**1. Introduction**

In the past decades, myeloma research has been focalized on the malignant cell leading to the identification of various genes (i.e., oncogenes and tumor suppressor genes) and of signaling pathways by which the identified genes themselves control survival and proliferation of cancer cells [1–4]. More recently, newly developed technologies have enabled us to investigate cancer cells at the genomic level. Such gene profiling studies are providing insight into the pathogenesis and risk stratification of plasma cell diseases, and help to predict both prognosis and treatment response [3, 4].

junctions, and a discontinuous basement membrane [16]. These alterations are consequent to the rapid neovascularization induced by tumor plasma cells by mean of three different pro-

Angiogenesis and Antiangiogenesis in Multiple Myeloma

http://dx.doi.org/10.5772/intechopen.76931

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In 1994, Vacca and colleagues [16] demonstrated for the first time that BM microvascular density was significantly increased in MM compared to monoclonal gammopathy of undetermined significance (MGUS) and moreover in active (diagnosis, relapse, and leukemic phase) versus non-active (complete/objective response and plateau) MM. The authors first hypothesized that progression from MGUS to MM is accompanied by an increase in BM microvascular density. Subsequent studies by other groups confirmed the observation of increased angiogenesis in active MM compared to healthy individuals or MGUS

Angiogenesis is the sprouting of new blood vessels from pre-existing ones and is finely regulated [17, 18]. Angiogenesis is essential for tumor growth, invasion, and metastasis starting from the balanced early avascular phase of cancer up to being uncontrolled and unlimited in time during the vascular phase [6, 17, 20]. The angiogenic switch from the avascular to the vascular phase is controlled by the many oncogenes, among which c-myc, c-fos, c-jun, and ets-1 have been recognized [20, 21]. They are activated in tumor plasma cells as a consequence of immunoglobulin translocations and genetic instability [20, 21], and induce the angiogenic phenotype in MM plasma cells [21]. MM plasma cells become CD45-negative and begin to produce VEGF [22]. The same angiogenic switch represents a crucial event for the progression from asymptomatic to symptomatic MM [23]. So, angiogenesis represents an important process in MM progression as well as an important

Vasculogenesis is responsible for the primary development of the vascular system during embryogenesis and is fundamental for the formation of the yolk sac vasculature, of the heart, and of the dorsal aortae [24]. It derives from the differentiation of endothelial progenitors, namely angioblasts, deriving from mesoderm and aggregate into a primitive capillary plexus [24]. Important evidence suggests that vasculogenesis contributes to neovascularization in the bone marrow of MM patients [25–27]. In fact, putative endothelial progenitor cells have been isolated from peripheral blood and several studies have suggested that angioblasts contribute to the formation of tumor neovessels [25, 26]. It has been demonstrated that when CD34+ VEGFR-2+ cells isolated from peripheral blood of MM patients were cultured on fibronectincoated plates and exposed to angiogenic cytokines, they acquire a typical spindle-shaped morphology and express endothelial cell markers (CD34, CD31, Flk-1, Tie-2, and E-selectins) [26]. Moreover, in the BM of MM patients, but not of MGUS patients, some endothelial cells of neovessel wall express on their surface the typical endothelial cell markers: factor VIII-related antigen (FVIII-RA), vascular endothelial-cadherin (VE-cadherin), VEGFR-2, and TIE/Tek, as well as the CD133 staminal antigen whose expression was found in the microvascular wall

together with FVIII-RA or VE-cadherin in some active MM patients [26].

cesses: (i) angiogenesis, (ii) vasculogenesis, and (iii) vasculogenic mimicry [17].

**2.1. Angiogenesis**

patients [17–20].

prognostic factor [17, 19, 20].

**2.2. Vasculogenesis**

Cancer cells interact with all cells composing the microenvironment and with components of extracellular matrix (ECM) [5, 6]. These interactions play the most important role in the epigenetic control of the malignant phenotype, as in primary sites as in the metastatic ones [6, 7]. Moreover, interactions between host cells in the niche microenvironment and ECM represent an intense area of research [5–9]. The aim of these studies is the better understanding of the pathophysiological events in the tumor process, including malignant cells, surrounding cells, and ECM components [5–9].

Multiple myeloma (MM) is a malignancy of plasma cells that home to and expand in the bone marrow (BM) [9]. MM is characterized by a high genomic heterogeneity but, generally, it shows the same histological features, [8–10]. The interactions between MM plasma cells and BM microenvironment (stromal cells, hematopoietic cells, ahnd ECM) represent near genetic modifications an important factor for disease progression [11–14]. Pathophysiological interactions of myeloma cells with the components of BM microenvironment are pivotal during the progression-associated bone disease and neovascularization [13]. These interactions are mediated by autocrine and paracrine loops that regulate multiple signaling pathways and influence many fundamental biological aspects of the malignant phenotype (i.e., apoptosis, survival, proliferation, invasion, bone damage, and angiogenesis) [12–14].

Neovascularization is the formation of new vessels from existing ones (angiogenesis) or from endothelial precursors (vasculogenesis) and represents one of the principal biological process controlled by the interactions between plasma cells and BM microenvironment. It is a constant hallmark of disease progression [11–15]. Angiogenesis is controlled by several angiogenic cytokines [14, 15]. The major of these are vascular endothelial growth factor (VEGF), fibroblast growth factor-2 (FGF-2), and hepatocyte growth factor (HGF) directly secreted not only by the tumor plasma cells but also by stromal cells [14, 15].

The observation of an increased BM angiogenesis in MM, an overexpression of angiogenic cytokines, and their correlation with disease activity, overall survival and the development of new antiangiogenic compounds, led to consider angiogenesis as a new target in the treatment of MM [11–15].
