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Autotaxin is a secreted enzyme that produces most of the extracellular lysophosphatidate from lysophosphatidylcholine, the most abundant phospholipid in plasma. Lysophosphatidate mediates many physiological and pathological processes by signaling through six G-protein-coupled receptors to promote cell survival, proliferation and migration. Knocking out autotaxin in mice is embryonically lethal as a result of impaired vasculogenesis and improper neural-crest folding. In the post-natal organism, autotaxin/ lysophosphatidate signaling mediates wound healing and tissue remodeling through acute inflammatory processes. However, in chronic inflammation, this signaling drives many diseases including rheumatoid arthritis, hepatitis, colitis, asthma and cancer. In cancer, lysophosphatidate promotes cell proliferation and migration, angiogenesis, metastasis and chemotherapy and radiotherapy resistance. Currently, there are no therapies targeting lysophosphatidiate signaling and this provides an opportunity for introducing new cancer treatments. Because most lysophosphatidate is produced by autotaxin activity, an inhibitor of the autotaxin catalytic site would block subsequent lysophosphatidate signaling. Therefore, it is important to understand how autotaxin activity is regulated by lysophosphatidate. It has been proposed that autotaxin is product-inhibited by lysophosphatidate or a related lipid called sphingosine-1-phosphate. This has led to the design of several lipid-mimetic autotaxin inhibitors. We now show that this competitive inhibition is ineffective at high concentrations of lysophosphatidylcholine that occur in vivo. Instead, lysophosphatidate and sphingosine-1-phosphate inhibit autotaxin expression through phosphatidylinositol-3-kinase activation. However, this physiological inhibition is overcome by inflammatory-mediated signaling. We propose that inflammation is vital for pathological autotaxin and lysophosphatidate production, and lysophosphatidate signaling in turn further drives an inflammatory environment. Consequently, an autotaxin inhibitor should be able to break this vicious cycle. However, this hypothesis has not been tested as historical autotaxin inhibitors have poor bioavailability profiles. We tested a novel non-lipid-mimetic ATX inhibitor (ONO-8430506) in mice which decreases plasma autotaxin activity by >80% and concentrations of unsaturated lysophosphatidates by >75% for 24 h. We also showed for the first time that inhibiting autotaxin decreases initial tumor growth and subsequent lung metastasis in a 4T1/Balb/c syngeneic orthotopic breast cancer mouse model by 60% compared to vehicle-treatment. When combined with doxorubicin, ONO-8430506 synergistically decreases tumor growth and lung and liver metastases by >70%, whereas doxorubicin alone had marginal effects. Significantly, 4T1 breast cancer cells express neglible autotaxin compared to the mammary fat pad. Autotaxin activity in the fat pad of non-treated mice is increased 2-fold by tumor growth. This increase correlates with increases in inflammatory chemokine and cytokine production that is suppressed by ATX inhibition. We also extended our studies of autotaxin-mediated cancer growth and inhibition to papillary thyroid cancer. The diagnosis of thyroid cancer by fine needle biopsies is imprecise in ≥25% of cases resulting in unnecessary surgery. Many thyroid cancer patients also become resistant to radiotherapy and chemotherapy. Our work addresses both of these problems. We demonstrate that high expression of inflammatory chemokines and cytokines and increased secretion of autotaxin by thyroid cancer cells provides a definitive identification of human papillary thyroid cancer from benign nodules. Autotaxin secretion is hijacked in thyroid cancer in a vicious inflammatory cycle in which lysophosphatidate stimulates autocrine chemokine and cytokine secretion. This in turn increases autocrine autotaxin production. We show that treating mice daily with ONO-8430506 decreases thyroid tumor growth in xenograft models by >50%. There were also decreases in multiple inflammatory chemokines and cytokines, platelet-derived growth factor and vascular endothelial growth factor in the tumors. This results in decreased cancer cell division and angiogenesis. Therefore, regardless of whether autotaxin is produced in an autocrine fashion like in thyroid cancer or in a paracrine manner like in breast cancer, this work describes a new paradigm where autotaxin secretion is inflammatory-mediated and an autotaxin inhibitor is therapeutically effective. Autotaxin inhibitors have great potential to improve cancer patient outcomes and we propose that they also could have utility in other chronic inflammatory-mediated conditions.
This revised second edition is improved linguistically with multiple increases of the number of figures and the inclusion of several novel chapters such as actin filaments during matrix invasion, microtubuli during migration and matrix invasion, nuclear deformability during migration and matrix invasion, and the active role of the tumor stroma in regulating cell invasion.
