Domenico Ribatti

The Evolution of Immunotherapy Against Tumors: An Historical Approach summarizes the literature concerning the development of the theory of immune surveillance against tumors. It discusses the evidence for and against this theory, along with the concept of immunoediting. Finally, current approaches in anti-tumor immunotherapy will be analyzed. The immune system plays a major role in the surveillance against tumors. To avoid attack from the immune system, tumor cells develop different strategies to escape immune surveillance. Evidence of immune surveillance comes from both animal models and clinical observations. Mice with a wide variety of immunodeficiencies have a high rate of tumor incidence and are more susceptible to transplanted or chemical carcinogen-induced tumors. Immunosuppressed patients have a high incidence of tumors. However, many patients develop cancer even in the presence of an apparently normal immune system. This indicates that tumor cells can escape immune surveillance.

New Insights on the Development of the Vascular System examines the most recent literature and data on the development of the vascular system, along with advice on new laboratory techniques and approaches to data analysis. This volume is a comprehensive handbook to the state-of-the-art in vascular system development. Several genetic and epigenetic mechanisms are involved in the early development of the vascular system, and there is extensive literature on the genetic background and molecular mechanisms responsible for blood vessel formation. Yet new data and techniques have been developed in recent years. Although scientific literature covers the descriptive aspects of embryonic vascular system development, modern techniques such as the technology of cell fusion, cell sorting and image analysis give new insight into the mechanisms by which vessels form and regress and how blood flow changes directions in the same vessels.

The Vascular Endothelium: A Holistic Approach for Oncology provides novel and integrated knowledge on the endothelial cells as a crucial component involved in the growth of different organs in both physiological and pathological conditions. By covering diverse aspects of anatomy, embryology, molecular biology and pathology, it details the important role of the endothelium for the pathogenesis of cancer and how this knowledge can improve the outcome of cancer research. The content is split in six parts: appearance and evolution of the endothelial cell, which discusses for instance comparative anatomy of the endothelium in relation to the vascular system; endothelial cell in embryology and organogenesis, covering the interaction between endothelial and hematopoietic cells; the lymphatic system, which brings information on lymphatic endothelial cell markers and molecular regulation of lymphangiogenesis; the anatomy of the endothelium in adults, showing the differences in the mature endothelial cells through the body; the physiology of the endothelial cells, with organ specific physiological activity of the endothelium; and the endothelial cells in cancer, discussing the use of endothelium as target for treatment and current therapeutic approaches. This book is a valuable resource for cancer researchers, oncologists and other members of biomedical field who are interested to learn more about the complexity of vascular endothelium and its impact on cancer and other related diseases.

Tumor Microenvironment Regulation of Tumor Expansion is a practical guide to understand and perform research on tumor microenvironments, and to support related clinical decisions. Tumor progression is linked to an imbalance between positive and negative regulators, and mainly depends on the release of specific growth factors by inflammatory or neoplastic cells. Inflammatory infiltrate contributes to tumor progression and the metastatic process, and there are many reports of associations between tumor inflammatory infiltrate, progression, and prognosis. Understanding different contexts of organs is a key factor in improving treatment outcome, especially in new therapeutic treatments targeting components of the tumor microenvironment. This book is a valuable resource for cancer researchers, clinicians, graduate students, and scientists in many biomedical fields who are interested in the complex relationship between the tumor microenvironment and its context in specific organs.

Mast cells (MC) are phylogenetically old cells which are distributed throughout the human organism. MC are found in almost all of the major organs and tissues of the body, particularly in association with connective tissue structures such as blood vessels, lymphatic vessels and nerves, and in proximity to surfaces that interface the external environment, such as those of the respiratory and gastrointestinal system and the skin. This selective accumulation at tissue sites where foreign material attempts to invade the host suggests that MC are among the first cells to initiate defensive mechanisms. MC have long been recognized as key cells of type I hypersensitivity reactions. Several lines of evidence, however, indicate that they not only express critical effector functions in classic IgE-associated allergic disorders, but also play important roles in host defense against parasites, bacteria and perhaps even viruses. Indeed, it is now clear that MC can contribute to host defense in thecontext of either acquired or innate immune responses through the release of a myriad of pro-inflammatory and immunoregulatory molecules and the expression of a wide spectrum of surface receptors for cytokines and chemokines. Moreover, there is growing evidence that MC exert distinct non-immunological functions, playing a relevant role in tissue homeostasis, remodeling and fibrosis as well as in the processes of tissue angiogenesis.

