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Role of Stromal Cells Recent Advances in Angiogenesis and Antiangiogenesis, 2009 81 T-cell fibroblast endothelial cell lGF-1, lL-6, VEGF, TNF- a, MMPs macrophage VEGF,FGF-2, TNF-a, MMPs, chemokines VEGF, FGF-2, TNF-a, TGF-b, MIP-1a VEGF mast cell VEGF, FGF-2 tryptase, chymase, histamine Fig. (1). Interplay between various microenvironment cells and factors promoting angiogenesis in multiple myeloma. Tumor macrophages are a source of pro-angiogenic cytokines, such as VEGF, FGF-2, IL-8, TNF-α, and TGF-β. In addition, tumor macrophages synthesize a broad spectrum of matrix metalloproteinases (MMPs), such MMP-2, MMP-7, MMP-9 and MMP-12 [15]. All these factors contribute to the angiogenic phase in MM. Recently, Scavelli et al. [16] have demonstrated that bone marrow macrophages of active MM patients (i.e., patients at diagnosis, relapse, or leukemic phase) are involved in the formation of new vessels through vasculogenic mimicry. In fact, when these macrophages were exposed to VEGF and FGF-2 (i.e., cytokines secreted by MM plasma cells into the microenvironment), they transformed into cells functionally and phenotypically similar to paired ECs (or MMECs), and generated capillary-like networks mimicking those of MMECs. Authors also found the macrophages (positive for their lineage marker, CD68) inside the neovessel wall which cooperated with classical MMECs (positive for Factor VIII-related antigen - FVIII-RA) in building the new vessel wall. Also, macrophages from patients with non-active MM (i.e., with complete/objective response or plateauphase), and those from patients with monoclonal gammopathy of undetermined significance (MGUS) diplayed similar, albeit weaker features. At ultrastructural level, macrophages from active MM patients appeared as long-shaped cells with thin IL-6 IGF-1, IL-6, VEGF, TNF-a osteoclast IL-6 VEGF, FGF-2, MMPs, CXC chemokines VEGF, TNF-a, IL-6 plasma cells VEGF, FGF-2, HGF-SF, TGF-b, MMPs, TNF-a, Ang1 ANGIOGENESIS cytoplasmic protrusions, short microvilli, fillipodes and pseudopodes. Also, their cytoplasmic protrusions formed tubular structures anastomosed with each other and those of nearby macrophages, reminiscent of vascular structures. 4. ROLE OF MAST CELLS IN VAS- CULOGENIC MIMICRY IN MULTI- PLE MYELOMA Mast cells are usually involved in type I hypersensitivity reactions. However, their granules contain a large number of cytokines, including angiogenic factors, such as VEGF, FGF-2, TNF-α and IL-8 [17-19], proteases, such as tryptase and chymase responsible for both basement membrane matrix degradation and activation of preformed growth factors [20, 21] . Moreover, heparin and histamin, contained in mast cell secretory granules, exert an angiogenic activity [22]. Mast cells are involved in tumor angiogenesis [23], through the release of angiogenic factors stored in their secretory granules in a typical piecemeal degranulation mode [24]. Ribatti et al. [25] have demonstrated that in MM bone marrow, angiogenesis and mast cell counts are highly correlated, and increase in parallel in patients with active and nonactive disease, as compared to those with MGUS.
82 Recent Advances in Angiogenesis and Antiangiogenesis, 2009 Vacca et al. FVIII-RA bp 696 MM macrophages exposed to VEGF + FGF-2 A B C VEGFR-2 bp 496 Tie2/Tek bp 502 VE-cadherin bp 592 GAPDH bp 347 d0 d1 d4 d7 MMECs -10 10 20 30 40 50 60 70 kDa 205 d0 d1 d4 d7 MMECs Fig. (2). Bone marrow macrophages of myeloma patients overlap phenotypically paired endothelial cells (MMECs) upon exposure to VEGF and FGF-2 for 7 days. (A) RT–PCR analysis showing the acquisition or enhancement of endothelial markers at similar levels of paired MMECs. (B) Real-Time RT-PCR fold expression of FVIII-RA, VEGFR-2, Tie2/Tek and VE-cadherin in MM macrophages exposed to VEGF and FGF-2. (C) Western blot analysis of cell lysates showing the endothelial proteins on VEGF-/FGF-2-stimulated MM macrophages at similar levels of MMECs (kDa, molecular weight in kilodaltons; GAPDH, glyceraldehyde-3-phosphate dehydrogenase; β-actin, control protein). More recently, Nico et al. [26] have shown that mast cells are also involved in the formation of new vessels in MM through vasculogenic mimicry, similarly to macrophages. At ultrastructural level, they clearly showed that vessels in MM are lined by mast cells with characteristic electron dense granules in their cytoplasm, and these data were confirmed by confocal laser microscopy showing vessels simultaneously marked by an antibody to tryptase (a mast cell marker) and an antibody to FVIII-RA (the MMEC marker) [26]. 5. ENDOTHELIAL DIFFERENTIA- TION OF HEMATOPOIETIC STEM AND PROGENITOR CELLS IN MULTIPLE MYELOMA Several data suggest the existence of endothelial progenitor cells (ECPs), their derivation from bone marrow, and their contribution to the formation of blood vessels in postnatal and adult life [27]. EPCs are closed associated with hematopoietic stem and progenitor cells (HSPCs) with a typical phenotype including the CD133, CD34 and VEGFR-2 molecules [28, 29]. Real-Time RT-PCR Fold expression b-actin 207 205 116 109 51 36 In patients with active MM, plasma cells and stromal cells in the bone marrow microenvironment recruit HSPCs, and induce their transformation into mature MMECs [30]. In fact, when HSPCs of MM patients are incubated with VEGF, FGF-2 and insulin-like growth factor (IGF) (i.e., typical cytokines secreted by both plasma cells and stromal cells into the miroenvironment) cells differentiate into ECs-like cells expressing typical endothelial markers, such as FVIII-RA, VEGFR-2 and VE-cadherin, and form capillary-like networks in vitro [31]. Bone marrow biopsies revealed HPSCs inside the neovessel wall in patients with MM, but not in those with MGUS, suggesting that in the former HSPCs contribute to the new vessel building together with MMECs [32]. Therefore, besides angiogenesis, HSPC-linked vasculogenesis contributes to neovascularization in MM patients. 6. CONCLUSIONS MM macrophages exposed to VEGF + FGF-2 Overall, these data indicate that in active MM patients, macrophages, mast cells and HSPCs contribute to neovascularization through a vasculogenic pathway, and that in non-active MM and MGUS they are prone
Page 2 and 3: Recent Advances in Angiogenesis and
Page 4 and 5: FOREWORD It has been known for a ve
Page 6 and 7: single proangiogenic protein. Howev
Page 8 and 9: v Vito Pistoia Head, Laboratory of
Page 10 and 11: 2 Recent Advances in Angiogenesis a
Page 12 and 13: 10 Recent Advances in Angiogenesis
Page 16 and 17: The Role of Mesenchymal Stem Cells
Page 22 and 23: Thymus and Angiogenesis Recent Adva
Page 32 and 33: Role of Thymidine Recent Advances i
Page 40 and 41: Tumor Targeting with Transgenic End
Page 44 and 45: Tumor Vascular Disrupting Agents Re
Page 50 and 51: Tumour Vascular Disrupting Agents R
Page 52: Index Recent Advances in Angiogenes

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