Blood Levels of Angiogenin and Vascular Endothelial Growth Factor Are Elevated in Myelodysplastic Syndromes and in Acute Myeloid Leukemia

Abstract

Angiogenesis is of prognostic importance not only in solid tumors but also in malignant blood diseases. We measured levels of vascular endothelial growth factor (VEGF), angiogenin (ANG), and basic fibroblast growth factor (bFGF) in peripheral blood samples from 65 patients with myelodysplastic syndrome (MDS), from 25 patients with de novo acute myeloid leukemia (AML), and from 50 healthy donors. In matched samples, VEGF levels in serum were substantially higher than VEGF levels in plasma (380.7 +/- 56 pg/ml vs. 45.3 +/- 4.5 pg/ml, mean +/- SEM, p < 0.001), whereas serum and plasma levels of ANG were comparable and significantly correlated (r = 0.8; p < 0.01). Compared to normal controls (1.3 +/- 0.09 pg), serum levels of VEGF corrected for the peripheral blood platelet count (VEGF/10(6) platelets, VEGF(PLT)) were elevated in patients with refractory anemia (RA; 3.1 +/- 0.8 pg, p < 0.01), and reached maximal values in patients with advanced stage MDS (RAEB, RAEB-t) (3.5 +/- 0.6 pg, p < 0.001), de novo AML (3.6 +/- 1.1 pg, p < 0.05), and chronic myelomonocytic leukemia (CMML; 3.7 +/- 0.9 pg; p < 0.001). Levels of soluble ANG were elevated in RA (351 +/- 25.7 ng/ml, p < 0.001), in RAEB/RAEB-t (402 +/- 17.9 ng/ml; p < 0.001), in CMML (413.8 +/- 29.5 ng/ml; p < 0.001), and in patients with AML (305.1 +/- 17.1 ng/ml; p < 0.01, controls 255.4 +/- 8.1 ng/ml). Serum bFGF was neither elevated in MDS nor in AML patients. These results suggest that VEGF(PLT) is a marker of disease progression in MDS. Moreover, we show for the first time that elevated blood levels of ANG can be found in patients with myeloid malignancies, suggesting a role of ANG in the pathogenesis of these diseases.

Serum levels of angiogenin, basic fibroblast growth factor and endostatin in patients receiving intensive chemotherapy for acute myelogenous leukemia

“…However, other investigators have described increased VEGF levels in patients with untreated AML. 54 Activated platelets release endostatin. 55 In contrast to VEGF, platelet-derived endostatin seems to have only a minor influence on the total serum levels because: (i) serum endostatin levels are considerably higher than the serum levels of VEGF (measured in ng/ml vs. pg/ml); (ii) endostatin levels and platelet counts showed no correlation for untreated AML patients, and increased levels were observed even in thrombocytopenic AML patients; (iii) endostatin levels were not altered after the development of severe therapy-induced thrombocytopenia.…”

Activating mutations of RTK/ras signal transduction pathway in pediatric acute myeloid leukemia

“…Findings implicate vascular endothelial growth factor (VEGF) in pathogenesis of AML, 8,17,[22][23][24][25] and there is evidence of increased marrow vascularization in patients with AML 17 as well as high levels of the VEGF ligand associated with poor outcome in AML. 8 Although activating mutations of the VEGF receptors have been constructed in vitro, 7,26 such mutations have not been identified in malignancies.…”

Myelodysplastic Syndromes: Review of Pathophysiology and Current Novel Treatment Approaches

“…In addition to increased TNF-alpha and INF-gamma in the marrow of MDS patients, varying levels of angiogenic factors including VEGF (vascular endothelial growth factor), bFGF (fibroblast growth factor), angiogenin, HGF (hepatic growth factor), EGF (epidermal growth factor), and TGF-beta (transforming growth factor) have been noted in the plasma of MDS patients. These findings, coupled with direct evidence of increased microvascular density (MVD) on marrow biopsies, support the development of early blood vessels in MDS [120][121][122][123]. Both plasma VEGF levels and increased MVD correlate with advanced MDS FAB class [124][125][126] and imply that increased VEGF may drive increased MVD eventually stimulating MDS progression to AML.…”