Mast cells (MC) are phylogenetically old cells which are distributed throughout the human organism. MC are found in almost all of the major organs and tissues of the body, particularly in association with connective tissue structures such as blood vessels, lymphatic vessels and nerves, and in proximity to surfaces that interface the external environment, such as those of the respiratory and gastrointestinal system and the skin. This selective accumulation at tissue sites where foreign material attempts to invade the host suggests that MC are among the first cells to initiate defensive mechanisms. MC have long been recognized as key cells of type I hypersensitivity reactions. Several lines of evidence, however, indicate that they not only express critical effector functions in classic IgE-associated allergic disorders, but also play important roles in host defense against parasites, bacteria and perhaps even viruses. Indeed, it is now clear that MC can contribute to host defense in thecontext of either acquired or innate immune responses through the release of a myriad of pro-inflammatory and immunoregulatory molecules and the expression of a wide spectrum of surface receptors for cytokines and chemokines. Moreover, there is growing evidence that MC exert distinct non-immunological functions, playing a relevant role in tissue homeostasis, remodeling and fibrosis as well as in the processes of tissue angiogenesis.

The aim if this book is to analyze the scientific biography of Judah Folkman, one of the most important scientist of the last century. More 50 years ago, Folkman found a revolutionary new way to think about cancer. Blood supply, Folkman hypothesized, was the key to tumor growth. Without new blood vessels, tumors simply did not thrive. In 1971, Folkman published his theory of angiogenesis in the “New England Journal of Medicine”. Angiogenesis, the formation and recruitment of new blood vessels, is necessary for tumor growth. Critics of the theory were silenced over time as Folkman and his colleagues reported the first purified angiogenic molecule, the first angiogenesis inhibitor and proposed the concept of angiogenic disease. The mechanism of angiogenesis is now a worldwide field of investigation. Over the years, Folkman and a growing team of researchers have isolated the proteins and unraveled the processes that regulate angiogenesis. Meanwhile, a new generation of angiogenesis research has emerged as well, widening the field into new areas of human disease and deepening it to examine the underlying biological processes responsible for those diseases.

This book is focused on the analysis of the role played by immune cell components in the angiogenic process associated with inflammation and tumor growth. 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. These may create the specific microenvironment that favors an increased rate of tissue vascularization. The link between chronic inflammation and tumorigenesis was first proposed by Rudolf Virchow in 1863 after the observation that infiltrating leukocytes are a hallmark of tumors and first established a causative connection between the lymph reticular infiltrate at sites of chronic inflammation and the development of cancer. Tumors were described as wounds that never heal and surgeons have long described the tendency of tumors to recur in healing resection margin and it has been reported that wound healing environment provides an opportunistic matrix for tumor growth. As angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators, this book will also provide information on some anti-angiogenic properties of immune cells that may be utilized for a potential pharmacological use as anti-angiogenic agents in inflammation as well as in cancer. The work is written for researchers in the field and also for graduate students which approach this matter.

The aim if this book is to analyze the scientific biography of Judah Folkman, one of the most important scientist of the last century. More 50 years ago, Folkman found a revolutionary new way to think about cancer. Blood supply, Folkman hypothesized, was the key to tumor growth. Without new blood vessels, tumors simply did not thrive. In 1971, Folkman published his theory of angiogenesis in the “New England Journal of Medicine”. Angiogenesis, the formation and recruitment of new blood vessels, is necessary for tumor growth. Critics of the theory were silenced over time as Folkman and his colleagues reported the first purified angiogenic molecule, the first angiogenesis inhibitor and proposed the concept of angiogenic disease. The mechanism of angiogenesis is now a worldwide field of investigation. Over the years, Folkman and a growing team of researchers have isolated the proteins and unraveled the processes that regulate angiogenesis. Meanwhile, a new generation of angiogenesis research has emerged as well, widening the field into new areas of human disease and deepening it to examine the underlying biological processes responsible for those diseases.

Immunology in the Twentieth Century: From Basic Science to Clinical Application grew out of common knowledge that those who survived many of the common infectious diseases rarely contracted the same disease again. This book charts the historical development of this vital branch of medicine in a concise volume, covering both the basic science involved and the clinical applications. Immunology as a distinctive subject developed in the mid-twentieth century as researchers started to understand how the adaptive immune system aids the defense against pathogens. The subject has grown in importance and diversified into specialist fields, such as immunohistochemistry, immunogenetics and immunopathology.

