Table Of ContentAngiogenesis and Anti-Angiogenesis
in Hematological Malignancies
Domenico Ribatti
Angiogenesis and
Anti-Angiogenesis in
Hematological Malignancies
1 3
Domenico Ribatti
Department of Basic Medical Sciences
Neurosciences and Sensory Organs
University of Bari Medical School
Bari
Italy
ISBN 978-94-017-8034-6 ISBN 978-94-017-8035-3 (eBook)
DOI 10.1007/978-94-017-8035-3
Springer Dordrecht Heidelberg New York London
Library of Congress Control Number: 2013957379
© Springer Science+Business Media Dordrecht 2014
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Acknowledgments
This work was supported by European Union Seventh Framework Programme
(FPT7/2007–2013) under grant agreement n 278570 to DR.
v
Contents
1 Introduction ................................................................................................ 1
1.1 Angiogenesis ...................................................................................... 1
1.2 Tumor Angiogenesis ........................................................................... 2
2 Angiogenesis in Multiple Myeloma .......................................................... 7
2.1 General Features of Multiple Myeloma ............................................. 7
2.2 Angiogenesis in Multiple Myeloma ................................................... 9
2.3 Angiogenic Cytokines and Multiple Myeloma Progression .............. 12
2.4 Signaling Pathways ............................................................................ 17
2.5 Invasive Ability of Plasma Cells ........................................................ 21
2.6 Multiple Myeloma Endothelial Cells ................................................. 21
2.7 The Role of Macrophages and Mast Cells ......................................... 28
2.8 The Role of Endothelial Precursor Cells
and of Hematopoietic Stem and Progenitor Cells .............................. 31
2.9 Prognostic Value of Angiogenesis in Multiple Myeloma ................... 32
3 Angiogenesis in Lymphomas ..................................................................... 35
3.1 General Features of Lymphomas ....................................................... 35
3.2 In Vitro and Vivo Experimental Models ............................................ 35
3.3 A ngiogenesis in Normal Lymph Nodes and in Benign
Lymphadenopathies ............................................................................ 37
3.4 A ngiogenesis in Non-Hodgkin Lymphomas ...................................... 37
3.5 T he Role of Myelo-Monocytic Cells and Circulating
Endothelial Cells ................................................................................ 44
3.6 T he Role of Macrophages and Mast Cells ......................................... 44
3.7 Genetically Modified Lymphoma Endothelial Cells .......................... 46
4 Angiogenesis in Leukemia ......................................................................... 49
4.1 General Features of Leukemias .......................................................... 49
4.2 Angiogenesis in Acute Lymphocytic Leukemia ................................. 49
4.3 Angiogenesis in Chronic Lymphocytic Leukemia ............................. 50
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viii Contents
4.4 Angiogenesis in Acute and Chronic Myeloid Leukemia and
Myelodysplastic Syndrome ................................................................ 52
4.5 Role of Matrix Metalloproteinases and Mast Cells ............................ 54
5 Anti-angiogenesis........................................................................................ 57
5.1 Introduction ........................................................................................ 57
5.2 Endostatin ........................................................................................... 57
5.3 T halidomide ....................................................................................... 59
5.3.1 T halidomide in the Treatment of Multiple Myeloma
and Waldenstrom’s Macroglobulinemia ................................. 59
5.3.2 Thalidomide in the Treatment of Leukemia,
Lymphoma and Myelodysplastic Syndrome .......................... 61
5.4 Side Effects ........................................................................................ 62
5.5 T halidomide Analogues ...................................................................... 62
5.6 Combination Therapy ......................................................................... 66
5.7 VEGF Neutralizing Antibodies .......................................................... 67
5.8 Receptor Tyrosine Kinase Inhibitors .................................................. 69
5.8.1 Receptor Tyrosine Kinase Inhibitors in the
Treatment of Multiple Myleoma ............................................ 69
5.8.2 Receptor Tyrosine kinase Inhibitors
in the Treatment of Leukemia ................................................ 70
5.9 Bortezomib ......................................................................................... 73
5.10 Zoledronic Acid .................................................................................. 75
5.11 Interleukins ......................................................................................... 79
5.12 Chemotherapeutics ............................................................................. 83
5.13 Histone Deacetylase Inhibitors and Vascular Disrupting Agents ....... 83
6 Concluding Remarks ................................................................................. 85
References ......................................................................................................... 89
Index .................................................................................................................. 111
List of Abbreviations
ALL acute lymphoblastic leukemia
AML acute myeloid leukemia
Ang angiopoietin
AQP4 aquaporin-4
ATL adult T cell leukemia
ATP adenosine triphosphate
CAM chorioallantoic membrane
CBC complete blood count
CECs circulating endothelial cells
CLL chronic lymphocytic leukemia
CML chronic myeloid leukemia
DLBCL diffuse large B-cell lymphomas
DVT deep vein thrombosis
ECM extracellular matrix
ECOG Eastern Cooperative Oncology Group
EGFR Epidermal growth factor receptor
EMEA European Agency for the Evaluation of Medicinal Products
EPC endothelial precursor cell
ERKs extracellular-signal regulated kinases
ETS expressed sequence tags
FACS fluorescent activating cell sorter
FDA Food and Drug Administration
FGF-2 fibroblast growth factor-2
FKHR forkhead transcription factor
FL follicular lymphoma
G-CSF granulocyte-colony stimulating factor
GF growth fraction
GFAP glial fibrillary acid protein
GIST gastrointestinal stromal tumor
GM-CSF granulocyte macrophage-colony stimulating factor
HDAC histone deacetylase
HGF/SF Hepatocyte growth factor/scatter factor
ix
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
List of Abbreviations xi
SelCiDs selected cytokine inhibitory drugs
SLL small lymphocytic leukemia
STAT signal transducers and activator of transcription
TGF-β transforming growth factor-β
TIMP tissue inhibitor of matrix metalloproteinase
TNF-α tumor necrosis factor alpha
uPA urokinase plasminogen activator
VCAM-1 vascular cell adhesion molecule-1
VDAs vascular disrupting agents
VE vascular endothelial
VEGF vascular endothelial growth factor
VEGFR vascular endothelial growth factor receptor
VLA-4 very late antigen-4
WHO World Health Organization
