Angiogenesis and Antiangiogenesis in Multiple Myeloma

Abstract

Multiple myeloma progression is characterized by a dense interaction between cancer cells and bone marrow microenvironment. The interactions of myeloma cells with various stromal cells and extracellular matrix components are the main regulator of the biological processes that underlie the progression of the disease and of the classic symptomatology correlated. The bone marrow of myeloma patients has recognized autocrine and paracrine loops that regulate multiple signaling pathways and the malignant phenotype of plasma cells. One of the pivotal biological processes which are responsible for myeloma progression is the formation of new vessels from existing ones, known as angiogenesis. It represents a constant hallmark of disease progression and a characteristic feature of the active phase of the disease. Near angiogenesis, other two ancestral processes were active in the bone marrow: vasculogenesis and vasculogenic mimicry. These processes are mediated by the angiogenic cytokines, interleukins, and inflammatory cytokines directly secreted by plasma cells and stromal cells. Neovascularization is also mediated by direct interaction between plasma cells and the various components of bone marrow microenvironment. The observation of the increased bone marrow angiogenesis in multiple myeloma and its correlation with disease activity and overall survival led to consider angiogenesis as a new target in the treatment of multiple myeloma.

Anti-VEGF Drugs in the Treatment of Multiple Myeloma Patients

“…The precursors of CAFs are resident fibroblasts and progenitor cells. BM infiltrating fibroblasts promote neovessel formation by the secretion of high amounts of growth factors and angiogenic cytokines, such as VEGF-A, FGF-2, tumor necrosis factor-alpha (TNF-α), urokinase, and matrix metalloproteinases–MMPs [ 7 , 9 , 13 , 40 , 41 , 42 , 43 ]. Moreover, fibroblasts synthesize inducible nitric oxide synthase, which increases blood flow [ 41 ].…”

“…The ECs that line newly formed vessels contain cytoplasmic vesicles and inclusions, broaden intercellular junctions, and are supported by an incomplete and highly permeable basement membrane [ 15 ]. These alterations are a result of microenvironment activation and stimulation induced by myeloma PCs, which promotes three different processes: (i) angiogenesis, (ii) vasculogenesis, and (iii) vasculogenic mimicry [ 9 ].…”

“…BM microvessel density is remarkably higher in patients with active MM compared to those with MGUS or healthy subjects and neovessel density correlates with the disease stage, shrinking during the remission/plateau phase, increasing in density in the diagnosis, relapse/refractory phase, and reaching maximum expansion in the leukemic phase [ 9 , 11 , 32 , 58 ].…”

“…The interaction of MM PCs with BM stromal cells (SCs) and extracellular matrix (ECM) components in the BM microenvironment is mediated by a plethora of autocrine and paracrine cytokine loops, as well as direct cell–cell and cell–ECM interactions. These direct and indirect interactions result in the activation of multiple signaling pathways that are responsible for modifications in the microenvironment during MM progression [ 9 ] and that are responsible for MM plasma cell apoptosis inhibition, survival, proliferation, and invasion. The expansion of neoplastic PCs in BM causes bone lysis and promotes microenvironment modulation and neovessel formation [ 10 , 11 , 12 ].…”

“…The development of a new vascular tree in the BM of MM patients is a pathologic process in which angiogenesis (the formation of new vessels from existing ones) [ 9 ], vasculogenesis (the formation of new vessels from endothelial precursors) [ 15 ], and vasculogenic mimicry (the completion of neovessels by other non-endothelial cells [ECs]) [ 16 ] work simultaneously for the constitution of the vascular niche [ 9 ]. BM neovascularization is related to the MM stage, disease progression, and patients’ response to therapy and survival [ 15 , 16 , 17 , 18 , 19 , 20 ].…”