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 Previous Article | Table of Contents | Next Article 
Blood, Vol. 95 No. 1 (January 1), 2000:
pp. 309-313
NEOPLASIA
Evidence of increased angiogenesis in patients with acute myeloid
leukemia
Jerry W. Hussong,
George M. Rodgers, and
Paul J. Shami
From the Department of Pathology, ARUP Laboratories, and Divisions
of Hematology and Oncology, Department of Medicine, University of Utah
and Salt Lake City VA Medical Centers, Salt Lake City, UT.
 |
Abstract |
Angiogenesis plays a key role in solid tumor growth. The purpose of
this work was to study angiogenesis in acute myeloid leukemia (AML). We
stained bone marrow samples from 20 adult patients with untreated AML
and 20 normal controls using endothelial cell markers (ULEX-E and von
Willebrand factor [vWF]). The number of vessels per millimeter length
of bone marrow core biopsy specimen was scored by light microscopy.
Using ULEX-E staining, AML marrows had (average ± SEM)
8.3 ± 3.6 vessels/mm (range, 3.7-19.3), whereas normal marrows had
4.3 ± 1.8 vessels/mm (range, 1.6-7.9). A similar difference was
noted using vWF staining (8.6 ± 3.0 vessels/mm vs 4.9 ± 2.2
vessels/mm in AML vs normal bone marrows, respectively). The
differences between the numbers of vessels/mm in AML and normal marrows
were highly significant (P < .0001 for both ULEX-E and vWF
staining). When analyzed by FAB category, there was no difference in
the average number of vessels/mm among the different subgroups of AML.
Using reverse transcriptase polymerase chain reaction, we observed that
the HL-60 and U937 human AML cell lines and 4 of 4 freshly isolated AML
cells from untreated patients expressed mRNA for vascular endothelial
growth factor (VEGF). Both cell lines as well as all fresh AML isolates
tested expressed VEGF protein. Basic fibroblast growth factor was
expressed only in HL-60 cells and in only 3 of 4 fresh AML samples.
These observations suggest that angiogenesis may play a role in the
pathogenesis of AML. Inhibition of angiogenesis could constitute a
novel strategy for the treatment of AML. (Blood. 2000;95:309-313).
© 2000 by The American Society of Hematology.
| |
Introduction |
Angiogenesis is a highly regulated process under the
tight control of inducers and inhibitors.1-3 It involves
degradation of the parent venule basement membrane, endothelial cell
proliferation and migration, development of sprouts, and generation of
new basement membrane.1-3 Angiogenesis plays a critical
role in solid tumor development and metastasis.1,2
Recently, a role for angiogenesis in the pathophysiology of hematologic
malignancies has been suggested.4-6 Vascular endothelial
growth factor (VEGF) and basic fibroblastic growth factor (bFGF) are 2 of the best characterized angiogenic factors.1,2 They are
produced by a number of neoplastic and non-neoplastic cell
types.1-3 Acute myeloid leukemia (AML) cells express
VEGF.5 Furthermore, elevated levels of bFGF were detected in urine from patients with acute lymphoblastic leukemia (ALL) and
lymphoma.4,6 In children with ALL, elevated levels of bFGF
in the urine were associated with increased density of bone marrow
vessels.4
The purpose of the current study was to determine the extent of
angiogenesis in AML. Our results show increased vessel density in bone
marrow specimens from patients with AML, thus suggesting a possible
role for angiogenesis in the pathophysiology of this disease.
| |
Materials and methods |
Histologic analysis
Twenty archival, paraffin-embedded bone marrow core biopsy specimens
from adult patients with AML were evaluated. The diagnosis of AML was
made according to standard French-American-British (FAB)
criteria. In addition, 20 bone marrow core biopsy
specimens from adult patients without evidence of malignancy were used
as controls. The control patients had undergone bone marrow biopsy for
a number of different reasons, including tumor staging and evaluation
of cytopenias. All of the specimens had been fixed in formalin or B-5
and embedded in paraffin. The hematoxylin and eosin (H&E)-stained
sections from each corresponding biopsy were reviewed and the
histologic diagnosis was confirmed. Bone marrow cellularity and blast
counts also were reviewed.
