Angiogenesis: Insights From A Systematic Overview by Gaetano Santulli


77579c8d81034b8.jpg Author Gaetano Santulli
Isbn 9781626181144
File size 5 MB
Year 2013
Pages 388
Language English
File format PDF
Category biology


 

WWW.EBOOK777.COM CELL BIOLOGY RESEARCH PROGRESS ANGIOGENESIS INSIGHTS FROM A SYSTEMATIC OVERVIEW No part of this digital document may be reproduced, stored in a retrieval system or transmitted in any form or by any means. The publisher has taken reasonable care in the preparation of this digital document, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained herein. This digital document is sold with the clear understanding that the publisher is not engaged in rendering legal, medical or any other professional services. WWW.EBOOK777.COM CELL BIOLOGY RESEARCH PROGRESS Additional books in this series can be found on Nova’s website under the Series tab. Additional e-books in this series can be found on Nova’s website under the e-book tab. WWW.EBOOK777.COM CELL BIOLOGY RESEARCH PROGRESS ANGIOGENESIS INSIGHTS FROM A SYSTEMATIC OVERVIEW GAETANO SANTULLI EDITOR New York WWW.EBOOK777.COM Copyright © 2013 by Nova Science Publishers, Inc. All rights reserved. No part of this book may be reproduced, stored in a retrieval system or transmitted in any form or by any means: electronic, electrostatic, magnetic, tape, mechanical photocopying, recording or otherwise without the written permission of the Publisher. For permission to use material from this book please contact us: Telephone 631-231-7269; Fax 631-231-8175 Web Site: http://www.novapublishers.com NOTICE TO THE READER The Publisher has taken reasonable care in the preparation of this book, but makes no expressed or implied warranty of any kind and assumes no responsibility for any errors or omissions. No liability is assumed for incidental or consequential damages in connection with or arising out of information contained in this book. 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If legal or any other expert assistance is required, the services of a competent person should be sought. FROM A DECLARATION OF PARTICIPANTS JOINTLY ADOPTED BY A COMMITTEE OF THE AMERICAN BAR ASSOCIATION AND A COMMITTEE OF PUBLISHERS. Additional color graphics may be available in the e-book version of this book. Library of Congress Cataloging-in-Publication Data ISBN:  (eBook) Library of Congress Control Number: 2013931733 Published by Nova Science Publishers, Inc. † New York WWW.EBOOK777.COM Contents Preface vii Chapter 1 Angiogenesis: Something Old, Something New Evangeli Lampri and Elli Ioachim Chapter 2 A Historical Appraisal of Angiogenesis Assays Since Judah Folkman and Before... Anca Maria Cîmpean, Domenico Ribatti and Marius Raica Chapter 3 Angiogenesis and Pulmonary Hypertension Daling Zhu, Cui Ma and Jing Li Chapter 4 Stem Cells and Angiogenesis in Skeletal Muscle Regeneration and Disease Carlos Hermano da Justa Pinheiro, Lucas Guimarães Ferreira and Marco Aurélio Salomão Fortes Chapter 5 Angiogenesis in Peripheral Artery Disease: An Emerging Therapy Targeting Skeletal Muscle Brian D. Duscha, Jennifer L. Robbins, Christopher D. Kontos, William E. Kraus and Brian H. Annex Chapter 6 Angiogenesis in Thalassemia Seref Olgar and Duran Canatan Chapter 7 Fibroblasts and Endothelial Cells: The Basic Angiogenic Unit François Berthod Chapter 8 Regulating Functions of Angiogenesis in Prevention and Therapy of Gastric Ulcers Snehasikta Swarnakar, Krishnendu Ganguly and Sumit Paul WWW.EBOOK777.COM 1 31 51 77 99 135 145 159 vi Contents Chapter 9 The Role of Angiogenesis in Renal Allograft B. Handan Özdemir Chapter 10 Angiogenesis and Lymphangiogenesis as Molecular Therapeutic Targets in Human Pterygium and Its Recurrences Anca Maria Cîmpean, Mihai Poenaru Sava and Marius Raica Chapter 11 Chapter 12 Chapter 13 The Role of Heparin Mimetic Peptide Nanofibers in Angiogenesis Process Rashad Mammadov, Elif Duman, Mustafa O. Guler and Ayse B. Tekinay 189 199 Mast Cells and Angiogenesis in Tumoral and Non-Tumoral Disease Azize Yasemin Goksu Erol and Fatma Aktepe 211 Angiogenesis in Tumor Microenvironment: Potential Approaches in Cancer Therapy Mehmet Sahin, Emel Sahin and Sadi Koksoy 239 Chapter 14 Angiogenesis in Breast Neoplasia Evangeli Lampri and Elli Ioachim Chapter 15 Targeting VEGF-Mediated Tumor Angiogenesis in Neuroblastoma Danielle Hsu and Eugene S. Kim Chapter 16 173 Molecular Pathways of Angiogenesis in Cervical Cancer Oana Tudoran, Ovidiu Balacescu and Ioana Berindan-Neagoe Index 273 295 311 327 WWW.EBOOK777.COM Preface This book provides an overview of the scientific methods used to search, analyse, appraise and synthesize studies on angiogenesis. It is intended to serve as a comprehensive piece of literature that encompasses all aspects from the molecular features of angiogenesis to the clinical value and potential pitfalls of angiogenic-based therapies. The primary motion to write this book is to provide an overview of the current status of the research in this field, with a focus on both tumoral and non-tumoral disease. Effects of various anti-angiogenic and pro-angiogenic molecules are also addressed in detail. This book comes at an important time in the development of so-called “translational medicine”. Its purpose is to explain all the molecular bases underlying the angiogenic process and apply them to the clinical world. Reviewed and addressed are the basic concepts and importance of new drugs in clinical trials to inhibit or promote angiogenesis. This book may be considered as a scholarly reference work for libraries and researchers across the world and as a supplementary text for courses in medicine, physiology, biochemistry, molecular and cellular biology. It is expected that readers, both basic researchers and clinicians, will gain a good understanding of the essential value of angiogenesis in health and disease. Chapter 1 – The cardiovascular system is the first