Recent Advances in Angiogenesis and Antiangiogenesis


by

Domenico Ribatti

DOI: 10.2174/97816080500481090101
eISBN: 978-1-60805-004-8, 2009
ISBN: 978-1-60805-693-4

  
  


Indexed in: Scopus

The book presents recent advances in the field of angiogenesis and antiangiogenesis. Starting with the hypothesis of Judah Folkman tha...[view complete introduction]
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Table of Contents

Foreword , Pp. i

Napoleone Ferrara

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Preface , Pp. ii-iii (2)

Domenico Ribatti

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Contributors , Pp. iv-v (2)

Domenico Ribatti

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Plexins and Neuropilins Regulate Integrin Conformation and Trafficking in Endothelial Cells , Pp. 1-9 (9)

Guido Serini, Donatella Valdembri and Federico Bussolino

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The Role of Osteopontin in Angiogenesis , Pp. 10-19 (10)

Daria Leali and Antonella Naldini

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The Role of Mesenchymal Stem Cells in Angiogenesis , Pp. 20-29 (10)

Lizzia Raffaghello and Vito Pistoia

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Cross-Link Between Inflammation and Angiogenesis , Pp. 30-39 (10)

Enrico Crivellato and Domenico Ribatti

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Thymus and Angiogenesis , Pp. 40-53 (14)

Marius Raica and Anca Maria Cimpean

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Zebrafish as a Tool to Study Tumor Angiogenesis , Pp. 54-58 (5)

Marco Presta

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The Contribution of Circulating Endothelial Cells to Tumor Angiogenesis , Pp. 59-66 (8)

Francesco Bertolini, Patrizia Mancuso, Paola Braidotti, Yuval Shaked and Robert S. Kerbel

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Role of Thymidine Phosphorylase/Platelet-Derived Endothelial Cell Growth Factor in Tumor Progression , Pp. 67-79 (13)

Sandra Liekens

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Role of Stromal Cells in Neovascularization of Multiple Myeloma , Pp. 80-84 (5)

Maria Fico, Giuseppe Mangialardi, Roberto Ria, Michele Moschetta, Domenico Ribatti and Angelo Vacca

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Recent Advances in Angiogenesis and Antiangiogenesis: The Neuroblastoma Model , Pp. 85-91 (7)

Fabio Pastorino and Mirco Ponzoni

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Tumor Targeting with Transgenic Endothelial Cells , Pp. 92-100 (9)

Gerold Untergasser and Eberhard Gunsilius

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Tumor Vascular Disrupting Agents , Pp. 101-111 (11)

Gillan Tozer and Chyso Kanthou

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Inhibitors of Angiogenesis Based on Thrombospondin-1 , Pp. 112-126 (15)

Giulia Taraboletti and Katiuscia Bonezzi

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Novel Antiangiogenic Molecules in Multiple Myeloma , Pp. 127-133 (7)

Aldo M. Roccaro and Irene M. Ghobrial

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Index , Pp. 134-135 (2)

Domenico Ribatti

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Foreword

It has been known for a very long time that blood vessels are essential to deliver oxygen, nutrients and key regulatory signals to the tissues. Early pioneers like Glenn Algire and Isaac Michaelson observed several decades ago that tumor growth and certain eye disorders resulting in impaired vision, including proliferative diabetic retinopathy, are accompanied by increased vascular proliferation and proposed that the new vessels play a pathogenic role in these disorders. In 1971 Judah Folkman was the first to appreciate the therapeutic potential of the field, proposing that anti-angiogenesis might represent a therapy for solid tumors. This vision has been, at least in part, fulfilled by the recent approval of several anti-angiogenic drugs for the treatment of advanced tumors and age-related macular degeneration. Also, as of February 2009, almost 40,000 Medline citations are found under the keyword “angiogenesis”, reflecting the interest among basic scientists and clinicians in this field

The progress in basic biology and in the clinical applications notwithstanding, much more needs to be done. Indeed, the clinical results with anti-angiogenic agents posed a series of questions that will need to be addressed before the field can advance in a meaningful way. To mention a few, it will be of great importance to identify the molecular pathways mediating tumor resistance to angiogenesis inhibitors, establish the most effective combinatorial therapies and identify the patients that are more likely to benefit from such treatments.

The book edited by Prof. Domenico Ribatti provides a broad overview of the molecular and clinical aspects of angiogenesis and addresses the aforementioned questions. Chapters written by experts in their respective fields will make the reader acquainted with a variety of topics ranging from the role of axon guidance molecules in angiogenesis, the role of circulating endothelial cells in tumorigenesis, to the characterization of novel cellular and pharmacological approaches to inhibit angiogenesis. As such, the volume should be particularly useful to basic investigators, oncologists, opthalmologists and clinicians interested in the latest advances in this exciting field.

