascular
3 permeability and pleural inflammation, such as LDH ratio
and protein ratio, in alignment with a recent study.17
The novel finding of this study is that Tie-2 levels in both
2 PF and systemic circulation was not found to differentiate
between transudates and exudates. This finding, supports
the recent report showed that Ang-2 levels but not Ang-1
1 levels were found elevated in exudative PEs.17 Angiogenesis
is a very complicated network which is closely regulated by
many angiogenic factors. VEGF and angiopoietins are the
0
two most important regulators. Ang-1 and Ang-2 have been
0 1 2 3 4 5 6 7 8 9 10
reported as the most potent regulators for neovasculariza-
VEGF Ratio (Pleural/Serum)
tion and are the activator and antagonist of Tie-2 receptor.
Figure 1 Relationship between PF/serum VEGF ratio and The binding of Ang-1 causes autophosphorylation of Tie-2
PF/serum LDH ratio. while the Ang-2 binding suppresses the autophosphoryla-
tion.20–22,29 Although, the exact role of angiopoietin/Tie-2
system remains enigmatic, there is evidence that this
system in the presence of VEGF is important for the
1.4 n = 66 initiation of angiogenesis and vascular sprouting in tu-
r = 0.361 mors.2,3,8,9,29 In support of this, it has been reported that
p = 0.004
1.2 VEGF and angiopoietin/Tie-2 system play a key role in the
transformation of normal lung to non-small cell lung
Protein Ratio (Pleural/Serum)

1.0 carcinoma.30–32 These results indicate that expression of

0.8
0.6
0.4
0.2
0.0
0 2
VEGF Ratio (Pleural/Serum)
Figure 2 Relationship between PF/serum VEGF ratio and
PF/serum total protein ratio.
Discussion
To the best of our knowledge, this is the first report on PF
levels of Tie-2. Our main findings were as follows: (1) PF
VEGF levels, but not bFGF and Tie-2 levels were significantly
elevated in pleural exudates than in transudates; (2) PF Tie-
2 levels were not different between malignant and
inflammatory PE, nor when compared with transudates;
and (3) VEGF ratio was found to correlate with LDH ratio and
total protein ratio.
This study confirms that VEGF, which has potent angio-
genic, mitogenic, and vascular permeability-enhancing
properties, could be implicated in the pathogenesis of
exudative PEs of different origin. In agreement with data
the angiopoietin/Tie-2 pathway is not uniform amongst
normal human tissues and tumor tissues in the different
studies.30–32 On the other hand, using immunohistochemical
detection, Peters et al.33 reported an increased proportion
of Tie-2-expresssing tumor vessels in breast carcinomas. The
balance between VEGF and angiopoietins/Tie-2 pathway has
been also investigated in other systems, with different and
not conclusive results.24,33–35 These differences could be
related to a variety of methods that have been used. In
our study, we did not find a differential role for the mole-
cule of Tie-levels in the different PEs. This finding may
4 6 8 10 indicate that Tie-2 does not operate along with VEGF in
pleural inflammation and the formation of exudative PEs
exudations.
In addition, in the present study, we did not find
differences between bFGF levels in exudates and transu-
dates. Two recent studies reported controversial results as
far the bFGF levels in PEs is concerned.7,36 The most recent
report showed reduced protein expression of bFGF and IL-8,
two potent angiogenic factors, in PEs from breast cancer,
with conserved expression of VEGF.36 The results of our
study are in agreement with this study.36
In conclusion, this study confirms that VEGF is up-
regulated in exudative PEs of different origin. On the other
hand, we have found that this pathogenetic effect is rather
not mediated through the pathway of angiopoietins/Tie-2,
as we did not detect any difference of Tie-2 levels in PEs.
However, the measurements of PF levels of the examined
angiogenic mediators could not be used for diagnostic
purposes. In contrast, we could suggest that our data hold
some, however, immature, pathogenetic, and therapeutic
implications. Our next step would be to verify this first
 ARTICLE IN PRESS
778 F. Economidou et al.

Table 3 Pleural fluid and serum bFGF in patients with PEs of different etiologies.

bFGF Levels (pg/mL)

Variables PF Serum p-Valuey

Malignancy 4.8210 (1640–1.94) 1.626 (16.6–0.2) o0.05

Inflammatory 4.8920 (13.87–2.18) 3.137 (5.5–0.9) o0.05
Undiagnosed exudates 3.1280 (8.91–1.89) 1.716 (7.5–0.6) o0.05
p-Valuez NS NS

NS ¼ non-significant.
 Values are given as the median (IQR), unless otherwise indicated.
y
Corresponds to the difference in PF and serum levels of FGF.
z
Corresponds to the differences among patients with PEs of various etiologies (Kruskal–Wallis test).

