The pathophysiologic functions of VEGF within the BM microenvironment. (A) Components of the bone marrow microenvironment and tumor angiogenesis. The BM microenvironment is a heterogeneous population of cells that are in tight association with the extracellular matrix (ECM) (fibronectin, laminin, collagen): immune cells (including NK cells, T lymphocytes, and monocytes) and dendritic cells (DCs); erythrocytes (Erys); hematopoietic stem cells (HSCs); progenitor and precursor cells; bone-marrow–derived circulating endothelial precursors (CEPs); endothelial cells (ECs); fibroblasts; osteoblasts and osteoclasts; and the tumor cells. Pro- and antiangiogenic molecules secreted by both the stromal and tumor cells contribute to tumor growth and progression. Tumor-derived angiogenic factors like VEGF promote tumor angiogenesis. Tumor vessels grow by co-option, sprouting, and intussusception, as well as by recruitment of CEPs and HSCs. Moreover, some tumor cells act as endothelial cells and form avascular conduits or mosaic blood vessels. (B) Additional biologic functions of VEGF. Besides angiogenesis, VEGF regulates hematopoiesis by mediating HSC survival and repopulation via both an autocrine loop and by inducing differentiation of multiple hematopoietic lineages. Moreover, VEGF inhibits maturation of DCs, increases bone-resorbing activity, modulates immune responses (eg, enhances NK cell adhesion to tumor endothelium), triggers CEP differentiation, and mediates monocyte and CEP recruitment to the vasculature. In the context of cancer, VEGF is an important growth, migration, and survival factor in Kaposi sarcoma, leukemia, and MM. These highly integrated processes involve paracrine, autocrine, and juxtacrine secretion of multiple growth factors, cytokines, and chemokines including IL-6, VEGF, IGF-1, and TNFα; and release of active metalloproteinases (MMPs, such as MMP9); as well as direct tumor–stromal cell and tumor cell–ECM contact.