Angiogenesis and Anti-Angiogenesis in Hematological Malignancies

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2 Angiogenesis and Anti-Angiogenesis in Hematological Malignancies

3 Domenico Ribatti Angiogenesis and Anti-Angiogenesis in Hematological Malignancies 1 3

4 Domenico Ribatti Department of Basic Medical Sciences Neurosciences and Sensory Organs University of Bari Medical School Bari Italy ISBN ISBN (ebook) DOI / Springer Dordrecht Heidelberg New York London Library of Congress Control Number: Springer Science+Business Media Dordrecht 2014 This work is subject to copyright. All rights are reserved by the Publisher, whether the whole or part of the material is concerned, specifically the rights of translation, reprinting, reuse of illustrations, recitation, broadcasting, reproduction on microfilms or in any other physical way, and transmission or information storage and retrieval, electronic adaptation, computer software, or by similar or dissimilar methodology now known or hereafter developed. Exempted from this legal reservation are brief excerpts in connection with reviews or scholarly analysis or material supplied specifically for the purpose of being entered and executed on a computer system, for exclusive use by the purchaser of the work. Duplication of this publication or parts thereof is permitted only under the provisions of the Copyright Law of the Publisher s location, in its current version, and permission for use must always be obtained from Springer. Permissions for use may be obtained through RightsLink at the Copyright Clearance Center. Violations are liable to prosecution under the respective Copyright Law. The use of general descriptive names, registered names, trademarks, service marks, etc. in this publication does not imply, even in the absence of a specific statement, that such names are exempt from the relevant protective laws and regulations and therefore free for general use. While the advice and information in this book are believed to be true and accurate at the date of publication, neither the authors nor the editors nor the publisher can accept any legal responsibility for any errors or omissions that may be made. The publisher makes no warranty, express or implied, with respect to the material contained herein. Printed on acid-free paper Springer is part of Springer Science+Business Media (

5 Acknowledgments This work was supported by European Union Seventh Framework Programme (FPT7/ ) under grant agreement n to DR. v

6 Contents 1 Introduction Angiogenesis Tumor Angiogenesis Angiogenesis in Multiple Myeloma General Features of Multiple Myeloma Angiogenesis in Multiple Myeloma Angiogenic Cytokines and Multiple Myeloma Progression Signaling Pathways Invasive Ability of Plasma Cells Multiple Myeloma Endothelial Cells The Role of Macrophages and Mast Cells The Role of Endothelial Precursor Cells and of Hematopoietic Stem and Progenitor Cells Prognostic Value of Angiogenesis in Multiple Myeloma Angiogenesis in Lymphomas General Features of Lymphomas In Vitro and Vivo Experimental Models Angiogenesis in Normal Lymph Nodes and in Benign Lymphadenopathies Angiogenesis in Non-Hodgkin Lymphomas The Role of Myelo-Monocytic Cells and Circulating Endothelial Cells The Role of Macrophages and Mast Cells Genetically Modified Lymphoma Endothelial Cells Angiogenesis in Leukemia General Features of Leukemias Angiogenesis in Acute Lymphocytic Leukemia Angiogenesis in Chronic Lymphocytic Leukemia vii

7 viii Contents 4.4 Angiogenesis in Acute and Chronic Myeloid Leukemia and Myelodysplastic Syndrome Role of Matrix Metalloproteinases and Mast Cells Anti-angiogenesis Introduction Endostatin Thalidomide Thalidomide in the Treatment of Multiple Myeloma and Waldenstrom s Macroglobulinemia Thalidomide in the Treatment of Leukemia, Lymphoma and Myelodysplastic Syndrome Side Effects Thalidomide Analogues Combination Therapy VEGF Neutralizing Antibodies Receptor Tyrosine Kinase Inhibitors Receptor Tyrosine Kinase Inhibitors in the Treatment of Multiple Myleoma Receptor Tyrosine kinase Inhibitors in the Treatment of Leukemia Bortezomib Zoledronic Acid Interleukins Chemotherapeutics Histone Deacetylase Inhibitors and Vascular Disrupting Agents Concluding Remarks References Index

8 List of Abbreviations ALL AML Ang AQP4 ATL ATP CAM CBC CECs CLL CML DLBCL DVT ECM ECOG EGFR EMEA EPC ERKs ETS FACS FDA FGF-2 FKHR FL G-CSF GF GFAP GIST GM-CSF HDAC HGF/SF acute lymphoblastic leukemia acute myeloid leukemia angiopoietin aquaporin-4 adult T cell leukemia adenosine triphosphate chorioallantoic membrane complete blood count circulating endothelial cells chronic lymphocytic leukemia chronic myeloid leukemia diffuse large B-cell lymphomas deep vein thrombosis extracellular matrix Eastern Cooperative Oncology Group Epidermal growth factor receptor European Agency for the Evaluation of Medicinal Products endothelial precursor cell extracellular-signal regulated kinases expressed sequence tags fluorescent activating cell sorter Food and Drug Administration fibroblast growth factor-2 forkhead transcription factor follicular lymphoma granulocyte-colony stimulating factor growth fraction glial fibrillary acid protein gastrointestinal stromal tumor granulocyte macrophage-colony stimulating factor histone deacetylase Hepatocyte growth factor/scatter factor ix