functional organ system to develop in the vertebrate embryo. Blood vessels nourish organs with vital nutrients and oxygen and, thus, new vessels form when the embryo needs to grow or wounds are to heal. A widely accepted view is that blood vessels arise through two mechanisms during development, vasculogenesis and angiogenesis. New vessels in the adult arise mainly through angiogenesis, although vasculogenesis also may occur. The existence of a postnatal vasculogenesis is also supported by the evidence that both endothelial cells and endothelial precursor cells co-exist in the circulation. Angiogenesis is a biological process by which new capillaries are formed and it occurs in many physiological and pathological conditions. It is controlled by the net balance between molecules that have positive and negative regulatory activity. This concept had led to the notion of the “angiogenic switch”, depending on an increased production of one or more of the positive regulators of angiogenesis. As blood vessels nurture almost every tissue (only a few tissues such as the cornea and cartilage are avascular), a normal tissue function depends on an intact vasculature. While the embryonic vascular system develops in anticipation of the demands of the growing embryo for oxygen and nutrients, angiogenesis in the adult organism occurs in response to the metabolical requirements of tissues and is efficiently triggered by hypoxia. A variety of diseases are associated with either insufficient or excess blood vessel growth. For example, WWW.EBOOK777.COM viii Gaetano Santulli the insufficient compensatory formation of blood vessels in ischaemic tissues is a major problem in coronary heart disease, or stroke. Conversely, when blood vessels grow excessively, malignant and inflamed tissues grow faster. But abnormal vessel growth contributes to the pathogenesis of numerous malignant, ischaemic, inflammatory, infectious and immune disorders and is implicated in many more disorders – some unexpectedly, such as preeclampsia, birth defects, respiratory distress of the preterm infant, obesity, motor neurone degeneration, dementia, diabetic proliferative retinopathy, viral infections and even hair loss. A plenitude of different proteins, including cell adhesion molecules, extracellular matrix components, transcription factors, angiogenic growth factors and their receptors orchestrate blood vessel differentiation and growth. An in-depth understanding of the mechanisms governing this process provides novel attractive opportunities for treatment of these ‘angiogenic’ disorders. Considerable benefit can be derived in the clinical setting from manipulating angiogenesis, either positively or negatively. There is a variety of important clinical situations in which it would be desiderable to promote angiogenic processes, such as for the induction of collateral vascularization in an ischemic heart or limb. Conversely, there are pathologic conditions in which preventing angiogenic processes could be useful in the treatment of a growing tumor or a chronic inflammatory process. Chapter 2 – Abnormal growth of blood vessels either is in excess or is insufficient, in many diseases as cancer, age related blindness, diabetes, cardiovascular disease or stroke and hence, vascular network has become, quickly a convenient therapeutic target. Historical papers describe the angiogenesis assays since the early 1960’s, when the tumor angiogenesis hypothesis has been launched. If most of the tumor angiogenesis assays are extensively used, descriptive and basic studies about human and animal vascular systems have been forgotten. In addition, preclinical researches of non-tumor angiogenesis in cardiovascular disease, eye pathology, or diabetes based on different experimental models, are more or less known. The present work briefly reviews the ancient basic studies of the vascular system (most of them, less known) and then updates the modern methodology used for angiogenesis study not only in tumors, but also for cardiovascular, ocular or cerebral vascular changes occurring in pathologic conditions. The past, present and future of the angiogenesis assays will meet together in this review. Chapter 3 – As one type of blood vessel formation, angiogenesis is referred to a new vascular generation process, involving basement membrane dissolution, endothelial cell migration, adhesion, proliferation, and tube formation, as well as sprouting, splitting, and remodeling of the preexisting vasculature, leading to the generation of new vessels and the growth of capillaries. For instance, a vascular labyrinth of capillaries bud and branch into a functional capillary bed. Angiogenesis normally occurs during embryonic development to form the primary vascular trees. It also takes place in adults in response to specific stimulus. In contrast, the other type of blood vessel formation is vasculogenesis, which is recognized as the de novo creation of vessels from endothelial cell progenitors in embryogenesis, which conduces to primary vasculature development of the body. Angiogenesis occurs in almost all organs and tissues, and dysregulation of angiogenesis is considered a common feature and is involved in the pathogenesis of over 50 different disease states including diabetic retinopathies, tumors, rheumatoid arthritis, atherosclerosis, as well as psoriasis. Both insufficient and excessive angiogenesis contribute to disorders. Insufficient angiogenesis is clearly described in ischemic tissue injury or cardiac failure, in WWW.EBOOK777.COM Preface ix which enhanced angiogenesis is demanded to improve the disease condition. During heart failure, as heart size and cardiac function are angiogenesis dependent, inhibition of angiogenesis in coronary leads to decreased capillary density, contractile dysfunction, and impaired cardiac growth. Cancer, arthritis, psoriasis, and blinding retinopathy are known to be