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 Table of Contents  
ORIGINAL ARTICLE
Year : 2013  |  Volume : 38  |  Issue : 1  |  Page : 41-46

Cellular vascular endothelial growth factor and serum angiogenin in acute myeloid leukemia ( clinical and prognostic significance)


Department of Clinical Pathology, Hematology Unit, Faculty of Medicine, Ain Shams University, Cairo, Egypt

Date of Submission29-Sep-2012
Date of Acceptance14-Oct-2012
Date of Web Publication20-Jun-2014

Correspondence Address:
Deena Samir Eissa
Department of Clinical Pathology, Ain Shams University Hospitals, Ramses St, Abbasia, 11566 Cairo
Egypt
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Source of Support: None, Conflict of Interest: None


DOI: 10.7123/01.EJH.0000423015.67835.8c

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  Abstract 

Background

Increased angiogenesis and angiogenic factors play an important role in hematologic malignancies. Acute myeloid leukemia (AML) is associated with a considerable increase in bone marrow vascularity. Vascular endothelial growth factor (VEGF) and angiogenin (ANG) are two prominent angiogenic mediators. Therefore, we aimed to examine the cellular expression of VEGF and serum ANG level in adult AML patients and to assess their prognostic impact on disease outcome.

Materials and methods

The study was carried out on 60 newly diagnosed adult AML patients compared with 25 age-matched and sex-matched controls. Patients were diagnosed and classified according to the French–American–British/WHO criteria by immunophenotyping and cytogenetic analysis. The cellular expression of VEGF in blast cells was assessed by flow cytometry. Serum levels of ANG were measured using a sandwich enzyme-linked immunosorbent assay.

Results

AML blasts significantly overexpressed VEGF (median percentage expression, 30%; median mean fluorescence intensity, 3.8) compared with normal individuals (<5%; 0.57; P<0.01). Similarly, the serum levels of ANG were significantly higher in AML patients (mean±SD, 212.5±77.1 ng/ml) compared with the controls (mean±SD, 66±2.5 ng/ml; P<0.01). High levels of VEGF, above the median (>30%), together with serum ANG levels of AML patients showed no relationship with the studied clinical and laboratory parameters, French–American–British subtypes, or cytogenetic risk groups (P>0.05); however, they were significantly associated with a poor response to treatment and a higher mortality rate (P<0.01).

Conclusion

Cellular VEGF expression and serum ANG levels are significantly increased in AML patients and have been identified as independent poor prognostic indicators linked to accelerated angiogenesis and consequently a more aggressive disease outcome.

Keywords: acute myeloid leukemia, angiogenesis, angiogenin, prognosis, vascular endothelial growth factor


How to cite this article:
Ismail MA, Eissa DS, Heiba NM. Cellular vascular endothelial growth factor and serum angiogenin in acute myeloid leukemia ( clinical and prognostic significance). Egypt J Haematol 2013;38:41-6

How to cite this URL:
Ismail MA, Eissa DS, Heiba NM. Cellular vascular endothelial growth factor and serum angiogenin in acute myeloid leukemia ( clinical and prognostic significance). Egypt J Haematol [serial online] 2013 [cited 2019 Dec 15];38:41-6. Available from: http://www.ehj.eg.net/text.asp?2013/38/1/41/134802


  Introduction Top


Angiogenesis, a complex process of new microvessel formation from pre-existing vasculature, has been identified to play a potentially crucial role in the pathophysiology of hematologic malignancies 1. Increased microvessel density has been documented in acute myeloid leukemia (AML), linked with a poor prognosis, and normalized after achievement of complete remission (CR) 1,2.

Tumor angiogenesis depends on the expression of specific mediators that initiate a cascade of events leading to the formation of new microvessels 3; among these mediators are vascular endothelial growth factor (VEGF) and angiogenin (ANG).