9 x List of Abbreviations HIF hypoxia-inducible factor HL Hodgkin lymphomas HOX homeobox HUVEC human umbilical vein endothelial cell ICAM-1 Intercellular Adhesion Molecule 1 IFN interferon IGF-1 insulin-like growth factor-1 IGH immunoglobulin heavy chain IgVhH immunoglobulin variable gene segments IKK I kappa B kinase IL interleukin IMIDs immunmodulatory drugs I-TAC interferon inducible T-cell alpha chemoattractant JAK Janus kinase LFA-1 lymphocyte function associated antigen-1 LI labeling index MALT mucosa associated lymphoid tissue MAPK mitogen-activated protein kinase MCL mantle cell lymphoma MCP-1 monocyte chemotactic protein-1 MDS myelodysplastic syndrome MEK mitogen-induced extracellular kinase MGUS monoclonal gammopathy of undetermined significance MiRNA micro RNA MM multiple myeloma MMP matrix metalloproteinase MVD microvascular density NF-kB nuclear factor kappa B NGF nerve growth factor NHL non Hodgkin lymphomas NOS nitric oxide synthase NSCLC non-small-cell lung cancer PCNSL primary central nervous system lymphoma PDGF platelet derived growth factor PDGFR platelet-derived growth factor receptor PECAM platelet endothelial cell adhesion molecule PI3K phosphatidylinositol-3 kinase PKC protein kinase C PTCL peripheral T cell lymphoma RTK receptor tyrosine kinase RT-PCR reverse transcriptase- polymerase chain reaction SCF stem cell factor SCID severe combined immunodeficiency SDF-1α stromal cell derived factor 1 alpha SDS-PAGE sodium dodecyl sulphate polyacrylamide gel electrophoresis

10 List of Abbreviations xi SelCiDs SLL STAT TGF-β TIMP TNF-α upa VCAM-1 VDAs VE VEGF VEGFR VLA-4 WHO selected cytokine inhibitory drugs small lymphocytic leukemia signal transducers and activator of transcription transforming growth factor-β tissue inhibitor of matrix metalloproteinase tumor necrosis factor alpha urokinase plasminogen activator vascular cell adhesion molecule-1 vascular disrupting agents vascular endothelial vascular endothelial growth factor vascular endothelial growth factor receptor very late antigen-4 World Health Organization

11 Chapter 1 Introduction 1.1 Angiogenesis Angiogenesis (new vessel formation) occurs during embryo development and in postnatal life, cyclically in the female genital system and in wound repair. In these situations, it is limited in time and the result of an equilibrium between the activator and the inhibitor systems that together keep the microcirculation in a quiescent state, with very low proliferation and turnover of the endothelial cells. The quiescent endothelium rests on a specialized form of the extracellular matrix (ECM)-the basement membrane-whose main constituents are laminin and type IV collagen (Ingber and Folkman 1989). Irrespective of the nature of the inducing stimulus, angiogenesis develops through five steps: (a) Basement membrane degradation by the proteolytic enzymes (metalloproteinases, collagenases, heparinase and plasminogen activators secreted by the endothelial cells, resulting in the formation of tiny sprouts which penetrate into the perivascular connective tissue; (b) Migration toward the stimulus of endothelial cells at the sprout tip; (c) Proliferation of the endothelial cells below the sprout; (d) Canalization, branching and formation of vascular loops, then of a functioning circulatory network; (e) Perivascular apposition of pericytes, and neosynthesis of basement membrane constituents by both the endothelial cells and the pericytes. Endothelial cell proliferation and migration coincide with limited laminin deposition, whereas cell differentiation and lumen formation coincide with further laminin deposition and type IV collagen deposition. New microvessels grow by at least three mechanisms: (a) New sprouts bud from preexisting vessels; (b) Circulating endothelial progenitor cells participate in new vessel formation; (c) Endothelial cells in preexisting vessels bridge the lumen to form new vessels by intussusception. This latter postulated that the capillary network increases its complexity and vascular surface by insertion of a multitude of transcapillary pillars, a process called intussusception (Djonov et al. 2000). All three mechanisms depend upon loosening of preexisting endothelial cells from their junctions with each other which are maintained by proteins such as vascular endothelial (VE)-cadherin and platelet-endothelial cell adhesion molecule D. Ribatti, Angiogenesis and Anti-Angiogenesis in Hematological Malignancies, DOI / _1, Springer Science+Business Media Dordrecht