Circulating Levels of Angiogenic Cytokines in Waldenstrom’s Macroglobulinemia: Clinical Correlations

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.