Table 4 Pleural fluid and serum Tie-2 in patients with PEs of different etiologies.

Tie-2 levels pg/mL

Variables PF Serum p-Valuey

Malignancy 0.74 (0.2–3.5) 0.44 (0.1–7.5) NS

Inflammatory 0.58 (0.3–1.7) 1.42 (0.2–4.8) NS
Undiagnosed exudates 0.46 (0.3–1.4) 0.49 (0.1–30.5) NS
p-Valuez NS NS

NS ¼ non-significant.
 Values are given as the median (IQR), unless otherwise indicated.
y
Corresponds to the difference in PF and serum levels of Tie-2.
z
Corresponds to the differences among patients with PEs of various etiologies (Kruskal–Wallis test).

observation by using more quantitative methods such as
reverse transcription-polymerase chain reaction (Real time
RT-PCR) and in situ hybridization (ISH). Finally, our results
suggest that VEGF may have a significant role in the
pathogenesis of exudation in the pleural cavity, possibly
via not only by its angiogenetic function but as an inducer of
vascular permeability as well.
Conflict of interest
None of the authors have a conflict of interest to declare in
relation to this work under this sub-heading.
References
1. Brown LF, Detmar M, Claffey K, et al. Vascular permeability
factor/vascular endothelial growth factors: a multifunctional
angiogenic cytokine. EXS 1997;79:233–69.
2. Antony VB. Immunological mechanisms in pleural disease. Eur
Respir J 2003;21:539–44.
3. McDonald DM. Angiogenesis and remodeling of airway vascu-
lature in chronic inflammation. Am J Respir Crit Care Med
2001;164:S39–45.
4. Hoshino M, Takahashi M, Aoike N. Expression of vascular
endothelial growth factor, basic fibroblast growth factor, and
angiogenin immunoreactivity in asthmatic airways and its
relationship to angiogenesis. J Allergy Clin Immunol 2001;107:
295–301.
5. Hoshino M, Nakamura Y, Hamid QA. Gene expression of vascular
endothelial growth factor and its receptors and angiogenesis in
bronchial asthma. J Allergy Clin Immunol 2001;107:1034–8.
6. Sack U, Hoffmann M, Zhao XJ, et al. Vascular endothelial growth
factor in pleural effusions of different origin. Eur Respir J
2005;25:600–4.
7. Ruiz E, Aleman C, Alegre J, et al. Angiogenic factors and
angiogenesis inhibitors in exudative pleural effusions. Lung
2005;183:185–95.
8. Cheng D, Rodriguez RM, Perkett EA, et al. Vascular endothelial
growth factor in pleural fluid. Chest 1999;116:760–5.
9. Grove CS, Lee YCG. Vascular endothelial growth factor: the key
mediator in pleural effusion formation. Curr Opin Pulm Med
2002;8:294–301.
10. Yancopoulos GD, Davis S, Gale NW, et al. Vascular-specific
growth factors and blood vessel formation. Nature 2000;407:
242–8.
11. Ferrara N, Carver-Moore K, Chen H, et al. Heterozygous
embryonic lethality induced by targeted inactivation of the
VEGF gene. Nature 1996;380:439–42.
12. Cheng D, Lee YCG, Rogers JT, et al. Vascular endothelial
growth factor level correlates with transforming growth
factor-ß isoform levels in pleural effusions. Chest 2000;118:
1747–53.
13. Hamed EA, El-Noweihi AM, Mohamed AZ, et al. Vasoactive
mediators (VEGF and TNF-a) in patients with malignant and
tuberculous pleural effusions. Respirology 2004;9:81–6.
14. Momi H, Matsuyama W, Inoue K, et al. Vascular endothelial
growth factor and proinflammatory cytokines in pleural effu-
sions. Respir Med 2002;96:817–22.
 ARTICLE IN PRESS
Angiogenic molecule Tie-2 and VEGF in the pathogenesis of pleural effusions
15. Yanagawa H, Takeuchi E, Suzuki Y, et al. Vascular endothelial
growth factor in malignant pleural effusion associated with lung
cancer. Cancer Immunol Immunother 1999;48:396–400.
16. Zebrowski BK, Yano S, Liu W, et al. Vascular endothelial growth
