Tumor Angiogenesis

TUMOR ANGIOGENESIS Edited by Sophia Ran Tumor Angiogenesis Edited by Sophia Ran Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2012 InTech All chapters are Open Access distributed under the Creative Commons Attribution 3.0 license, which allows users to download, copy and build upon published articles even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. As for readers, this license allows users to download, copy and build upon published chapters even for commercial purposes, as long as the author and publisher are properly credited, which ensures maximum dissemination and a wider impact of our publications. Notice Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published chapters. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Molly Kaliman Technical Editor Teodora Smiljanic Cover Designer InTech Design Team First published February, 2012 Printed in Croatia A free online edition of this book is available at www.intechopen.com Additional hard copies can be obtained from [email protected] Tumor Angiogenesis, Edited by Sophia Ran p. cm. ISBN 978-953-51-0009-6 Contents Preface IX Chapter 1 Heparin-Like Drugs with Antiangiogenic Activity 1 María Rosa Aguilar, Luis García-Fernández, Raquel Palao-Suay and Julio San Román Chapter 2 Regulation of Angiogenesis in Human Cancer via Vascular Endothelial Growth Factor Receptor-2 (VEGFR-2) 27 Shanchun Guo, Laronna S. Colbert, Tanisha Z. McGlothen and Ruben R. Gonzalez-Perez Chapter 3 The Effect of Chinese Herb on Tumor Angiogenesis by Inhibiting Vessel Endothelial Cells 67 Jian Jin, Li-Ying Qiu, Hui Hua and Lei Feng Chapter 4 Beyond VEGF: The NOTCH and ALK1 Signaling Pathways as Tumor Angiogenesis Targets 85 Olivier Nolan-Stevaux and H. Toni Jun Chapter 5 Platelet Regulation of Angiogenesis, Tumor Growth and Metastasis 115 Jessica Cedervall and Anna-Karin Olsson Chapter 6 Malignant Transformation in Skin is Associated with the Loss of T-Cadherin Expression in Human Keratinocytes and Heterogeneity in T-Cadherin Expression in Tumor Vasculature 135 Kseniya Rubina, Veronika Sysoeva, Ekaterina Semina, Natalia Kalinina, Ekaterina Yurlova, Albina Khlebnikova and Vladimir Molochkov Chapter 7 Modeling Tumor Angiogenesis in Zebrafish 167 Massimo M. Santoro Chapter 8 The Role of VEGF in the Process of Neovasculogenesis 181 Aleksandra Sobczyńska-Rak VI Contents Chapter 9 Cancer Related Inflammation and Tumor Angiogenesis 197 Ping Wu Chapter 10 Infantile Hemangiomas: A Disease Model in the Study of Vascular Development, Aberrant Vasculogenesis and Angiogenesis 213 Alvin Wong and June K. Wu Chapter 11 MicroRNAs Regulation of Tumor Angiogenesis 231 Munekazu Yamakuchi Chapter 12 New Molecular Targets for Anti-Angiogenic Therapeutic Strategies 249 Amanda G. Linkous and Eugenia M. Yazlovitskaya Chapter 13 Molecular Mechanisms of Tumor Angiogenesis 275 Kelly Burrell and Gelareh Zadeh Preface Angiogenesis is the main process responsible for formation of new tumor blood that play an essential role in expansion of the tumor mass and dissemination of metastatic cells. Tumor angiogenesis significantly differs from the tightly controlled normal neovascularization driven by physiological needs. This is because the tumor environment contains excessive levels of vascular endothelial growth factor-A (VEGF-A) as well as many other pro-angiogenic factors that are produced by neoplastic, stromal, and infiltrating immune cells. This imbalance of pro-angiogenic versus anti-angiogenic factors promotes generation of numerous but abnormal blood vessels that exhibit severe structural and functional defects. The chaotic and poorly-perfused tumor vascular network creates a chronically inflamed site that promotes thrombosis, and impedes drug delivery, causing further complications to the cancer patient. Most importantly, the structural and functional abnormalities of tumor vessels promote hematogenous metastasis, which is the main cause for decreased survival of patients with solid tumors. It is, therefore, not surprising that tumor angiogenesis is regarded as an important target for developing anti-cancer strategies with many studies focused on mechanisms of the tumor blood vessel formation and their impact on tumor pathology and progression. This book covers a variety of topics related to the biology of tumor vasculature. This includes reviews on VEGF-A-dependent and independent mechanisms controlling the formation of new vessels; contribution