associated with excessive vascular growth. For example, tumor angiogenesis shows recruitment of hematopoietic and circulating endothelial precursor cells, and impaired cell recruitment blocks tumor angiogenesis and growth. There is a potential possibility that transplantation of endothelial progenitor cells may increase unfavorable angiogenesis, and promote tumors, diabetic retinopathy, and atherosclerosis in some patients. Besides, angiogenesis is also the major process by which the lung vasculature grows and expands. Until quite recently, disordered angiogenesis has not been appreciated as a prominent contributor to multiple lung disease progressions such as pulmonary hypertension, emphysema, bronchial asthma, pulmonary fibrosis, late-phase of acute respiratory distress syndrome, postinjury phase of acute lung injury, and chronic lung disease. Moreover, chronic airway infection and partial pneumonectomy are confirmed to stimulate pulmonary angiogenesis. This might largely be due to the affected angiogenic/angiostatic balance, which is the major process and central component in the morphologically aberrant lung vasculature growth and expansion, and airway remo- deling. This review will take comprehensive insight into the phenotype changes and process of pulmonary vascular angiogenesis during pulmonary hypertension, analyze the cellular and molecular events that modulate angiogenesis, explain the mechanism of disordered angiogenesis, and provide better understanding of the role of angiogenesis as well its remodeling in the development of pulmonary hypertension. Information in this review will provide critical evidence for future therapeutic strategies of pulmonary hypertension. Chapter 4 – The formation of new blood vessels is needed to normal development and maturation of skeletal muscle during early life and it is also important to carry out reparative activity in muscle during adulthood. Upon injury, cells can die by apoptosis or become adapted to a new environment. In the adult organism, the angiogenesis is an important physiological phenomenon which occurs in response to some stimulus such as physical exercise, electrical stimulation, hypoxia, inflammation and low temperature as to sustain appropriated muscle cell function. Angiogenesis involves formation of new blood vessels from a pre-existing vascular tree through angiogenic factors. Angiogenesis plays an important role in regeneration, response to ischemia, vascular diseases and cancer (metastatic tumor and rhabdomyosarcoma) in skeletal muscle. Induced expression of vascular endothelial growth factor (VEGF) improves regeneration of many tissues such as skin, bone, liver, and cardiac and skeletal muscle tissue. The therapeutic approaches of muscular disorders focus on both the pro-angiogenic therapies and stimulation of skeletal myofiber regeneration. Chapter 5 – Peripheral artery disease (PAD) is characterized by impaired blood flow to the lower extremities causing claudication, exercise intolerance and a decreased quality of life. Despite the fact that stenosis of conduit vessels are largely responsible for PAD diagnosis, and re-vascularization of these arteries are routinely performed as a treatment strategy, hemodynamics of conduit vessels do not entirely explain the functional limitation observed in PAD patients. Due to the inherent purpose the microvasculature plays in blood delivery and oxygen exchange to skeletal muscle, angiogenesis of the microvasculature may play a prominent role in PAD and has become the focus of both basic science and a WWW.EBOOK777.COM x Gaetano Santulli therapeutic target for PAD clinical trials. This review will discuss what is currently known about skeletal muscle capillary density in PAD patients compared to normal subjects, how capillary density relates to exercise intolerance and how exercise training may be the best therapeutic intervention for initiating angiogenesis to improve exercise tolerance. Last, the authors will discuss the mechanisms of angiogenesis in skeletal muscle and the use of growth factors in therapeutic clinical trials. Chapter 6 – The vascular system is vital for organ function and life. In recent years its value has been described in different benign and malign processes. Many factors have been characterized to stimulated angiogenesis. These stimulants are cytokines and growth factors that are of the polypeptide and non-polypeptide structure. The most important angiogenic stimulant factors are tyrosine kinase receptors. The key regulatory factor of this family is vascular endothelial growth factor (VEGF). Regulatory mechanisms of angiogenesis are relatively well established. It is believed that angiogenesis is a highly regulated process balanced by inhibitors and stimulators of endothelial cell proliferation, endothelial cell migration, and capillary formation. The thalassemia syndromes are a heterogeneous group of inherited anemias characterized by ineffective erythropoiesis and hemolytic anemia. Besides to transfusion, serum ferritin levels rise significantly during inflammation and angiogenesis. A role for these mutations in angiogenesis hasn’t been found. It was demonstrated that VEGFR2 is a crucial receptor that mediates extramedullary hematopoiesis. The role of angiogenesis in hemoglobinopathies and especially thalassemia was not studied in detail. The relation of angiogenesis with mutations, hematopoiesis, anemia, organomegaly, extramedullary hematopoiesis, using chelator therapy and BMT are still not demonstrated. Moreover, the used anti-angiogenic therapies were not tried in thalassemic patients, yet. In the future, in vivo and in vitro studies will demonstrate the potential of clinical application of angiogenesis in hemoglobinopathies and on their prevention and therapy. Chapter 7 – One of the key features during the angiogenic process is undoubtedly the interaction between endothelial cells and the