VEGF is a 34–42 kDa dimeric glycoprotein encoded by a gene located on chromosome 6p21.3 and existing in several isoforms depending on the site of alternative gene splicing during transcription 4. VEGF is a potent mitogen for endothelial cells (ECs) that exerts its effects by binding to two primary signaling receptor tyrosine kinases, VEGFR 1 and 2 5, and plays a pivotal role in solid tumor angiogenesis associated with tumor aggressiveness, dissemination, and invasion 6,7. In AML, VEGF expression has been examined using western blotting, radioimmunoassay 8, immunohistochemical analysis (IHC) 9, and real-time PCR 10. To the best of our knowledge, there are no existing studies that have utilized flow cytometry (FCM) for the assessment of VEGF expression in AML.

Human ANG is a basic 14.1 kDa single-chain soluble protein synthesized in the liver and encoded by a gene on chromosome 14q11.1 11. It is one of the most potent angiogenic agents that binds to high-affinity receptors on ECs and smooth muscle cells, leading to the activation of cell-associated proteases that trigger cellular responses, resulting in cell migration, invasion, proliferation, and formation of tubular structures 12. It also has weak RNAse activity, being a member of the RNAse superfamily with 35% homology to pancreatic RNAse 11. Several reports have discussed the level of ANG in AML patients, but with contradictory data on its effect on the disease outcome 13–15.

Accordingly, the aim of this study was to examine the cellular expression of VEGF and serum ANG levels in adult AML patients and to assess their prognostic impact on disease outcome.


  Materials and methods Top


Materials

The study was carried out on 60 newly diagnosed adult AML patients attending the Hematology/Oncology Unit of Ain Shams University Hospitals. These included 38 men and 22 women, with a male to female ratio (M : F) of 1.7 : 1. Their ages ranged from 20 to 68 years (mean±SD, 39.8±13.6 years). Twenty-five age-matched and sex-matched healthy individuals, whose bone marrow (BM) samples were free from hematologic disease, were enrolled as a control group, 16 men and 9 women (M : F, 1.8 : 1) ranging in age from 22 to 65 years (mean±SD, 41.6±11.3 years). The study was approved by the local research ethical committee and written informed consent was provided by all participants.

Patients were diagnosed and classified according to the French–American–British (FAB) and WHO revised criteria for myeloid neoplasms 16. They were subjected to full history taking, clinical examination, and radiological investigations. Peripheral blood (PB) and BM aspiration samples were withdrawn for laboratory investigations including (i) complete blood count using Coulter LH 750 (Beckman Coulter Inc., Fullerton, California, USA); (ii) microscopic examination of Leishman-stained PB and BM smears; (iii) immunophenotyping of blast cells using a panel of phycoerythrin/fluorescein isothyocyanate-conjugated monoclonal antibodies (moAbs) to progenitor markers (HLADR, CD34), myeloid markers (CD13, CD33, CD15, CD61, CD117, cytoMPO, and glycophorin A), monocytic marker (CD14), and lymphoid markers (CD19, CD20, CD10, CD79a, CD2, CD3, CD5, CD7, cytoCD3; Beckman Coulter Inc., Hialeah, Florida, USA); and (iv) cytogenetic analysis by conventional G-banding and fluorescence in-situ hybridization using probes for t(8;21), inv(16), t(15;17), −5/del(5q), and −7/del(7q; Vysis, Downers Grove, Illinois, USA). Patients were categorized into their respective cytogenetic risk group as follows: favorable risk group, t(8;21), inv(16), t(16;16), t(15;17); unfavorable risk group, 11q23 rearrangement, −5/del(5q), −7/del(7q), t(6;9), inv(3q), or a complex karyotype of at least three unrelated cytogenetic abnormalities; and intermediate risk group, normal karyotype or other miscellaneous single cytogenetic abnormalities 16. The clinical and laboratory data of the AML patients are summarized in [Table 1].
Table 1: Clinical and laboratory data of acute myeloid leukemia patients

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  Methods Top


Intracytoplasmic detection of vascular endothelial growth factor by flow cytometry