Napoleone Ferrara, M.D
Genentech Inc
San Francisco, CA
USA


Preface

Angiogenesis, the process by which new blood vessels are formed, is an important event in both physiological and pathological conditions. Angiogenic and antiangiogenic molecules released by accessory cells control neovascularization, notably the migration and proliferation of endothelial cells, their morphogenetic differentiation in capillaries and the concurrent remodeling of the extracellular matrix. Under physiological conditions, these steps are tightly controlled, and loss of such control is an important feature of several diseases.

Increased production of angiogenic stimuli and/or reduced production of angiogenic inhibitors leads to abnormal neovascularization, such as occurs in cancer, chronic inflammatory diseases, diabetic retinopathy, macular degeneration and cardiovascular disorders.

Starting with the hypothesis of Judah Folkman that tumor growth is angiogenesis dependent, this area of research now has a solid scientific foundation. Several clinical studies have shown a positive correlation between the number of vessels in the tumor, metastasis formation and disease prognosis.

Many solid and hematologic tumors in advanced stages are not curable with the currently available anticancer treatments, which primarily target the tumor cells. The genetic instability of tumor cells permits the occurrence of multiple genetic alterations that facilitate tumor progression and metastasis, and cell clones with diverse biological aggressiveness may coexist within the same tumor. These two properties allow tumors to acquire resistance to cytotoxic agents, which is still the main cause of treatment failure in cancer patients.

Whereas conventional chemotherapy, radiotherapy, and immunotherapy are directed against tumor cells, antiangiogenic therapy is aimed at the vasculature of a tumor and will either cause total tumor regression or keep tumors in a state of dormancy.

A number of approaches have been proved to inhibit tumor angiogenesis. Since tumor-associated angiogenesis develops as a physiological mechanism, its inhibition should not lead to emergence of resistance; and since each neovessel supplies hundreds of tumor cells, inhibition of angiogenesis should potentiate the oncostatic effect. By contrast, vascular targeting focused on specific molecular determinants of the neovasculature to be used for local delivering of a toxic effect that leads to a vascular damage and tumor necrosis

Numerous compounds inhibit angiogenesis, but few of them proved effective in vivo and only a couple of agents were able to induce tumor regression. Antiangiogenic tumor therapy has gained much interest in preclinical and clinical assessment

It has been estimated that over 10000 cancer patients worldwide have received experimental form of antiangiogenic therapy. However, the results from these clinical trials have not shown the dramatic antitumor effects which were expected following preclinical studies. This may be because of inadequate trial design in earlier studies. From the results obtained so far in clinical trials it can be concluded that the future clinical success of angiogenesis inhibitors could be related to their use in combination with chemotherapy or radiotherapy.

The main problem in the development of antiangiogenic agents is that multiple angiogenic molecules may be produced by tumors, and tumors at different stages of development may depend on different angiogenic factors for their blood supply. Therefore, blocking a single angiogenic molecule was expected to have little or no impact on tumor growth. Currently, most of the FDA-approved drugs as well as those in phase III clinical trials target a single proangiogenic protein. However, in apparent contrast with this view, experiments with neutralizing antibodies and other inhibitors demonstrated that blockade of vascular endothelial growth factor (VEGF) alone can substantially suppress tumor growth and angiogenesis in several models. Therefore, eventually other angiogenic proteins may be expressed by a tumor in which only VEGF is inhibited and give the clinical appearance of acquired "drug resistance".

A clinical challenge in antiangiogenesis is the finding of biological markers that help to identify subsets of patients more likely to respond to a given antiangiogenic therapy, as well as to determine optimal dosing of therapy, to detect early clinical benefit or emerging resistances and to decide whether to change therapy in second-line treatments.

An ideal angiogenesis inhibitor should be orally bioavailable with acceptable short-term and long-term toxicity and have a clinically useful antitumor effect. Moreover, carefully constructed clinical trials with valid endpoints need to be executed. Finally, cancer genomics and proteomics are likely to identify novel tumor-specific endothelial targets and accelerate drug discovery. With the advent of specific and potent new agents, oncologists have a variety of direct and indirect antiangiogenic agents to choose from when designing therapy protocols.

This book was undertaken to discuss the biological process and molecular mechanisms involved in angiogenesis and to discuss some agents that have shown to inhibit angiogenesis. I express my gratitude to all my colleagues who have contributed to this book.