extracellular matrix. Adhesion of these cells to the extracellular matrix through integrins regulates their proliferation, survival and migration and is essential for their assembly into vessels. However, this fibrillar scaffold is not sufficient to promote angiogenesis, and necessitates another key element, the fibroblast. Fibroblasts are so basic and ubiquitous cells in connective tissues that they tend to be ignored. The purpose of this book chapter is to show that fibroblasts are not only the manager of the extracellular matrix, but they play a critical role to support the angiogenic process at the microenvironmental scale, through extracellular matrix remodeling and local delivery of growth factors. In addition, they also enhance the stability of the nascent capillaries. Indeed, endothelial cells once organized into tubes can induce nearby fibroblasts to differentiate into pericytes that will enwrap the microvessels providing stability and regulating perfusion. This sequence of events can be recapitulated in vitro using a tridimensional tissueengineered connective tissue seeded with human microvascular endothelial cells. This model promote the spontaneous formation in standard culture conditions of a network of capillarylike tubes made of endothelial cells that will be stabilized by pericyte recruitment from fibroblasts. Tubes form after 10 days of in vitro maturation and can be maintained for more than 50 days, providing an ideal model for long-term studies on angiogenesis. WWW.EBOOK777.COM Preface xi In spite of the huge complexity of the angiogenic process, the close cooperation of fibroblasts with endothelial cells through the creation of an intimate local microenvironment truly corresponds to the basic angiogenic unit. Angiogenesis is a critical step in the assembly of tissues during embryonic development, as well as during wound healing and tumor growth. It is also the biggest challenge in the new emerging field of regenerative medicine in which organ failure aims to be restored by cell or tissue transplantation. In such approach, the first worry is to assess whether any tissue of even less than a few millimeters in size will be able to survive the first days or weeks after graft. The highest risk for the transplant is necrosis mainly due to insufficient blood supply. Since passive diffusion of oxygen and nutrients is known not to exceed about 100 µm, adequate vascularization of a graft thicker than 200 µm needs to be achieved quickly through the process of neovascularization. Unfortunately, this process is too lengthy to promote adequate blood supply of an organ before necrosis occurs. To try to answer multiple clinical needs for organ replacements, regenerative medicine has developed various approaches of tissue engineering to reconstruct these organs. However, whatever sophisticated they can be, they all face the same challenge, to be vascularized fast enough after transplantation to promote survival. Thus, the solution should be the same for all of them, and is based on a better control of angiogenesis. Actually, even if the neovascularization process could be highly speeded up through growth factor expression or alternative strategies, this will probably not be sufficient to prevent necrosis. It seems that the only valuable strategy to achieve a complete vascularization of a tissue-engineered organ in a few hours after graft is the reconstruction of a prevascular network in the whole organ prior to transplantation. Indeed, it is well known by plastic surgeons that skin autografts or cadaveric skin grafts are vascularized in a matter of hours. This achievement is due to the process of inosculation, in which the capillary network of the graft is able to connect to the host’s one very quickly. As soon as both network are connected, blood flow can be established in the whole transplant immediately. Such success of fast vascularization could be obtained with tissue-engineered organs provided that they contain their own capillary network. Thus, building a human capillary network in tissueengineered organs should be a priority in regenerative medicine, and requires determining how to efficiently promote and control angiogenesis in tissues in vitro. Chapter 8 – AP, activator protein; b.w., body weight; ECM, extracellular matrix; ERK, extracellular-regulated kinase; i.p., intraperitoneal; IL, interleukin; JNK, c-Jun N-terminal kinase; MMPs, matrix metalloproteinases; NSAIDs, non-steroidal anti-inflammatory drugs; NF B, nuclear factor kappa beta; O2.-, superoxide radical;.OH, hydroxyl radical; H2O2, hydrogen peroxide; ROS, reactive oxygen species; RT-PCR, reverse transcriptase-PCR; TIMP, tissue inhibitor of metalloproteinase. Chapter 9 – The angiogenic process involves several cell types and mediators, which interact to establish a specific microenvironment suitable for the formation of new capillaries from pre-existing vessels. This chapter brings together a variety of subjects all directly related to the processes of angiogenesis in renal allografts.Both innate and adaptive immune cells are involved in the mechanisms of endothelial cell proliferation, migration and activation, through the production and release of a large spectrum of pro-angiogenic mediators. In this chapter, the authors will focus on the immune cell component of the angiogenic process in inflammation and renal allograft rejection. Pro-angiogenic growth factors such as VEGF will be briefly described. The review includes the potential of angiogenesis in the development of WWW.EBOOK777.COM xii Gaetano Santulli interstitial fibrosis and chronic allograft rejection. The concept that inflammation and angiogenesis together promotes fibrosis, provoke a question that if any drug which had an anti-inflammatory and anti-angiogenic effects could be able to prevent the development of an early interstitial fibrosis in renal allografts. Adapting such a therapeutic strategy