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Cancer drug development remains a costly and inefficient endeavor that often translates to limited clinical success. While most therapies focus on stalling the growth of or eradicating tumor cells directly, the microenvironment in which these cells inhabit plays a hugely influential role in defining drug efficacy and disease progression. The supporting vasculature system as well as the interstitial extracellular matrix are particularly consequential to the transport, distribution, and uptake of therapeutics. While it is known that the host microenvironment may enable the advancement of malignancy and even the development of resistance, much of the mechanistic understanding by which this regulation occurs remains unclear. This is due in part to a lack of physiologically relevant models, though advancements in the emerging field of "tumor engineering" are beginning to challenge this. The transition away from incompatible animal models and simplified two-dimensional cultures has brought about the creation of advanced three-dimensional models in order to better simulate and test the microenvironmental characteristics that define human cancers. Nonetheless, few systems are able to capture the full range of authentic, complex in vivo events such as neovascularization, intravasation, and variable oxygen distribution. This work will explore the details of developing biologically-inspired, highly controlled in vitro tumor microenvironments to replicate and investigate these events. Such systems have the potential to mediate successful translation of preclinical research to clinical significance, while also providing mechanistic insight into the early stages of tumor progression and metastasis.
Because of their ability to differentiate and develop into functional vasculature, stem cells hold tremendous promise for therapeutic applications. However, the scientific understanding and the ability to engineer these cellular systems is still in its early stages, and must advance significantly for the therapeutic potential of stem cells to be realized. Stem cell differentiation and function are exquisitely tuned by their microenvironment. This book will provide a unique perspective of how different aspect of the vasculature microenvironment regulates differentiation and assembly. Recent efforts to exploits modern engineering techniques to study and manipulate various biophysical cues will be described including: oxygen tension during adult and embryonic vasculogenesis (Semenza and Zandstra), extracellular matrix during tube morphogenesis and angiogenesis (Wirtz, Davis, Ingber), surface topography and modification (Chen and Gerecht), shear stress and cyclic strain effect on vascular assembly and maturation (Vunjak-Novakovic and Niklason), and three dimensional space for angio-andvasculogensis (Ferreria and Fischbach).
Vascularization in Tissue Engineering presents a comprehensive picture of blood vessel development and the recent developments on the understanding of the role of angiogenesis in regenerating biological tissues. The first-half of this book, consists of three chapters, emphasizing the fundamental knowledge about cell pathways, growth factors, co-culture strategies, cell interactions, and vascularization in pathological scenarios. The second half takes this knowledge a step further and explains the vascular microenvironment, scaffolds, and related applications in regenerative medicines. This section also provides information about biomaterial scaffolds and stem cell cultures for wound-healing and tissue regeneration. Readers will learn about cutting edge technologies in this field. This volume is a handy reference for students and researchers seeking information about the angiogenic processes and applied biotechnology in tissue engineering.
Advances in tissue engineering have been accomplished for years by employing biomimetic strategies to provide cells with aspects of their original microenvironment necessary to reconstitute a unit of both form and function for a given tissue. We believe that the most critical hallmark of cancer is loss of integration of architecture and function; thus, it stands to reason that similar strategies could be employed to understand tumor biology. In this commentary, we discuss work contributed by Fischbach-Teschl and colleagues to this special issue of Tissue Engineering in the context of 'tumor engineering', that is, the construction of complex cell culture models that recapitulate aspects of the in vivo tumor microenvironment to study the dynamics of tumor development, progression, and therapy on multiple scales. We provide examples of fundamental questions that could be answered by developing such models, and encourage the continued collaboration between physical scientists and life scientists not only for regenerative purposes, but also to unravel the complexity that is the tumor microenvironment. In 1993, Vacanti and Langer cast a spotlight on the growing gap between patients in need of organ transplants and the amount of available donor organs; they reaffirmed that tissue engineering could eventually address this problem by 'applying principles of engineering and the life sciences toward the development of biological substitutes. Mortality figures and direct health care costs for cancer patients rival those of patients who experience organ failure. Cancer is the second leading cause of death in the United States (Source: American Cancer Society) and it is estimated that direct medical costs for cancer patients approach $100B yearly in the United States alone (Source: National Cancer Institute). In addition, any promising therapy that emerges from the laboratory costs roughly $1.7B to take from bench to bedside. Whereas we have indeed waged war on cancer, the training grounds have largely consisted of small rodents, despite marked differences between human and mouse physiology, or plastic dishes, even though just like our tissues and organs most tumors exist