Dieses Fachbuch erläutert die molekularen Grundlagen von Entzündungen, spannt den Bogen zu Infektionskrankheiten und den Zusammenhang zwischen Entzündungen und chronischen Erkrankungen, behandelt abschließend den Heilungsprozess und zeigt Therapiemöglichkeiten.
Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance, Volume 12, discusses new approaches that are being undertaken to counteract tumor plasticity, understand and tackle the interactions with the microenvironment, and disrupt the rewiring of malignant cells or bypass biological mechanism of resistance by using targeted radionuclide therapies. This book provides a unique opportunity to the reader to understand the fundamental causes of drug resistance and how different approaches are applied. It is a one-stop-shop to understand why it is so difficult to treat cancer, and why only a very few patients respond to therapy and a significant portion develop resistance. Despite a rapid development of more effective anti-cancer drugs and combination therapies, cancer remains the leading cause of lethality in the developed world. The main reason for this is the ability of heterogeneous subpopulations of tumor cells interacting with constantly evolving tumor microenvironment to resist elimination and eventually, trigger cancer relapse. In this book, experts review current concepts explaining molecular and biological mechanisms of cancer drug resistance and discussing advancing approaches for overcoming these therapeutic challenges. - Provides the most updated knowledge on the mechanisms of cancer drug resistance and the emerging therapeutic approaches reviewed by experts in the field - Brings detailed analyses of most important recently reported developments related to drug resistance and their relevance to overcoming it in cancer patients - Discusses in-depth molecular mechanisms and novel concepts of cancer resistance to conventional and advanced therapies
Biological Mechanisms and the Advancing Approaches to Overcoming Cancer Drug Resistance, Volume 12, discusses new approaches that are being undertaken to counteract tumor plasticity, understand and tackle the interactions with the microenvironment, and disrupt the rewiring of malignant cells or bypass biological mechanism of resistance by using targeted radionuclide therapies. This book provides a unique opportunity to the reader to understand the fundamental causes of drug resistance and how different approaches are applied. It is a one-stop-shop to understand why it is so difficult to treat cancer, and why only a very few patients respond to therapy and a significant portion develop resistance. Despite a rapid development of more effective anti-cancer drugs and combination therapies, cancer remains the leading cause of lethality in the developed world. The main reason for this is the ability of heterogeneous subpopulations of tumor cells interacting with constantly evolving tumor microenvironment to resist elimination and eventually, trigger cancer relapse. In this book, experts review current concepts explaining molecular and biological mechanisms of cancer drug resistance and discussing advancing approaches for overcoming these therapeutic challenges. Provides the most updated knowledge on the mechanisms of cancer drug resistance and the emerging therapeutic approaches reviewed by experts in the field Brings detailed analyses of most important recently reported developments related to drug resistance and their relevance to overcoming it in cancer patients Discusses in-depth molecular mechanisms and novel concepts of cancer resistance to conventional and advanced therapies
The book Research on Melanoma: A Glimpse into Current Directions and Future Trends, is divided into sections to represent the most cutting-edge topics in melanoma from around the world. The emerging epigenetics of disease, novel therapeutics under development and the molecular signaling aberrations are explained in detail. Since there are a number of areas in which unknowns exist surrounding the complex development of melanoma and its response to therapy, this book illuminates and comprehensively discusses such aspects. It is relevant for teaching the novice researcher who wants to initiate projects in melanoma and the more senior researcher seeking to polish their existing knowledge in this area. Many chapters include visuals and illustrations designed to easily guide the reader through the ideas presented.
Resistance to therapies, both targeted and systemic, and metastases to distant organs are the underlying causes of breast cancer-associated mortality. The second edition of Breast Cancer Metastasis and Drug Resistance brings together some of the leading experts to comprehensively understand breast cancer: the factors that make it lethal, and current research and clinical progress. This volume covers the following core topics: basic understanding of breast cancer (statistics, epidemiology, racial disparity and heterogeneity), metastasis and drug resistance (bone metastasis, trastuzumab resistance, tamoxifen resistance and novel therapeutic targets, including non-coding RNAs, inflammatory cytokines, cancer stem cells, ubiquitin ligases, tumor microenvironment and signaling pathways such as TRAIL, JAK-STAT and mTOR) and recent developments in the field (epigenetic regulation, microRNAs-mediated regulation, novel therapies and the clinically relevant 3D models). Experts also discuss the advances in laboratory research along with their translational and clinical implications with an overarching goal to improve the diagnosis and prognosis, particularly that of breast cancer patients with advanced disease.
This book is a printed edition of the Special Issue "The Tumor Microenvironment of High Grade Serous Ovarian Cancer" that was published in Cancers