for the prevention of interstitial fibrosis may prove beneficial, as data from previous studies have demonstrated that angiogenesis inhibitorssuch as rapamycin and statins reduces microvessel density, inflammation and the development of early interstitial fibrosis. In conclusion, although it is becoming increasingly clear that leukocytes, inflammation, and angiogenesis promotes the development of interstitial fibrosis and chronic allograft rejection, antiinflammatory and anti-angiogenic drugs may emerge in the future as useful drugs to prevent the development of interstitial fibrosis and therefore the development of chronic allograft rejection. The endothelial cell layer is the guardian of molecular traffic between the blood and surrounding tissue, and endothelial integrity plays a pivotal role in many aspects of vascular function, including angiogenesis. Angiogenesis is the formation of new blood vessels from pre-existing vessels, results from stimulation of endothelial cells. Angiogenesis is initiated by the release of angiogenic factors including vascular endothelial growth factor (VEGF) as a reaction to tissue hypoxia or nutrient deprivation. Stimulation of endothelial cells with VEGF’s induce endothelial cells to secrete several proteases and plasminogen activators, resulting in the degradation of the vessel basement membrane, which in turn allows endothelial cells to invade the surrounding matrix. These endothelial cells migrate, proliferate and eventually differentiate to form a new, lumen containing vessel. Finally this unstable vessel burgeon deposit a new basement membrane and secrete growth factorssuch as plateletderived growth factor (PDGF),which induces the recruitment of mesenchymal cells to the new vessel where they differentiate into mature pericytes, ensuring the stability of the neovessel. The supporting cells and the basement membranethat surround the endothelial cells are critical for vesselstability. This is a complex process that involves the concerted action of several other factors, such as the angiopoietins and ephrins, which act on specific receptors to regulate vessel stability. The resulting new vessels are capable of blood flow, aimed at relieving the hypoxic/nutrient-deprived state that was their stimulus fortheir formation. When the local development of neo-vessels is notsufficient to relieve hypoxic burden or when other factors such astumor formation or inflammation are driving this process, then additionalvessels will be created by angiogenesis. Angiogenesis plays a key role in various physiological and pathological conditions, including embryonic development, wound repair, inflammation, and tumor growth and is a prominent feature of vascular diseases like atherosclerosis and transplant associated vasculopathy and chronic allograft rejection. Angiogenesis in physiological conditions is characterized by strict regulation; the vessels develop in an organized fashion and once the need is met to supply the tissue with nutrients and oxygen, production of the stimulatory factor ceases and the endothelial cells become stagnant. In pathologic conditions, stimulation of vessel formation is exaggerated because of the uncontrolled release of angiogenic growth factors and/or alterations in the production of natural angiogenic inhibitors, with a consequent alteration of the angiogenic balance. As a consequence of newly formed vessels develop in disorganized bundles, where vessels may be non functional and often lack supporting pericytes or smooth muscle cells. This is incontrast WWW.EBOOK777.COM Preface xiii to the strictly organized vessels formed under physiological conditions. Additionally endothelial cells of newly formed vessels in pathologic conditions often continue to produce VEGF, which stimulates microvessel permeability. Chapter 10 – Among pathologic conditions of the eye, human pterygium remains one of the most controversial ocular disease. Pterygium is a disease characterized by the encroachment of a fleshy, triangular portion of the bulbar conjunctiva into the cornea. Several theories about its pathogenesishave been launched, including inflammation, connective tissue degeneration, genetic instability orangiogenesis but none of them were widely accepted.Nowadays, the irritation of the eye by ultraviolet radiation in sunny, dry, dusty areas and repeated microtrauma can lead to the development of pterygium in susceptible individuals. Despite of its classification by pathologists as a benign lesion, this epithelial and fibrovascular outgrowth of the ocular surface has a proliferative, invasive and highly vascularized microscopic appearance and acts as a clinically aggressive lesion by invading cornea and pupillary field. Histologically, pterygium was defined as a thickening or thinning of the epithelium, with elastoid and basophilic degeneration of the underlying connective tissues. This connective basis shows fibrinoid changes in the form of oval islets of different size, parallel to convexity of pterygium, or is in the form of unified focus. The number, size and the type of blood vessels showed excessive variability. Together with a better immunohistochemical understanding of pterygium connective tissue compartments, an extensive characterization of pterygial connective tissue angiogenesis was done in the last years, starting from angiogenic growth factors and microvessel density to data about anti-angiogenic and antivascular effects of angiogenesis inhibitors administered in primary and recurrent pterygium . It is known that pterygium is a lesion with limited local invasion and inability to send metastases but cells display genetic characteristics of a tumor. Additional to this feature, a rich network of blood vessels appears in the development of human pterygium. Chapter 11 – Albeit the roles of growth factors (e.g. VEGF) and their receptors in angiogenesis have been emphasized extensively, the