Bone marrow sections were stained immunohistochemically for the
endothelial cell marker von Willebrand factor (vWF) (Dako, Carpinteria,
CA; 1:1600) or ULEX-E (Vector, Burlingame, CA; 1:500). Immunohistochemistry was performed with a Ventana 320 automated stainer
(Ventana, Tucson, AZ) using an indirect avidin-biotin-peroxidase detection method. The tissues were cut into 3-µm sections, placed on
silanated slides, and incubated at 56°C for 30 minutes. The sections were dewaxed and dehydrated through serially
diluted ethanol solutions to distilled water. All sections underwent
antigen retrieval in 10 mmol/L citrate buffer using a microwave
pressure cooker for 15 and 30 minutes for vWF and ULEX-E, respectively. Vessels were identified based on the combination of endothelial cell
staining for vWF and ULEX-E and morphology. The total number of vessels
was counted over the whole length of the biopsy core specimen. Vessel
scoring was expressed as the number of vessels per millimeter length of
the biopsy core.
Leukemia cells and nucleic acid isolation
HL-60 and U937 cells were from American Type Culture Collection
(Rockville, MD). Cells were maintained in suspension culture at a
density of 150 000 cells/mL in RPMI-1640 with 10% fetal bovine serum
at 37°C in a 5% CO2 humidified atmosphere. Fresh
leukemia samples were obtained from the peripheral blood of untreated
patients newly diagnosed with AML according to the FAB criteria. All
patients had circulating leukemic blasts. The protocol was approved by the University of Utah and the Salt Lake City VA Institutional Review
Boards. After subjects gave informed consent, 10 mL of heparinized
blood was obtained. The mononuclear fraction was isolated on a
Ficoll-Hypaque density gradient. The percentage of leukemia cells was
determined using Wright staining of a cytospin from the mononuclear
cell fraction. All samples had more than 95% leukemic blasts. Fresh
leukemic cells thus obtained were used for RNA isolation. For both
leukemic cell lines and freshly isolated AML cells, total cellular RNA
was isolated using the QIAGEN RNeasy Mini Kit (QIAGEN, Santa Clara, CA)
using the manufacturer's protocol.
Reverse transcriptase polymerase chain reaction (RT-PCR)
RT-PCR was done using the GeneAmp RNA PCR kit from Perkin-Elmer
(Foster City, CA). In brief, cDNA was reverse transcribed from total
cellular RNA using oligo dT priming following the manufacturer's protocol. PCR amplification was done under the following conditions: 95°C for 3 minutes for initial melting; 95°C for 1 minute,
55°C for 1 minute, and 72°C for 1 minute for a total of 35 cycles; and 72°C for 7 minutes for final extension. PCR primers
were as follows: upstream actin,
5'-CGCTGCGCTGGTCGTCGACA-3'; downstream actin,
5'-GTCACGCACGATTTCCCGCT-3'; upstream VEGF,
5'-TCGGGCCTCCGAAACCATGA-3'; downstream VEGF,
5'-CCTGGTGAGAGATCTGGTTC-3'; upstream bFGF,
5'-GGTCCTGTTTTGGATCCA-3'; and downstream bFGF,
5'-AGAGAGAGGAGTTGTGTC-3'.
Immunohistochemical stains for VEGF expression
Cytospin slides from HL-60, U937, and representative fresh AML cell
isolates were stained immunohistochemically using an anti-human VEGF
antibody (1:100) from Santa Cruz Biotechnology Inc. (Santa Cruz, CA).
Immunohistochemistry was performed with a Ventana 320 automated stainer
(Ventana) using an indirect avidin-biotin-peroxidase detection method.
The cytospin preparations were fixed in cold 100% acetone for 10 minutes. All preparations were pretreated with Immuno+Master antigen
enhancer (American Histology Reagent Company, Inc., Lodi, CA) before staining.
Statistical analysis
Results are expressed as the averages of vessel scores from normal
or leukemic marrows with standard error of the mean (SEM). SEM was
calculated as the standard deviation divided by the square root of the
number of samples. Statistical analysis was done using the
Student's t test. Differences were considered statistically significant at P < .05.
| |
Results |
The patients with AML consisted of 8 women and 12 men; the control
patients consisted of 12 women and 8 men. The mean age of the AML
patients was 59 years (range, 24-87 years). In the control group, the
mean age was 49 years (range, 27-71 years). The FAB distribution of the
AML cases was as follows: 2 M0, 6 M1, 6 M2, 4 M4, and 2 M7. The
cellularity (average ± SEM) was 78% ± 26% (range, 25% to
100%) and 49% ± 8% (range, 35% to 65%) for AML and normal
marrows, respectively (P < .0001). Using ULEX-E staining,
AML marrows had (average ± SEM) 8.3 ± 3.6 vessels/mm (range,
3.7-19.3) while normal marrows had 4.3 ± 1.8 vessels/mm (range,
1.6-7.9). Using vWF staining of the same specimens, AML marrows had
8.6 ± 3.0 vessels/mm (range, 3.7-15.8) and normal marrows had
4.9 ± 2.2 vessels/mm (range, 1.5-10.1). The differences between the
numbers of vessels/mm in AML and normal marrows were highly significant
(P < .0001 for both ULEX-E and vWF staining). ULEX-E and
vWF exhibited similar staining patterns. Figures
1 and 2 show examples of
vascularity in normal and AML marrows.