This book traces significant aspects of the history of immunology, exploring the immune system and immunodeficiency. The author recounts human hematopoietic development, and how a distinction of the immune system into thymus-dependent and thymus-independent components has been demonstrated in different animal species, including amphibians, birds, and mammals. Other themes explored in this book include discoveries about the role of the thymus of the Bursa of Fabricius in the development of immunologic competence, and observations on the changes in the lymphoid organs after bursectomy and thymectomy in chickens. Readers will discover how the bursa provides a unique microenvironment for the proliferation and differentiation of B cells, while thymectomized and irradiated animals were deficient in lymphocytes that mediated inflammatory responses, as assessed by skin graft rejection, delayed-type hypersensitivity, and graft versus host reaction. A clear perspective for understanding several diseases and also the entire lymphoid system emerges through the experiments and extensive histopathological studies of patients with primary immunodeficiency diseases that are described in these chapters. Researchers in the life sciences, in biomedicine and the history of medicine will all find something of value in this highly engaging work. It will also appeal to those with an interest in public health and neurobiology.

This work describes the importance of tumor microenvironment in favouring tumor progression and angiogenesis. Under physiological conditions, angiogenesis is dependent on the balance of positive and negative angiogenic modulators within the vascular microenvironment and requires the functional activities of a number of molecules, including angiogenic factors, extracellular matrix proteins, adhesion molecules and proteolytic enzymes. In normal tissues, vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. Tumor angiogenesis is linked to a switch in the balance between positive and negative regulators, and mainly depends on the release by inflammatory or neoplastic cells of specific growth factors for endothelial cells, that stimulate the growth of the blood vessels of the host or the down-regulation of natural angiogenesis inhibitors. In particular, the inflammatory infiltrate may contribute to tumor angiogenesis, and there are many reports of associations between tumor inflammatory infiltrate, vascularity and prognosis. New therapeutic approaches have been developed with the aim to control tumor angiogenesis through targeting of different components of tumor microenvironment.

The book presents recent advances in the field of angiogenesis and antiangiogenesis. Starting with the hypothesis of Judah Folkman that tumor growth is angiogenesis dependent, this area of research now has a solid scientific foundation. Tumor growth, metastasis, progression, dormancy and apoptosis depend on angiogenesis: several clinical studies have shown a positive correlation between the number of vessels in the tumor, metastasis formation and disease prognosis. A number of approaches have been developed to inhibit tumor angiogenesis, and numerous compounds discovered that inhibit angiogenesis, but only a few of them proved effective in vivo and only a couple of agents were able to induce tumor regression. These and other related developments described in the book should prove to be of interest to a large number of readers wishing to keep abreast with the latest developments in the field.

This book is focused on the analysis of the role played by immune cell components in the angiogenic process associated with inflammation and tumor growth. 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. These may create the specific microenvironment that favors an increased rate of tissue vascularization. The link between chronic inflammation and tumorigenesis was first proposed by Rudolf Virchow in 1863 after the observation that infiltrating leukocytes are a hallmark of tumors and first established a causative connection between the lymph reticular infiltrate at sites of chronic inflammation and the development of cancer. Tumors were described as wounds that never heal and surgeons have long described the tendency of tumors to recur in healing resection margin and it has been reported that wound healing environment provides an opportunistic matrix for tumor growth. As angiogenesis is the result of a net balance between the activities exerted by positive and negative regulators, this book will also provide information on some anti-angiogenic properties of immune cells that may be utilized for a potential pharmacological use as anti-angiogenic agents in inflammation as well as in cancer. The work is written for researchers in the field and also for graduate students which approach this matter.

In Vivo Models to Study Angiogenesis provides the latest information and an overview of the most common assays for studying angiogenesis in vivo. Under physiological conditions, angiogenesis is tightly controlled, whereas increased production of angiogenic stimuli and/or reduced production of angiogenic inhibitors leads to abnormal neovascularization, such as occurs in cancer, chronic inflammatory disease, diabetic retinopathy, macular degeneration and cardiovascular disorders. Several genetic and epigenetic mechanisms are involved in the early development of the vascular system. This book presents the latest information from the extensive literature and research available. Evidence is now emerging that blood vessels themselves have the ability to provide instructive regulatory signals to surrounding non-vascular target cells during organ development. Thus, endothelial cell signaling is currently believed to promote fundamental cues for cell fate specification, embryo patterning, organ differentiation and postnatal tissue remodeling.