indispensable role of glycosaminoglycans, especially heparan sulfates, has been discerning recently. These sugar polymers act as co-receptors for many growth factors, such as three key angiogenic growth factors: VEGF, FGF-2 and PDGF. Binding of heparan sulfates to growth factors enhances growth factor receptor interaction, and effect of signaling. To exploit the activatory role of heparan sulfates in induction of angiogenesis, researchers designed materials either carrying heparin or functional groups mimicking heparin. Here, the authors review their recent efforts in producing heparin mimetic materials for angiogenesis. Briefly, the authors designed novel peptide nanofiber scaffolds that can bind to growth factors similar to heparin, while inducing in vitro and in vivo angiogenesis. This material can provide a useful platform for therapy of chronic wound healing, where angiogenesis is impaired. Chapter 12 – Angiogenesis, which can be defined as the growth of new blood vessels from preexisting ones, is an essential process for physiological and pathological processes. Mast cells were first recognized by their roles in mediating allergic reactions and protecting body against parasitic infections. Today, these cells are implicated in the pathogenesis of a variety of diseases, including obesity, diabetes, ischemic heart diseases, and tumors. Their involvement in non-specific inflammatory reactions, tissue remodelling and wound healing has also been explored in the last decades. Mast cell inhibitor were found to be candidates for the therapy of angiogenic diseases, such as proliferative diabetic retinopathy, age-related WWW.EBOOK777.COM xiv Gaetano Santulli macular degeneration, and rheumatoid arthritis. The role of mast cells in angiogenesis involving the aforementioned diseases is a topic of attention and is an area of interest for many researchers. Mast cells have been shown to accumulate near newly formed vascular sprouting. Some regulators of angiogenesis are potent chemotactic factors for tissue mast cells which lead mast cells to migrate to the area of angiogenesis. The newly recruited mast cells would consequently amplify the angiogenic process. In this content, mast cells include a variety of mediators which induce angiogenesis. On the other hand, mast cells release anti-angiogenic mediators, as well. Further, the role of mast cells in tumor development in terms of angiogenesis is a very important issue of today’s researchers. Although some researchers suggest the presence of a tumor-promoting role of mast cells, based on their angiogenic secretions; many researchers emphasize on the tumor-inhibitory role of mast cells based on their anti-angiogenic mediators, cytotoxic effects, or tumor phagositising ability. In this context, the authors found that mast cell counts did not correlate with the extent of angiogenesis in the tumor stroma of endometrial carcinoma in human. This chapter aims to clarify the possible reasons that lead researchers to think mast cells as promoters or inhibitors of angiogenesis. Mast cells’ involvement in angiogenesis in tumoral/non-tumoral diseases, and tissue repair will be discussed in detail in this chapter. The therapeutic implications of mast cells in tumor growth and inflammatory diseases will be reviewed, as well. Chapter 13 – The new blood vessel formation, termed angiogenesis, occurs not only under physiological conditions, but also in some pathological events such as cancer. Solid tumors need blood vessels to obtain oxygen and nutrients so that they can grow and spread. Otherwise, tumors generally cannot grow beyond 1-2 mm3 in size. Angiogenesis is an essential factor for metastasis process and it is generally associated with poor prognosis in a variety of cancer types. Strategies to suppress angiogenesis have gained great attention in preclinical and clinical area to prevent and to treat cancers. In this chapter the authors compiled how tumor-derived angiogenesis inducers direct the formation of new blood vessels in tumor microenvironment. They also mentioned recent findings related to anti-angiogenic approaches notably about epigenetics in tumor biology. Chapter 14 – Angiogenesis, the formation of new blood vessels, is an essential step for breast cancer progression and dissemination. The fact that angiogenesis is also present and changes during the life cycle of a woman, makes more interesting its implication in tumor development. Tumor angiogenesis is the result of an imbalance between positive and negative angiogenic factors released by tumor and host cells into the microenvironment of the neoplastic tissue, in an uncontrolled and immature way. This complex process depends on a great variety of angiogenic factors, one of the most important being the vascular endothelial growth factor (VEGF). In the case of breast neoplasias, a large number of angiogenesisrelated markers has been studied, with the result that these markers possess great clinical significance and are also used as risk predictors for distant spread, prognostic factors for response to treatment, and can become predictive factors for tumor outcome. In addition, stromal components, adhesion molecules and other biological markers seem to partake in breast cancer angiogenesis. Recently, the appearance of anti-angiogenic drugs has allowed them to be used in clinical practice and the results reported to date have positioned them in WWW.EBOOK777.COM Preface xv the front line of clinical research. Here the authors review the molecular basis of tumoral neoangiogenesis, as it is a very active area for current research in breast cancer. The growth and spread of most solid tumors occur through a range of defects that develop both within and outside the cancer cell. Defects in cell-signalling pathways alter proliferation, transcription, growth, migration, differentiation and death of cancer cells. In addition, changes in the surrounding