There is considerable increase in MVD in the bone marrow of patients with MDS.38 The most extensively studied cytokine thought to be responsible for the development of neovascularization is VEGF.39 Others, such as TNFa and bFGF are also involved, but VEGF appears to be the major player. VEGF and its type III receptor are overexpressed by myeloblasts and monocytes derived from the malignant clone. The increase in MVD in the bone marrow is associated with a higher percentage of blasts, which in turn correlates with increased levels of VEGF, TNFa, and bFGF. This has been shown in MVD studies where ALIPs (abnormal localized immature precursors) within the bone marrows of MDS patients express higher levels of VEGF and VEGFR, specifically VEGFR-1. VEGF has multiple activities: stimulating release of proteases from endothelial cells resulting in degradation of the extracellular matrix; recruiting mediators of apoptosis, such as TNFa and soluble Fas (CD95) ligand; and activating cell adhesion molecules. VEGF also stimulates engraftment of myeloid leukemic and hematopoietic stem cells and regulates maturation of receptor-positive cells, thus stimulating endothelial cell maturation while inhibiting hematopoietic precursor, osteoblast, and dendritic cell maturation. VEGF deregulation can thus have severe repercussions on effective hematopoiesis.
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