Fresh PB or BM samples obtained in ethylene diamine tetra-acetic acid anticoagulated evacuated tubes were processed within 6 h of collection; in cases of unavoidable delay, they were preserved at room temperature (22–24°C) for a maximum of 24 h. As the cellular staining for VEGF is limited to the cytoplasm, cells were first fixed and permeabilized in 3.5% paraformaldehyde/PBS and then in 50% cold acetone/PBS. This was followed by incubation with 10 µl of anti-human VEGF phycoerythrin-conjugated moAbs (R&D systems Inc., Minneapolis, Minnesota, USA) at 18–24°C in the dark for 30–45 min. Analysis was carried out on a Coulter Epics XL flow cytometer (Beckman Coulter Inc.). Blast cells of AML patients were gated on a forward scatter/side scatter (FS/SS) dot-plot histogram, whereas blast cells of healthy controls were gated using moAbs for CD45 (Beckman Coulter Inc.), followed by the determination of the percentage of cells expressing VEGF together with its mean fluorescence intensity (MFI). [Figure 1] shows a representative example of gated AML blasts expressing VEGF.
Figure 1: Representative example of gated acute myeloid leukemia (AML) blasts expressing VEGF. A gate was drawn on AML blasts (a) and the percentage of blast cells expressing VEGF was identified (b). VEGF, vascular endothelial growth factor.

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Determination of serum angiogenin concentration by an enzyme-linked immunosorbent assay

Clotted PB samples obtained on plain evacuated tubes were used. Serum was separated by centrifugation at 1000g for 10 min and preserved at −70°C until subsequent analysis. Quantitative determination of soluble ANG was carried out using the Human ANG ELISA Kit (RayBiotech Inc., Parkway Lane, Norcross, Georgia, USA). Samples and standards were added to the microtiter plate wells coated with ANG anti-human moAbs, followed by the addition of biotin-conjugated antibody, enzyme-conjugated avidin, and a substrate solution. The enzyme–substrate reaction was terminated by the addition of a stop solution and the color change was measured spectrophotometrically at a wavelength of 450 nm. A standard curve was constructed, from which the ANG concentrations of the samples were deduced.

Patients were assigned to their treatment protocols according to their respective risk groups and were followed up over a period of 18 months (median, 10 months) by complete blood count and BM examination to assess remission. Morphologic CR was defined by (i) PB neutrophil count greater than 1.5×109/l and platelet count greater than 100×109/l, (ii) absence of blasts in PB, (iii) less than 5% blasts with no detectable Auer rods in a BM sample showing greater than 20% cellularity with maturation of all cell lines, and (iv) absence of extramedullary leukemia. An incomplete response (IR) was defined as 5–10% blasts or less than 5% blasts in the presence of Auer rods in a BM sample with adequate cellularity and a PB sample without leukemic cells. Resistance (R) is indicative of no response on the basis of the presence of blasts and the absence of BM hypocellularity. Relapse (RL) after CR is the reappearance of leukemic blasts in PB or greater than 5% blasts in BM not attributable to any other cause (e.g. BM regeneration after consolidation therapy) 17.

Statistical analysis

Data were analyzed using SPSS version 15 (SPSS Inc., Chicago, Illinois, USA) on the Windows 7 operating system. Qualitative data were expressed in the form of number and percentage; differences among groups were assessed using Fisher’s exact test. Quantitative data were reported as mean±SD or median and range, as appropriate. Comparison between groups was carried out using Wilcoxon’s Rank-Sum test and Student’s t-test for nonparametric and parametric data, respectively. The correlation between variables was assessed using Spearman’s rank correlation coefficient. Multivariate analysis using the Cox-proportional hazard regression model [hazard ratio (HR)] was used to identify significant independent prognostic factors on the basis of event-free survival. A P-value of less than 0.05 was considered statistically significant in all analyses.


  Results Top


Cellular vascular endothelial growth factor expression

AML patients had a significantly higher VEGF percentage expression (median, 30%; range, 5.6–75.8%) and MFI (median, 3.8; range, 0.6–5.3) compared with the controls (<5%; MFI: median, 0.57; range, 0.00–0.78; P<0.01). It is noteworthy that the only M0 sample included in the study showed the lowest VEGF percentage positivity (5.6%) and MFI (0.6); other AML subtypes had VEGF percentage positivity values greater than 10% and MFIs greater than 1.0.