stroma and immune response allow the tumour to expand, form new blood vessels and spread to other organs. Thus, angiogenesis has a vital role in the survival and expansion of solid tumors, including breast neoplasias. Angiogenesis is an extremely complex process, which involves many different cell types, all of which must coordinate their growth patterns to establish a well-defined vasculature for nourishment of either normal or tumor tissue. It is a multistep process, which involves changes in the extracellular matrix, and endothelial cell proliferation, migration, and differentiation into capillaries. Studies of tumour biology reveal a complex network of autocrine and paracrine interactions between tumour cells, stromal cells, and endothelial cells, which are in turn influenced by the composition of the extracellular matrix. The development of new blood vessels within a tumour depends on the local balance between angiogenic and anti-angiogenic factors. These factors may be produced by the tumour cells themselves or by the associated stromal and inflammatory cells. The switch from an avascular to the vascular phenotype is a key event for the development of solid tumours. Primarily dormant avascular tumour nodules are able to grow to a diameter of 1–2 mm. In order to develop further, the tumour nodules have to become vascularized, a process referred to as the “angiogenic switch”. Cells which are located beyond 2mm are at risk of necrosis through apoptosis. Although tumor cells are resistant to hypoxia and can prevent their own apoptosis, they have a great ability to form new blood vessels in order to support their own existence and to obtain access to bloodstream. A large number of angiogenesis–related markers have been studied in breast tumors in order to be used as predictive factors of survival, metastasis or response to treatment. There is now considerable evidence that breast cancer is an angiogenic-dependent disease and that angiogenesis plays an essential role in breast cancer development, invasion, and metastasis Moreover, the use of anti-angiogenic drugs in clinical practice and the results reported to date shed more and more light in the pathway of angiogenesis in breast cancer. Chapter 15 – Angiogenesis is critical to tumor growth and metastasis and is dependent on growth factors, such as vascular endothelial growth factor (VEGF). The most characterized angiogenic factor, VEGF, is an endothelial cell mitogen and permeability factor and has been found to be overexpressed in almost all human cancers. The major regulator of VEGF is hypoxia inducible factor-1α (HIF-1α), which plays a central role in tumor adaptation to hypoxia through transcription of a variety of angiogenic genes and glycolytic enzymes. Hypoxia, which is a defining characteristic of solid tumors, stabilizes the alpha and beta subunits of HIF-1α to activate downstream angiogenic pathways. In a number of tumor model systems, antagonism of the VEGF pathway results in inhibition of angiogenesis and tumor growth. Specifically, VEGF inhibition has been shown to suppress tumor growth, decrease microvasculature, and induce apoptosis of endothelial cells. This close relationship between hypoxia, angiogenesis, and tumor growth makes VEGF and VEGF receptors strong targets for anti-neoplastic therapies. In this article, the authors will review the state of VEGF-targeted WWW.EBOOK777.COM xvi Gaetano Santulli therapies, the results of recent clinical trials, as well as the future of novel anti-VEGF therapeutics. We will follow this with a review of VEGF treatment in the aggressive, pediatric malignancy, neuroblastoma, and discuss combination therapy of VEGF treatments with chemotherapy and other molecular targeted drugs. Chapter 16 – The transformation of normal healthy cells into tumors is a multistep process which involves six essential biological processes called hallmarks of cancer. First, cells must activate and sustain the proliferative signaling pathways, evade growth suppressors and cell death activators, thus allowing cells to divide uncontrollably and form tumors. By inducing the angiogenic process, tumors are able to feed, invade and metastasize to other sites. Blood vessels are required to supply oxygen and nutrients and to remove waste products from tissues. De novo blood vessels are formed during embryonic development through vasculogenesis and after maturation, the vascular system regenerates slowly. Angiogenesis is the physiological process by which new blood vessels are sprouted from pre-existing ones, such as capillaries and venules. The process is triggered by the release of angiogenic growth factors by diseased or injured tissues. The growth factors disperse into the surrounding tissues until they find and bind specific receptors, which are mostly located on endothelial cells (EC) that form the nearby blood vessels. Upon binding, signaling cascades are activated within the ECs, start to proliferate and release proteases to degrade the basement membrane, making space for the new vessel. The ECs migrate throughout the dissolved matrix using adhesion molecules as “grappling hooks” to pull the new blood vessel sprout forward and rearrange to form the new tube while the matrix is reconstructed around the vessel. The new blood vessels are surrounded by specialized muscle cells (smooth muscle cells, pericytes) that provide structural support and stabilization. In healthy adult organisms, angiogenesis is an occasional occurrence, in wound healing and for a few days each month in female reproductive tract. Cyclic angiogenesis is essential for female reproduction; therefore, female gynecological tumors are frequently more vascularized due to favorable environment for rapidly inducing and sustaining prolific angiogenesis. WWW.EBOOK777.COM In: Angiogenesis Editor: Gaetano Santulli ISBN: 978-1-62618-114-4 © 2013 Nova Science Publishers, Inc. Chapter 1 