Circulating Levels of Angiogenic Cytokines in Waldenstrom’s Macroglobulinemia: Clinical Correlations
Evangelos Terpos, Dimitrios Christoulas, Efstathios Kastritis and Meletios A. Dimopoulos
Affiliation: Department of Clinical Therapeutics, National and Kapodistrian, University of Athens, School of Medicine, Alexandra General Hospital, 80 Vas. Sofias Avenue, 11528 Athens, Greece.
Keywords: Angiogenesis, angiopoietins, C-C motif ligand 3 (CCL3), tumor associated macrophages, vascular endothelial
growth factor (VGF), Waldenstrom’s Macroglobulinemia.
Angiogenesis is involved in several diseases, including hematological malignancies and solid tumors as an
essential step of disease progression. In Waldenstrom’s macroglobulinemia (WM) the bone marrow microvessel density is
increased in 30%-40% of patients with symptomatic disease, but not in patients with monoclonal gammopathy of undetermined
significance of IgM type (IgM-MGUS) and in patients with asymptomatic WM. The serum levels of angiogenic
cytokines such as vascular endothelial growth factor (VEGF), VEGF-A, basic fibroblast growth factor, angiogenin and
angiopoietin-2 (Ang-2) are markedly elevated in WM patients, while Ang-1 levels and the corresponding Ang-1 to Ang-2
ratio are significantly decreased, indicating an angiogenic shift. Circulating angiogenin and angiopoietin-1/angiopoietin-2
ratio correlate with disease activity and clinical features of WM. Ang-2 may also have a prognostic significance for WM
patients as high levels of Ang-2 were found to be associated with significantly shorter progression-free survival. The
chemokine C-C motif ligand 3 (CCL3) is a chemo-attractant for macrophages and mast-cells and was found to be elevated
in the serum of patients with WM. CCL3 is produced by WM cells and correlates with inferior overall survival. In turn,
activated inflammatory cells synthesize angiogenic regulators and modulate angiogenesis. This paper summarizes all
available data for the role of angiogenic cytokines and supporting cells in the biology of WM and their correlation with
clinical and laboratory features of the disease.
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