Domenico Ribatti
University of Bari

List of Contributors

Editor(s):
Domenico Ribatti
Department of Human Anatomy, University of Bari Medical Schoo
Italy




Contributor(s):
Francesco Bertolini
Unit Director, European Institute of Oncology
Milan
Italy


Katiuscia Bonezzi
Assistant, Tumor Angiogenesis Unit Department of Oncology
Mario Negri Institute for Pharmacological Research,
Bergamo
Italy


Paola Braidotti
Assistant Professor, Department of Medicine, Surgery and Dentistry
University of Milan Medical School and “San Paolo” Hospital
Milan
Italy


Federico Bussolino
Department of Oncological Sciences
Full Professor, Institute for Cancer Research and Treatment, University of Torino Medical School
Candiolo
Italy


Anca Maria Cimpean
Assistant Professor, Department of Histology and Molecular Pathology
“Victor Babes” University of Medicine and Pharmacy
Timisoara
Romania


Enrico Crivellato
Assistant Professor, Section of Anatomy, Department of Medical and Morphological Researches
University of Udine Medical School,
Udine
Italy


Maria Fico
Postdoctoral Researcher, Department of Biomedical Sciences and Human Oncology
Bari
Italy


Eberhard Gunsilius
Assistant Professor of Medicine, Tumor Biology & Angiogenesis Laboratory, Department of Internal Medicine V
Innsbruck
Austria


Irene M. Ghobrial
Assistant Professor in Medicine, Department of Medical Oncology
Boston
USA


Chyso Kanthou
Tumour Microcirculation Group, Section of Oncology
Sheffield
UK


Robert S. Kerbel
Full Professor, Sunnybrook Health Science Centre, Molecular and Cellular Biology, Department of Medical Biophysics
Toronto
Canada


Daria Leali
Postdoctoral Researcher, Unit of General Pathology and Immunology,Department pf Biomedical Sciences and Biotechnology
University of Brescia Medical School
Brescia
Italy


Sandra Liekens
Postdoctoral Researcher, Department of Microbiology and Immunology
Leuven
Belgium


Giuseppe Mangialardi
Postdoctoral Researcher, Department of Biomedical Sciences and Human Oncology
University of Bari Medical School
Bari
Italy


Patrizia Mancuso
Milan
Italy


Michele Moschetta
Postdoctoral Researcher, Department of Biomedical Sciences and Human Oncology
Bari
Italy


Antonella Naldini
Associate Professor, Unit of Neuroimmunophysiology, Department of Physiology
Siena
Italy


Fabio Pastorino
Fellow, Fondazione Italiana per la Lotta al Neuroblastoma, “G. Gaslini” Children’s Hospital
Genoa
Italy


Vito Pistoia
Head, Laboratory of Oncology
G. Gaslini Children’s Hospital
Genoa
Italy


Mirco Ponzoni
Head, Experimental Therapies Unit
Genoa
Italy


Marco Presta
Full professor, Unit of General Pathology and Immunology, Department of Biomedical Sciences and Biotechnology
Brescia
Italy


Lizzia Raffaghello
Fellow, Fondazione Italiana per la Lotta al Neuroblastoma
Genoa
Italy


Marius Raica
Full Professor, Department of Histology and Molecular Pathology
Timisoara
Romania


Roberto Ria
Assistant Research, Department of Biomedical Sciences and Human Oncology
Bari
Italy


Domenico Ribatti
Full Professor, Department of Human Anatomy and Histology
Bari
Italy


Aldo M. Roccaro
Instructor in Medicine, Department of Medical Oncology
Boston
USA


Guido Serini
Assistant Researcher, and Department of Oncological Sciences
Candiolo
Italy


Yuval Shaked
Assistant Professor, Department of Molecular Pharmacology, Rappaport Faculty of Medicine
Haifa
Israel


Giulia Taraboletti
Head, Tumor Angiogenesis Unit, Department of Oncology
Bergamo
Italy


Gillian M. Tozer
Full Professor, Tumour Microcirculation Group, Section of Oncology
School of Medicine & Biomedical Sciences, University of Sheffield
Sheffield
UK


Gerold Untergasser
Assistant Professor, Tumor Biology & Angiogenesis Laboratory, Department of Internal Medicine V
Innsbruck
Austria


Angelo Vacca
Full Professor, Department of Biomedical Sciences and Human Oncology
Bari
Italy


Donatella Valdembri
Fellow, Department of Oncological Sciences
Candiolo
Italy




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