Angiogenesis: Something Old, Something New 1 2 Evangeli Lampri*1 and Elli Ioachim2 Cancer Biobank Center of the University of Ioannina, Greece Pathology Department, General Hospital “G. Hatzikosta”, Ioannina, Greece The cardiovascular system is the first functional organ system to develop in the vertebrate embryo. [1] Blood vessels nourish organs with vital nutrients and oxygen and, thus, new vessels form when the embryo needs to grow or wounds are to heal. [2] A widely accepted view is that blood vessels arise through two mechanisms during development, vasculogenesis and angiogenesis. New vessels in the adult arise mainly through angiogenesis, although vasculogenesis also may occur. The existence of a postnatal vasculogenesis is also supported by the evidence that both endothelial cells and endothelial precursor cells co-exist in the circulation. Angiogenesis is a biological process by which new capillaries are formed and it occurs in many physiological and pathological conditions. It is controlled by the net balance between molecules that have positive and negative regulatory activity. This concept had led to the notion of the “angiogenic switch”, depending on an increased production of one or more of the positive regulators of angiogenesis. [1] As blood vessels nurture almost every tissue (only a few tissues such as the cornea and cartilage are avascular), a normal tissue function depends on an intact vasculature. [2] While the embryonic vascular system develops in anticipation of the demands of the growing embryo for oxygen and nutrients, angiogenesis in the adult organism occurs in response to the metabolical requirements of tissues and is efficiently triggered by hypoxia. A variety of diseases are associated with either insufficient or excess blood vessel growth. For example, the insufficient compensatory formation of blood vessels in ischaemic tissues is a major problem in coronary heart disease, or stroke. Conversely, when blood vessels grow excessively, malignant and inflamed tissues grow faster. But abnormal vessel growth contributes to the pathogenesis of numerous malignant, ischaemic, inflammatory, infectious and immune disorders and is implicated in many more disorders – some unexpectedly, such * [email protected] WWW.EBOOK777.COM 2 Evangeli Lampri and Elli Ioachim as preeclampsia, birth defects, respiratory distress of the preterm infant, obesity, motor neurone degeneration, dementia, diabetic proliferative retinopathy, viral infections and even hair loss. [2,3] A plenitude of different proteins, including cell adhesion molecules, extracellular matrix components, transcription factors, angiogenic growth factors and their receptors orchestrate blood vessel differentiation and growth. [3, 4] An in-depth understanding of the mechanisms governing this process provides novel attractive opportunities for treatment of these ‘angiogenic’ disorders. Considerable benefit can be derived in the clinical setting from manipulating angiogenesis, either positively or negatively. There is a variety of important clinical situations in which it would be desiderable to promote angiogenic processes, such as for the induction of collateral vascularization in an ischemic heart or limb. Conversely, there are pathologic conditions in which preventing angiogenic processes could be useful in the treatment of a growing tumor or a chronic inflammatory process. [1, 2] The History of Blood and Lymph Vessels Study on blood vessels has been of interest since ancient times. More than 6000 years ago, Egyptian physicians recognized that ‘there were vessels in him for every part of the body, which were hollow, having a mouth which opens to absorb medications and eliminate waste elements’. Aristotle considered that ‘blood vessels are like watercourses in gardens: they start from one spring, and branch off into numerous channels, and then into still more, so as to carry a supply to every part of the garden. [2] However, the Ancient Greek physician Galen originally proposed that the blood does not circulate but is locally regenerated by the body when its supplies are consumed. [5] In primitive animals, such as the worm Caenorhabditis elegans and the fruitfly Drosophila melanogaster, oxygen is capable of diffusing throughout theirs small body to all cells. In other species, which developed later in evolution and grew to larger sizes, a vascular network distributes oxygen in the blood to distant cells. Only in 1628 did William Harvey discover that the heart pumps the blood around the body throughout arteries and that veins return the blood to the heart. A few decades later in 1661, Marcello Malphighi identified the capillaries as the smallest vessels that close the circulatory loop between arteries and veins. Around the same time, Caspar Aselius discovered another type of vessel, the lymphatic vessel. Because of the blood pressure, blood plasma continuously leaks from the capillaries, and lymph vessels return this fluid back to the blood circulation. Although blood vessels arose earlier in evolution, lymph vessels are only present in amphibians onwards. [5] Terms Which Refer to Angiogenesis The blood vessels may be small which only consist of endothelial cells (ECs), or larger which are surrounded by mural cells [pericytes (PCs) in medium-sized and smooth muscle cells (SMCs) in large vessels]. WWW.EBOOK777.COM

Author Gaetano Santulli Isbn 9781626181144 File size 5 MB Year 2013 Pages 388 Language English File format PDF Category Biology Book Description: FacebookTwitterGoogle+TumblrDiggMySpaceShare Angiogenesis: Insights From A Systematic Overview     Download (5 MB) Perry’s Arcana: With a Collation and Systematic Review American-type Options A Closer Look At Biology, Microbiology, And The Cell Motivational Strategies in the Language Classroom Strategic Integrated Marketing Communications Load more posts

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