We used the median VEGF percentage expression (30%) to categorize patients as high and low VEGF expressers; 29/60 (48.3%) patients showed VEGF expression greater than 30%. This high VEGF level was not linked to standard risk parameters including clinical and hematologic data, FAB subtypes, or cytogenetic risk groups (P>0.05). However, a high VEGF level was related significantly to a poor response to treatment; 27/29 (93.1%) high VEGF patients either developed an IR, R, or RL, and only 2/29 (6.9%) achieved CR. In contrast, 15/31 (48.4%) low VEGF patients showed a poor response to treatment (IR-R/RL), whereas 16/31 (51.6%) patients achieved CR (P<0.01). In terms of the mortality rate, 20/29 (69%) high VEGF and 11/31 (35.5%) low VEGF expressers died during the study period (P<0.01) [Table 2].
Table 2: Relationship between vascular endothelial growth factor expression and various studied parameters in acute myeloid leukemia patients

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Serum angiogenin concentration

The AML patients studied showed a significantly higher serum ANG level (mean±SD, 212.5±77.1 ng/ml; range, 90–360 ng/ml) compared with the controls (66±2.5; 60–70 ng/ml; P<0.01; [Figure 2].
Figure 2: The mean serum angiogenin (ANG) level is significantly higher in acute myeloid leukemia (AML) patients compared with controls (P<0.01).

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As shown in [Table 3], the ANG concentration was not related to patients’ clinical data (age, sex, hepatosplenomegaly, and lymphadenopathy), laboratory parameters (total leukocytic count, hemoglobin level, platelet count, and PB and BM blasts), FAB subtypes, or cytogenetic risk groups (P>0.05); however, it showed a significant relationship with poor response to treatment and higher mortalities (P<0.01). Poor responders (IR-R/RL) had significantly higher serum ANG levels (mean, 258 ng/ml) compared with those who achieved CR (mean, 107 ng/ml; P<0.01) [Figure 3].
Figure 3: The mean serum angiogenin (ANG) level is significantly higher in patients with incomplete response-resistance and relapse (IR-R/RL) compared with patients who achieved complete remission (CR; P<0.01).

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Table 3: Relationship between serum angiogenin level and various studied parameters in acute myeloid leukemia patients

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Multivariate analysis of cellular VEGF expression (HR, −3.1) and serum ANG level (HR, −3.9) showed them to be independent unfavorable risk predictors for poor disease outcome in adult AML patients.


  Discussion Top


AML is a malignant clonal disorder of immature cells in the hematopoietic hierarchical system. In adult patients, intensive chemotherapy yields CR rates ranging from 50 to 80%. However, the majority of responding patients will eventually have a relapse, with only 30–40% of young patients and less than 20% of elderly patients being long-term survivors 18. With the recently recognized and increasingly important role played by angiogenesis in hematologic malignancies, investigation of the angiogenic process in AML has become an urgent justified need in an attempt for more elaborate risk stratification of patients together with the potential guidance to promising new antiangiogenic therapeutic modalities 19. We, therefore, aimed to examine the levels of two major angiogenic factors, cellular VEGF and serum ANG, in adult AML patients and to assess their prognostic impact on disease outcome.

In terms of cellular VEGF, we chose to investigate its expression in AML blasts by FCM, being a feasible, readily available technique applied routinely for the diagnosis of all suspected AML samples. Our data indicated significantly higher VEGF expression (percentage and MFI) in AML blasts than in normal BM. It is noteworthy that the blasts of the only M0 case studied expressed the lowest VEGF (5.6%; MFI, 0.6), which is in agreement with the report by Ghannadan et al. 9, who documented a very low expression of VEGF in M0 blasts by IHC. This could be explained either that VEGF is not expressed in the earliest phases of AML development, but rather later during progenitor cell differentiation, or, alternatively, that VEGF is degraded or released by M0 blasts at a higher rate compared with other AML subtypes 9. Study of a larger number of M0 cases is required to confirm this finding.

On subdividing AML patients according to the median VEGF percentage expression, the high VEGF level enabled the identification of a subset of patients with a poor response to treatment and a higher mortality rate. This increased VEGF expression, however, was not related to the standard clinical and laboratory parameters, FAB subtypes, or cytogenetic risk groups. Multivariate analysis confirmed the negative independent influence of high VEGF expression on event-free survival.

