Elsevier

Leukemia Research

Volume 37, Issue 4, April 2013, Pages 410-415
Leukemia Research

Synergistic effect of vascular endothelial growth factor and angiopoietin-2 on progression free survival in multiple myeloma

https://doi.org/10.1016/j.leukres.2012.12.014Get rights and content

Abstract

Bone marrow neoangiogenesis plays an important role in multiple myeloma (MM) and depends on the interplay of angiogenic cytokines. We investigated the levels of angiogenic cytokines such as vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), angiopoietin (Ang)-1, Ang-2 and hypoxia inducible factor-1 alpha (HiF-1α) in MM patients and their association with treatment outcome. Serum levels and mRNA expression of VEGF, Ang-2, Ang-1, bFGF and HiF-1α were evaluated in 71 MM patients using enzyme-linked immunosorbent assay and reverse transcriptase polymerase chain reaction. In multivariate Cox regression analysis, serum levels of VEGF  756 pg/ml (HR 2.2, 95% CI 1.02–4.91; p = 0.045) and relative mRNA expression levels of Ang-2  0.93 (HR 21.0, 95% CI 6.27–70.45; p < 0.001) were predictive of inferior progression free survival (PFS) and patients with concomitant increase in VEGF and Ang-2 had poor outcome compared to the rest of the patients (HR 32.6, 95% CI 7.20–148.36; p < 0.001). These results suggest that VEGF and Ang-2 act in synergy and their expression levels at presentation are predictive of PFS in MM.

Introduction

Tumor cells promote vessel formation through expression of angiogenic molecules or their induction in the microenvironment. Vascular endothelial growth factor (VEGF), basic fibroblast growth factor (bFGF), Angiopoietin (Ang)-1, Ang-2 and hypoxia inducible factor-1 alpha (HiF-1α) are pro-angiogenic molecules that have been identified to drive tumor related angiogenesis [1], [2]. Multiple myeloma (MM) was the first hematological malignancy in which a prognostic relevance of angiogenesis was demonstrated [3], [4].Various studies demonstrated that serum levels of angiogenic cytokines such as bFGF, VEGF and Ang-2 are elevated in MM patients compared to normal controls [5], [6], [7], [8].

For several angiogenic cytokines, a correlation has been shown with prognosis and disease stage in myloma. Iwasaki et al. demonstrated a prognostic significance of serum VEGF in myeloma patients [7]. Furthermore, Neben observed a prognostic relevance for bFGF while Andersen et al., could not find any prognostic significance for bFGF in MM patients [9], [10]. Giuliani found that Ang-1 and not Ang-2 expression is upregulated in plasma cells obtained from MM patients and a correlation exists between Ang-1 expression and bone marrow micro vessel density in these patients [11]. In contrast, Uneda could find expression of Ang-2 and not Ang-1 and suggested that Ang-2 bears prognostic relevance in myeloma patients [12]. Though, the reports indicate correlation of cytokines with prognosis in MM; a more detailed insight into the complex interactions between these cytokines is required.

So far, the precise molecular mechanisms underlying the progressive increase in angiogenesis in MM remain unclear. In this study, we hypothesized that the circulating levels of angiogenic cytokines VEGF, bFGF, Ang-1, Ang-2 and HiF-1α predict prognosis in MM patients. We, therefore, performed a univariate and multivariate analysis to investigate the prognostic value of serum levels of VEGF, bFGF-1 Ang-1, Ang-2 and HiF-1α levels for PFS in MM patients. The correlation of circulating levels of these angiogenic cytokines with PFS in MM patients revealed that VEGF and Ang-2 are independent predictors and raised level of both VEGF and Ang-2 is associated with relatively poor outcome.

Section snippets

Patients and methods

Subjects: A total of 71 newly diagnosed MM patients registered at Dr. Bhim Rao Ambedkar Institute Rotary Cancer Hospital, All India Institute of Medical Sciences (Dr B.R.A. IRCH, AIIMS) between November 2007 and September 2010 were enrolled in this study. The study was approved by the Institute Ethics Committee, and informed consent was obtained from all the patients.

Treatment: Fifty six patients received thalidomide-200 mg daily + dexamathosone −20 mg/m2, PO day 1–4 & day 9–12 q12 days, 11

Statistical analysis

The levels of all angiogenic cytokines are presented as mean ± SD. Correlation of angiogenic cytokine with clinical parameters was evaluated by Spearman Rho test. Association of angiogenic cytokines with stage of disease was assessed by one way-ANOVA. Comparison between progressed and non-progressed patients was done using Student's t-test/Wilcoxon Rank Sum test as appropriate. No standard cut-off values are available for angiogenic cytokines in literature and therefore, the best threshold value

Results

Progression free survival was calculated from the date of diagnosis to disease progression or death from any cause. At 4 years, after a median follow-up of 32.4 months (range: 1–49), 31 of 71 (44%) patients progressed. Baseline characteristics and demographic characteristics of MM patients are summarized in Supplementary Table 1.

Discussion

Bone marrow angiogenesis in MM is regulated by angiogenic cytokines such as VEGF, bFGF, Ang-1, Ang-2 and the degree of bone marrow angiogenesis has an impact on disease progression in MM [3], [10], [14]. The present study was undertaken to test the hypothesis that the peripheral levels of angiogenic cytokine such as VEGF, bFGF, Ang-1, Ang-2 and HiF-1α are predictive of outcome in MM. Of all the angiogenic cytokines, VEGF is the most widely studied cytokine in human malignancies. Earlier studies

Conflict of interest statement

None of the authors of this paper has a financial or personal relationship with other people or organizations that could inappropriately influence or bias the content of the paper.

Acknowledgements

The original concept was funded by Department of Biotechnology (DBT), New Delhi, India and AB received Senior Research Fellowship from Indian Council of Medical Research (ICMR), New Delhi, India. The authors wish to thank all the patients for taking part in the study.

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