within three-dimensional proteinacious milieus. One could argue that this is comparable to training for a desert war in the arctic. In this special issue of tissue engineering, Fischbach-Teschl and colleagues build a strong case for engineering complex cultures analogous to normal organs to tractably model aspects of the human tumor microenvironment that simply cannot be reproduced with traditional two-dimensional cell culture techniques and that cannot be studied in a controlled fashion in vivo. This idea has gained considerable traction of late as concepts presented and convincingly shown years ago have only now begun to be appreciated. Perhaps, then, it is time to organize those who wish to build complex tumor models to study cancer biology under a common umbrella. Accordingly, we propose that tumor engineering be defined as the construction of complex culture models that recapitulate aspects of the in vivo tumor microenvironment to study the dynamics of tumor development, progression, and therapy on multiple scales. Inherent in this definition is the collaboration that must occur between physical and life scientists to guide the design of patterning techniques, materials, and imaging modalities for the study of cancer from the subcellular to tissue level in physiologically relevant contexts. To date, the most successful tissue engineering approaches have employed methods that recapitulate the composition, architecture, and/or chemical presentation of native tissue. For instance, induction of blood vessel growth for therapeutic purposes has been achieved with sequential release of vascular endothelial growth factor (VEGF) and platelet derived growth factor to induce and stabilize blood vessels. This approach imitates that which occurs during physiological angiogenesis as a result of heterotypic interactions between endothelium and stroma. Employing such biomimetic strategies has already led to success in cancer research. Studying tumors in 3D has proven far more accurate in reproducing in vivo growth characteristics and chemotherapeutic resistance than 2D approaches. A number of animal studies and co-culture experiments have identified also the importance of interactions with other nonmalignant cell types - such as endothelial cells, fibroblasts, adipocytes, leukocytes, and circulating progenitors - to support and sustain tumor growth, invasion, and metastasis. Reproducing not only the 'dynamic reciprocity' but also the 'dynamic cooperativity' between these constituents in a spatially, temporally, and functionally accurate fashion presents quite a challenge for engineering tumors. So, why do it? The reason is to ask important fundamental questions that cannot easily be answered in vivo or on tissue culture plastic for the reasons mentioned.
This volume will outline how to recreate the tumor microenvironment, to culture primary tumors without the need for developmental priming factors, and to deliver targeted therapeutics in a manner that recapitulates pharmacokinetics in vivo. Much of what may be learned from this volume will aid in understanding many aspects of the enhanced study of tumor cell biology in a physiologic context, open new avenues for drug screening and biomarker development, and accelerate the preclinical evaluation of novel personalized medicine strategies for patients in real time.
Author : William D. Figg Publisher : Springer Science & Business Media Page : 592 pages File Size : 21,31 MB Release : 2008-05-24 Category : Medical ISBN : 0387715185
Dr. Judah Folkman is considered the "father of angiogenesis." Because of Folkman's discovery and research, the possibilities of angiogenic therapy have broadened beyond cancer to many noncancerous diseases. Angiogenesis: An Integrative Approach from Science to Medicine is a comprehensive, concise summary of tumor angiogenesis. It is an up-to-date and authoritative reference for the angiogenesis field as it relates to oncology. This book represents the first collection in a volume of which Folkman is co-editor. Folkman has authored nearly 400 original papers and more than 100 book chapters.
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.
Breast cancer is the leading cause of cancer deaths among females globally. Although localized or early stage cancer is largely curable, the five-year survival rate significantly decreases after metastasis. The crosstalk between tumor microenvironment and neoplastic cells is the key for promoting tumor growth and stimulating tumor angiogenesis and metastasis to distant organs. In the first section of this study, the effect of stromal stiffening on the angiogenic activity of cancer cells was explored. In the second section of this study, the effect of microenvironment on bone metastasis was studied. Also, the effect of decellularized ECM (dECM) on the activity of breast cancer cells was investigated.
Tumor Vascularization discusses the different types of growth of tumor blood vessels and their implications on research and healthcare. The book is divided into three parts: the first one, General Mechanisms, discusses different vessel growth mechanisms, such as sprouting angiogenesis, non-angiogenesis dependent growth, intussusceptive microvascular growth, vascular co-option and vasculogenic mimicry. The second and third parts, entitled Clinical Implications and Therapeutic Implications are dedicated to translating recent findings in this field to patient treatment and healthcare. This book is a valuable source for cancer researchers, oncologists, graduate students and members of the biomedical field who are interested in tumor progression and blood vessels. Explains new, non-orthodox concepts recently developed and related to the modality of growth of tumor blood vessels Provides information on the types of angiogenesis, non-angiogenesis dependent growth and vascular co-option, discussing both their similarities and differences Encompasses a discussion on clinical implications of tumor vascularization to translate research findings into treatment