Our findings are in agreement with reports assessing cellular VEGF by radioimmunoassay 8 and real-time PCR 10,20. However, although Padro et al. 21 confirmed the increased expression of VEGF in AML samples examined by IHC, unlike our findings, they were unable to relate the VEGF level to disease outcome, probably because of the relatively small sample size (32 patients) and the different method of detection used.

As the AML BM shows increased angiogenesis manifested by increased microvessel density 1, it is likely that blast-derived VEGF plays a role in microvessel formation in AML. VEGF mediates its biologic effect through VEGFRs, and reports of receptor overexpression 21 with a poor prognostic role 10 support the aberrant VEGF signaling model proposed to operate in BM of AML patients. VEGF, in AML blasts, is considered to participate in several autocrine pathways (by acting on their own receptors) to promote blast proliferation, survival, and chemotherapy resistance, as well as paracrine mechanisms (by acting on EC receptors) to mediate vascular EC-controlled angiogenesis 19,22. In fact, there is evidence of a reciprocal positive feedback loop between leukemic cells and ECs, in which VEGF is considered to play an important role, which strongly favors the potential for refractory and relapsed diseases 19. Moreover, researchers have recently reported the role of VEGF signaling in the preservation of several cell types within the marrow stem cell niches, which are proposed to be a protective microenvironment for AML cells that could be responsible for relapse 22. These effects mediated by VEGF presumably explain the relationship between high VEGF levels and poor clinical outcome in AML patients observed in our and other studies 8, 10, 20.

In the present study, the serum ANG concentration, measured by ELISA, was higher in AML patients than in control individuals. The ANG level showed no relationship with the studied clinical and laboratory parameters, FAB subtypes, or cytogenetic risk groups. However, elevated serum ANG level was observed in patients with a poor treatment response and higher mortalities and was found to exert a negative independent influence on event-free survival.

Similar results were reported by Brunnner et al. 13 and Glenjen et al. 23, whereas Negaard et al. 24 detected no significant difference in the ANG levels between AML patients and controls, probably because of the limited number of AML patients enrolled in their study carried out on a variety of hematologic malignancies. In contrast to our findings, Kapelko-Slowik et al. 15 correlated the elevated serum ANG levels with the total leukocytic count, and they, along with Verstovesk et al. 14, related high ANG concentrations to prolonged survival periods in AML, the mechanism of which remains unclear, however, could be attributed to the fact that at concentrations greater than or equal to 500 ng/ml, ANG (through its weak RNAse activity) abolishes cell-free protein synthesis in circulating malignant cells by inactivation of the 40S ribosomal subunit 25. In the study by Verstovesk et al. 14, the median ANG concentration was 600 ng/ml. These very high values were not reported in our studied population (range, 90–360 ng/ml).

In support of our observed poor clinical outcome in patients with high serum ANG levels and its identification as an independent poor prognostic risk factor, Bruserud et al. 26 documented an increased proliferation of AML blasts cultured in ANG-enriched media compared with those cultured in ANG-free media. It is postulated that ANG, either released from AML blasts and/or other hematopoietic or stromal cells secondary to leukemia, has a direct effect on AML blast proliferation, growth enhancement, increased angiogenesis, and poor prognosis 23,26.

Given the signs of increased angiogenesis in AML BM, together with the elevated levels of various angiogenic factors, it seems rational to examine antiangiogenic therapeutic strategies in AML. The variability in the expression of these angiogenic factors among patients introduces the possibility of a ‘personalized medicine’ approach to treating AML 19. The identification of the prognostic role of different angiogenic factors and the utilization of feasible techniques for their assessment could play a role in the implementation of such emerging therapeutic approaches.