of inflammatory cells and platelets to tumor neovascularization; identification of new molecular targets for inhibition of tumor angiogenesis; and potential clinical use of novel anti-angiogenic therapies based on heparin-like compounds and Chinese herbal extracts. The book covers also two emerging subjects in the field: a recently developed zebrafish model of tumor angiogenesis, and microRNA regulation of blood vessel formation at the tumor site. Collectively, the chapters in the book provide a current update on central findings in the tumor angiogenesis field, while highlighting potential targets for inhibition. We hope that this book will be useful for oncologists, cancer basic researchers, and biologists with interests in vascular and endothelial cell behavior in the context of cancer. Sophia Ran, Ph.D. Associate Professor Southern Illinois University, School of Medicine Springfield, IL USA 1 Heparin-Like Drugs with Antiangiogenic Activity María Rosa Aguilar, Luis García-Fernández, Raquel Palao-Suay and Julio San Román Biomaterials Group, Polymeric Nanomaterials and Biomaterials Department, Institute of Polymer Science and Technology (CSIC), Madrid Biomedical Research Networking Centre in Bioengineering, Biomaterials and Nanomedicine (CIBER-BBN) Spain 1. Introduction The process of angiogenesis consists in the sprouting of new blood vessels from existing ones. This is a natural process that occurs in the human body and is essential for organ growth and repair. In the embryonic stage, the blood vessels provide the necessary oxygen, nutrients and instructive trophic signals to promote organ morphogenesis (Coultas et al., 2005). After birth the angiogenic process only contributes to organ growth and during adulthood the angiogenic process only occurs in the placenta during the pregnancy and in the cycling ovary, while most blood vessels remain quiescent. However the angiogenic activity could be reactivate because endothelial cells retain their angiogenic activity in response to a physiological stimulus (wound healing and repair) (Alitalo et al., 2005). This angiogenic activity is also critical in the development of solid tumors and metastasis (Ferrara, 2004; Folkman, 1990). Generally, a solid tumor expands until 1-2 mm3 is reached. At this point vascularization is required in order to ensure a supply of nutrients, oxygen, growth factors and proteolytic enzymes to the tumor (Folkman, 1990). To activate the angiogenic activity of endothelial cells, the tumor switches to an angiogenic phenotype and recruits blood vessels from the surrounding tissue, developing a dense vasculature that provides nutrients to the cancerous tissue (Figure 1). Numerous proangiogenic proteins are involved in tumor angiogenesis. Two of the most important families of pro-angiogenic proteins are the vascular endothelial growth factors (VEGF) and the fibroblast growth factors (FGF) (Garcia-Fernandez et al., 2010c). Most of these GF isoforms (this is not the case of the smallest isoform of VEGF-A (V121), that does not present a heparin-binding domain) need to interact with heparan sulfate proteoglycans molecules (HSPG) in order to recognize their specific tyrosine kinase receptor on cell membrane and activate the angiogenic process. These cell surface molecules are low affinity receptors that do not transmit a biological response, but are essential for these growth factors to recognize their union site to the signaling receptor (FGFR or VEGFR). Therefore, disruption of the interaction of these growth factors (GF) with cell surface HSPG seems an evident target for angiogenesis (Folkman, 1971; Folkman, 1990; Folkman, 1995). HSPGs are heparin-like molecules that favor the pro-angiogenic proteins oligomerization (Figure 1), which is necessary for the interaction with the endothelial cells membrane 2 Tumor Angiogenesis receptors. Heparin is a natural polysaccharide composed of alternating units of sulphated glucuronic acid and glucosamine derivatives, it presents anticoagulant activity and interacts with the most important pro-angiogenic proteins in tumor angiogenesis (e.g. different isoforms of FGF and VEGF) (Fernández-Tornero et al., 2003; Lindahl et al., 1994). Fig. 1. Structure of a heparin-linked biologically active dimer of acidic fibroblast growth factor. Heparin is shown as stick-and-ball model (carbon: grey; oxygen: red; sulfur: yellow; nitrogen:

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