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| Fig 1.
Vascularity of normal and AML marrow specimens.
Normal or AML bone marrow samples were stained with H&E or for vWF
expression (see Methods) for vessel scoring. Legends (all ×200):
A = normal bone marrow with H&E stain; B = normal bone marrow with
vWF stain; C = AML bone marrow with H&E stain; D = AML bone marrow
with vWF stain. The normal bone marrow shows strong staining for vWF in
megakaryocytes but no evidence of increased vessels. The AML marrow has
significantly more vessels than the normal marrow. These sections are
representative of the whole series.
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| Fig 2.
High-power view of vascularity of normal and AML marrow
specimens.
Normal or AML bone marrow samples were stained for vWF expression (see
Methods). A = 600× view of normal bone marrow showing positive
staining in a megakaryocyte as well as 1 vessel. B = 400× view
of representative AML marrow showing numerous vessels. Note that some
of the vessels are large with irregular and bizarre shapes.
C = 600× view of representative AML marrow showing details of
vascular endothelial cell staining.
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There was no significant difference in vessel scores among samples from
different FAB subcategories (not shown). There was also no correlation
between bone marrow cellularity and vessel score in either normal or
AML bone marrows (Figure 3). In AML samples, there was a positive correlation between vessel score and
percentage of marrow myeloblasts (Figure
4).
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| Fig 3.
Vessel score and bone marrow cellularity.
Normal (A) and AML (B) marrows were scored for vessel number (see
Methods) using vWF staining. Scores were correlated with cellularity.
There was no clear correlation between the number of vessels/mm and
marrow cellularity in either normal or AML marrows. Similar results
were obtained with ULEX-E staining.
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| Fig 4.
Correlation between vessel score and percentage of blasts
in AML bone marrow specimens.
AML marrows were scored for vessel number using ULEX-E (A) or vWF (B)
staining (see Methods). Scores were correlated with percentage of
blasts. Using either stain, there was a positive correlation between
vessel scores and percentage of marrow blasts.
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To determine whether AML cells are a source of angiogenic factors and
therefore could stimulate angiogenesis in vivo, we used RT-PCR to study
the mRNA expression of VEGF and bFGF in 2 human AML cell lines (HL-60
and U937) as well as in AML cells freshly isolated from untreated
patients. VEGF was expressed by HL-60 and U937 cells as well as all
fresh AML samples (Figure 5A). The extent
of VEGF mRNA expression varied among the different patient isolates
tested (Figure 5A). In contrast, only HL-60 cells and 3 of 4 fresh AML
cells expressed bFGF (Figure 5B). Immunohistochemical stains of
cytospins from HL-60, U937, and fresh AML samples showed that they
expressed VEGF protein (Figure 6).
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| Fig 5.
Expression of VEGF (A) and bFGF (B) RNA in AML cells.
VEGF and bFGF expression was assayed by RT-PCR (see Methods) in AML
cells freshly isolated from untreated patients and in HL-60 and U937
cells. Lane 1 = molecular weight (MW) marker; lanes 2 to 5 = AML
patients; lane 6 = HL-60 cells; lane 7 = U937 cells. All samples
expressed VEGF, whereas only 3 of 4 fresh samples and HL-60 cells
expressed bFGF. Patient 4 had weaker VEGF expression than the others.
Actin controls showed equal amounts of RNA (not shown). Negative
controls without RNA and without reverse transcriptase were negative
(not shown).
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| Fig 6.
Expression of VEGF protein in AML cells.
Cytospin of AML cells freshly isolated from an untreated patient was
stained immunohistochemically for VEGF expression (see Methods). AML
cells expressed VEGF protein in the cytoplasm, which is typical of this
growth factor. Similar results were obtained with HL-60, U937, and 5 other fresh AML samples.
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Discussion |
We demonstrate in this study evidence of increased angiogenesis in
AML. Although bone marrow specimens from AML patients were more
cellular than those of normal controls, there was no clear correlation
between cellularity and vessel scores in either group. Consequently, it
is unlikely that increased cellularity would be the only cause of
increased angiogenesis in AML. A more likely explanation would be the
secretion of angiogenic factors by leukemia cells, which in turn
stimulate the development of new vessel beds. Indeed, we demonstrated
that AML cells from all samples studied expressed VEGF mRNA, and the
majority of them also expressed bFGF. We also demonstrated that AML
cells expressed VEGF protein. Furthermore, there was a positive
correlation between the percentage of marrow blasts and vessel score.