  Conclusion Top


The present study documents the increased cellular VEGF expression and serum ANG levels in AML patients, with their high levels enabling the identification of a subset of patients with a more aggressive disease course. As these angiogenic mediator levels vary on a patient-to-patient basis, their levels could be used as a prognostic indicator and utilized in future large-scale clinical trials to determine the possible use of case-tailored antiangiogenic therapy.[26]

 
  References Top

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2.Kuzu I, Beksac M, Arat M, Celebi H, Elhan AH, Erekul S. Bone marrow micro-vessel density (MVD) in adult acute myeloid leukemia (AML): therapy induced changes and effects on survival. Leuk Lymphoma. 2004;45:1185–1190  Back to cited text no. 2
    
3.Carmeliet P, Jain RK. Angiogenesis in cancer and other diseases. Nature. 2000;407:249–257  Back to cited text no. 3
    
4.Tischer E, Mitchell R, Hartman T, Silva M, Gospodarowicz D, Fiddes JC, et al. The human gene for vascular endothelial growth factor. Multiple protein forms are encoded through alternative exon splicing. J Biol Chem. 1991;266:11947–11954  Back to cited text no. 4
    
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9.Ghannadan M, Wimazal F, Simonitsch I, Sperr WR, Mayerhofer M, Sillaber C, et al. Immunohistochemical detection of VEGF in the bone marrow of patients with acute myeloid leukemia. Correlation between VEGF expression and the FAB category. Am J Clin Path. 2003;119:663–671  Back to cited text no. 9
    
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13.Brunner B, Gunsillus E, Schumacher P, Zwierzina H, Gastl G, Stauder R. Blood levels of angiogenin and vascular endothelial growth factor are elevated in myelodysplastic syndromes and in acute myeloid leukemia. J Hematother Stem Cell Res. 2002;11:119–125  Back to cited text no. 13
    
14.Verstovsek S, Kantarjian H, Aguayo A, Manshouri T, Freireich E, Keating M, et al. Significance of angiogenin plasma concentrations in patients with acute myeloid leukemia and advanced myelodysplastic syndrome. Br J Haematol. 2001;114:290–295  Back to cited text no. 14
    
15.Kapelko-Slowik K, Urbaniak-Kujda D, Dybko J, Jazwiec B, Kielbinski M, Slowik M, et al. Angiogenin serum concentration in patients with acute lymphoblastic leukemia and acute myeloid leukemia [abstract]. Haematologica. 2008;93(s1):1288  Back to cited text no. 15
    
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17.Cheson BD, Bennett JM, Kopecky KJ, Büchner T, Willman CL, Estey EH, et al. Revised recommendations of the international working group for diagnosis, standardization of response criteria, treatment outcomes, and reporting standards for therapeutic trials in acute myeloid leukemia. J Clin Oncol. 2003;21:4642–4649  Back to cited text no. 17
    
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21.Padro T, Bieker R, Ruiz S, Steins M, Retzlaff S, Bürger H, et al. Overexpression of vascular endothelial growth factor (VEGF) and its cellular receptor KDR (VEGFR-2) in the bone marrow of patients with acute myeloid leukemia. Leukemia. 2002;16:1302–1310  Back to cited text no. 21
    
22.Kampen KR, Ter Elst A, de Bont ES. Vascular endothelial growth factor signaling in acute myeloid leukemia. Cell Mol Life Sci. 2012 DOI: 10.1007/s00018-012-1085-3. [Epub ahead of print]  Back to cited text no. 22
    
23.Glenjen N, Mosevoll KA, Bruserud Ø. Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia. Int J Cancer. 2002;101:86–94  Back to cited text no. 23
    
24.Negaard HF, Iversen N, Bowitz-Lothe IM, Sandset PM, Steinsvik B, Ostenstad B, et al. Increased bone marrow microvascular density in haematological malignancies is associated with differential regulation of angiogenic factors. Leukemia. 2009;23:162–169  Back to cited text no. 24
    
25.St Clair DK, Rybak SM, Riordan JF, Vallee BL. Angiogenin abolishes cell-free protein synthesis by specific ribonucleolytic inactivation of 40S ribosomes. Biochemistry. 1988;27:7263–7268  Back to cited text no. 25
    
26.Bruserud Ø, Glenjen N, Ryningen A. Effects of angiogenic regulators on in vitro proliferation and cytokine secretion by native human acute myelogenous leukemia blasts. Eur J Haematol. 2003;71:9–17  Back to cited text no. 26
    


    Figures

  [Figure 1], [Figure 2], [Figure 3]
 
 
    Tables

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