Among innovative treatments, antiangiogenic therapy seems to represent a promising approach, whose rationale is based on tumour growth inhibition by starving cancer cells of vital nutrients [2]. Recent evidences indicate that angiogenic processes are increased and are fundamental not only in solid tumours but also in hematologic diseases, including MM, as well [3, 4]. Scarce angiogenic

activities have been found in monoclonal gammopathy of undetermined significance (MGUS) as compared to the overt malignant forms, where marrow neoangiogenesis parallels tumour progression and correlates with poor prognosis, suggesting an angiogenesis-dependent regulation of disease activity [5–7]. Neoangiogenesis is under the control Ibrutinib cost selleck compound of various cytokines, that are expressed by neoplastic plasma cells, so that their involvement in MM pathophysiology has been strongly supported by different reports [8]. These modulators include vascular endothelial growth factor (VEGF), hepatocyte growth

factor (HGF) and basic fibroblast growth factor (bFGF), that have been extensively investigated in biological samples derived from MM patients. However, data concerning their potential prognostic power as well as their reciprocal interactions are still conflicting [8–10] and remain to be better elucidated. VEGF is a major regulator of tumour-associated angiogenesis exhibiting various biological activities, including regulation of embryonic stem cell development and local generation of inflammatory cytokines [11]. VEGF gene encodes for at least

five isoforms which are anchored to the extracellular matrix through the heparin-binding domains. They are mitogenic to vascular endothelial cells and induce vascular permeabilization [11]. VEGF expression is regulated by several factors including interleukins (IL-1β, IL-6, IL-10), fibroblast growth factor (FGF-4) and insulin-like growth factor1(IGF-1) [12]. bFGF is an 18 to 24 kD polypeptide, mainly produced by cells of mesenchymal origin, which shares a key role of mediator BCKDHB of angiogenesis with VEGF in vitro [13] and in vivo [14]. This molecule is normally bound to heparin and heparan sulphate proteoglycans in the extracellular matrix, particularly in the basement membranes, around vessels and stromal cells. It binds to a family of four distinct, high affinity tyrosine kinase receptors (FGFR-1–4) and stimulates endothelial cell proliferation in vitro [13]. IGF-I is a mitogen and anti-apoptotic cytokine/growth factor/hormone produced by several types of cells (fibroblasts, hepatocytes, chondroblasts..) [15]. Its potential role as a growth factor for myeloma cells has been deeply analyzed and data of Ge NL et al [16] suggest that IGF-I significantly contributes to the expansion of MM cells in vivo by activation of two distinct pathways: Akt/Bad and MAPK kinase.