Milestones in Immunology: Based on Collected Papers contains scientific milestones relating to the history of medicine over the past two centuries. The book highlights the contributions of pioneering scientists whose discoveries have paved the way for researchers working in the field of immunology. As the science of immunology grew from knowledge that survivors of common infectious diseases rarely contracted them again, the book uses this as a central thesis, helping readers understand how the adaptive immune system aids in defense against pathogens. In addition, the book covers special fields, such as immunohistochemistry, immunogenetics and immunopathology. For the past century, immunology has fascinated and inspired some of the greatest scientists of our time. Numerous Nobel Prizes have been awarded for fundamental discoveries in immunology, from Paul Ehrlich’ work on antibodies (1908) to the studies of Zinkernagel and Doherty (1986) elucidating mechanisms of cell-mediated immunity.

It has been generally accepted that angiogenesis is involved in the pathogenesis of hematological malignancies, like acute and chronic leukemia, lymphoma, myelodysplastic syndromes, myeloproliferative neoplasms and multiple myeloma. The extent of angiogenesis in the bone marrow has been correlated with disease burden, prognosis and treatment outcome. Reciprocal positive and negative interactions between tumor cells and bone marrow stromal cells, namely hematopoietic stem cells, fibroblasts, osteoblasts/osteoclasts, endothelial cells, endothelial progenitor cells, T cells, macrophages and mast cells, mediated by an array of cytokines, receptors and adhesion molecules, modulate the angiogenic response in hematological tumors. More recently, it has been emphasized the pro-angiogenic role of the so called “vascular niche”, indicating a site rich in blood vessels where endothelial cells and mural cells such as pericytes and smooth muscle cells create a microenvironment that affects the behavior of several stem and progenitor cells, in hematological malignancies.

This book traces significant aspects of the history of immunology, exploring the immune system and immunodeficiency. The author recounts human hematopoietic development, and how a distinction of the immune system into thymus-dependent and thymus-independent components has been demonstrated in different animal species, including amphibians, birds, and mammals. Other themes explored in this book include discoveries about the role of the thymus of the Bursa of Fabricius in the development of immunologic competence, and observations on the changes in the lymphoid organs after bursectomy and thymectomy in chickens. Readers will discover how the bursa provides a unique microenvironment for the proliferation and differentiation of B cells, while thymectomized and irradiated animals were deficient in lymphocytes that mediated inflammatory responses, as assessed by skin graft rejection, delayed-type hypersensitivity, and graft versus host reaction. A clear perspective for understanding several diseases and also the entire lymphoid system emerges through the experiments and extensive histopathological studies of patients with primary immunodeficiency diseases that are described in these chapters. Researchers in the life sciences, in biomedicine and the history of medicine will all find something of value in this highly engaging work. It will also appeal to those with an interest in public health and neurobiology.

This work describes the importance of tumor microenvironment in favouring tumor progression and angiogenesis. Under physiological conditions, angiogenesis is dependent on the balance of positive and negative angiogenic modulators within the vascular microenvironment and requires the functional activities of a number of molecules, including angiogenic factors, extracellular matrix proteins, adhesion molecules and proteolytic enzymes. In normal tissues, vascular quiescence is maintained by the dominant influence of endogenous angiogenesis inhibitors over angiogenic stimuli. Tumor angiogenesis is linked to a switch in the balance between positive and negative regulators, and mainly depends on the release by inflammatory or neoplastic cells of specific growth factors for endothelial cells, that stimulate the growth of the blood vessels of the host or the down-regulation of natural angiogenesis inhibitors. In particular, the inflammatory infiltrate may contribute to tumor angiogenesis, and there are many reports of associations between tumor inflammatory infiltrate, vascularity and prognosis. New therapeutic approaches have been developed with the aim to control tumor angiogenesis through targeting of different components of tumor microenvironment.

The study of medical history is interesting in itself and may help to modify the view sometimes expressed that medical students and doctors are lacking in culture of any sort. Moreover, some historical perspective is often advantageous when one is considering the multitude of advances that are now taking place in the theory and practice of medicine. This book, containing a series of collected papers concerning immunology and pathology and vascular biology and angiogenesis, drives us through scientific milestones in the history of medicine in the course of the past two centuries and highlights the contribution of pioneering scientists whose discoveries have paved the way to many researchers working in the fields of cell biology, developmental biology, immunology, pathology, and oncology. This book will serve as a resource for scientists, historians of medicine and philosophers of science and medicine.