factor levels and induction of permeability in malignant pleural
effusions. Clin Cancer Res 1999;5:3364–8.
17. Kalomenidis I, Kollintza A, Sigala I, et al. Angiopoietin-2 levels are
elevated in exudative pleural effusions. Chest 2006;129:1259–66.
18. Lim SC, Jung SI, Kim YC, Park KO. Vascular endothelial growth
factor in malignant and tuberculous pleural effusions. J Korean
Med Sci 2000;15:279–83.
19. Ishimoto O, Saijo Y, Narumi K, et al. High level of vascular
endothelial growth factor in hemorrhagic pleural effusion of
cancer. Oncology 2002;63:70–5.
20. Sato TN, Tozawa Y, Deutsch U, et al. Distinct roles of the
receptor tyrosine kinases Tie-1 and Tie-2 in blood vessel
formation. Nature 1995;376:70–4.
21. Suri C, Jones PF, Patan S, et al. Requisite role of angiopoietin-1,
a ligand for the TIE2 receptor, during embryonic angiogenesis.
Cell 1996;87:1171–80.
22. Maisonpierre PC, Suri C, Jones PF, et al. Angiopoietin-2, a
natural antagonist for Tie2 that disrupts in vivo angiogenesis.
Science 1997;277:55–60.
23. Holash J, Maisonpierre PC, Compton D, et al. Vessel cooption,
regression, and growth in tumors mediated by angiopoietins and
VEGF. Science 1999;284:1994–8.
24. Teichert-Kuliszewska K, Maisonpierre PC, Jones N, et al.
Biological action of angiopoietin-2 in a fibrin matrix model of
angiogenesis is associated with activation of Tie2. Cardiovasc
Res 2001;49:659–70.
25. Light WR, MacGregor MI, Luchsinger PC, et al. Pleural effusions:
the diagnostic separation of transudations and exudates. Ann
Intern Med 1972;77:507–14.
26. Light RW. Physiology of the pleural space. In: Pleural diseases,
4th ed. Philadelphia, PA: Lippincott Williams & Wilkins; 2001.
p. 8–20 [chapter 2].
779
27. Light RW. Clinical manifestations and useful tests. In: Pleural
diseases, 4th ed. Philadelphia, PA: Lippincott Williams &
Wilkins; 2001. p. 42–86 [chapter 4].
28. Clifford CA, Hughes D, Beal MW, et al. Plasma vascular
endothelial growth factor concentrations in healthy dogs and
dogs with hemangiosarcoma. J Vet Intern Med 2001;15:
131–5.
29. Davis S, Aldrich TH, Jones PF, et al. Isolation of angiopoietin-1,
a ligand for the TIE2 receptor, by secretion-trap expression
cloning. Cell 1996;87:1161–9.
30. Takahama M, Tsutsumi M, Tsujiuchi T, et al. Enhanced
expression of Tie2, its ligand angiopoietin-1, vascular endothe-
lial growth factor, and CD31 in human non-small cell lung
carcinomas. Clin Cancer Res 1999;5:2506–10.
31. Wong MP, Chan SY, Fu KH, et al. The angiopoietins, tie2 and
vascular endothelial growth factor are differentially expressed
in the transformation of normal lung to non-small cell lung
carcinomas. Lung Cancer 2000;29:11–22.
32. Takanami I. Overexpression of Ang-2 mRNA in non-small cell
lung cancer: association with angiogenesis and poor prognosis.
Oncol Rep 2004;12:849–53.
33. Peters KG, Coogan A, Berry D, et al. Expression of Tie2/Tek in
breast tumor vasculature provides a new marker for evaluation
of tumor angiogenesis. Br J Cancer 1998;77:51–5.
34. Zhang ZL, Liu ZS, Sun Q. Expression of angiopoietins, Tie2 and
vascular endothelial growth factor in angiogenesis and progres-
sion of hepatocellular carcinoma. World J Gastroenterol 2006;
12:4241–5.
35. Chang H, Wang BW, Kuan P, et al. Cyclical mechanical stretch
enhances angiopoietin-2 and Tie2 receptor expression in
cultured human umbilical vein endothelial cells. Clin Sci
2003;104:421–8.
36. Konstantinovsky S, Nielsen S, Vyberg B, et al. Angiogenic
molecule expression is downregulated in effusions from
breast cancer patients. Breast Cancer Res Treat 2005;94:
71–80.