Both VEGF and bFGF are among the most potent mitogens for endothelial
cells and stimulators of angiogenesis.1,2 They also work
synergistically to stimulate angiogenesis.7
Most of the early work on angiogenesis was done in solid tumors. More
recently, a mounting body of evidence has been accumulating suggesting
a role for angiogenesis in the pathophysiology of hematopoietic malignancies. Children with ALL have increased angiogenesis in their
marrow and increased urinary levels of bFGF.4
Interestingly, urinary levels of bFGF did not decrease significantly
when the patients were in remission 31 days after cytotoxic
chemotherapy.4 Although the authors did not report
long-term follow-up measurements, this suggests that the source of bFGF
in ALL may not be the leukemia cells. Fiedler et al5 have
shown that AML cells express VEGF as well as the VEGF receptors
(VEGFR-1 and VEGFR-2). These findings raise the possibility that VEGF
may play the role of an autocrine growth factor for AML cells. Along
these lines, VEGF was shown to protect AML cells from
chemotherapy-induced apoptosis by upregulating MCL1 (a member of the
BCL2 family).8 Bellamy et al9 studied a panel
of hematopoietic tumor cell lines and found that they all expressed
VEGF, whereas only 50% of them expressed bFGF.
Perhaps the most compelling evidence showing a role for angiogenesis in
hematopoietic malignancies has been generated from patients with
multiple myeloma. In multiple myeloma, there is a correlation between
the extent of bone marrow angiogenesis and plasma cell proliferative
index.10 In the latter study, there was also a correlation
between angiogenesis and disease progression. Furthermore, patients
with active multiple myeloma have increased angiogenesis, whereas
patients with inactive disease or monoclonal gammopathy of undetermined
significance do not.11 The same group of investigators also
has demonstrated that human lymphoblastoid cell lines produce
angiogenic factors, induce an angiogenic phenotype in endothelial
cells, and secrete various matrix metalloproteinases.12
The question arises as to why there would be increased angiogenesis in
the bone marrow of AML patients. A strictly "mechanical" explanation for the supply of nutrients and oxygen to the leukemic cells and the removal of metabolites from these cells is not completely satisfying because AML cells invading the marrow do not form a well-circumscribed "mass" like solid tumors. Furthermore, our results do not support this explanation because we did not observe a
correlation between marrow cellularity and vessel score. A more plausible explanation would be a positive synergistic relationship between AML and endothelial cells. We and others have shown that AML
cells make angiogenic factors.5,9 As part of their study of
VEGF expression in AML cells, Fiedler et al5 showed that VEGF stimulates granulocyte macrophage colony-stimulating factor (GM-CSF) production by human umbilical cord endothelial cells. Likewise, Bellamy et al9 have shown that VEGF stimulates
the production of M-CSF, G-CSF, interleukin-6, and stem cell factor (SCF) in endothelial cells. All of this work supports the
hypothesis of a positive synergistic relationship between AML and
endothelial cells through the paracrine production by each of mutually
mitogenic growth factors.
In conclusion, by demonstrating increased angiogenesis in the bone
marrow of AML patients, we lend support to previous studies suggesting
that angiogenesis may play a role in the pathophysiology of
hematopoietic malignancies. Furthermore, our work shows that angiogenesis may be clinically relevant in the pathophysiology of
AML and thus raises the possibility of using angiogenesis inhibitors as
a novel therapeutic strategy for this disease.
| |
Acknowledgments |
We would like to acknowledge Sheryl Tripp and Lai Yi Wang for excellent
technical support.
| |
Footnotes |
Submitted March 19, 1999; accepted August 30, 1999.
P.J.S is a Translational Research Awardee from the Leukemia Society of
America. This work was also supported by the VA Research Service (GMR)
and ARUP Laboratories (J.W.H).
Reprints: Paul J. Shami, University of Utah and Salt Lake City
VA Medical Centers, Box 151M, 500 Foothill Blvd, Salt Lake City, UT
84148; e-mail: p.shami{at}m.cc.utah.edu.
The publication costs of this
article were defrayed in part by
page charge payment. Therefore,
and solely to indicate this fact,
this article is hereby marked
"advertisement"
in accordance with 18 U.S.C.
section 1734.
| |
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Top
Abstract
Introduction