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Cancer development results from a multi-step process that involves a set of genetic abnormalities allowing the clonal selection of cells with proliferative advantages. Some of these genetic abnormalities increase the autonomous proliferation of tumor cells by aberrant activation of signal transduction of growth factors that provide survival and proliferative signals in normal cells under physiological conditions.
The in vitro tumorgenesis model studied in this master thesis is based on cytokine-dependent cells that acquired cytokine-independence through two selection steps. First, BaF3 cells expressing a non-functional IL-9 receptor developed IL-9 responsiveness. This adaptation to IL-9 was accompanied by overexpression of the JEAK1 protein kinase, which is associated with IL-9 receptor and implicated in its signal transduction. IL-9-responsive cells could further give rise to totally cytokine-independent, autonomous clones.
In the first part of this work, we showed that these autonomous clones harbour point mutations in JAK1. Certain of these mutations were recently described in patients with acute lymphoblastic leukaemia, further illustrating the relevance of our model. We subsequently characterized the different JAK1 mutants functionally. All of them constitutively activated signalling molecules downstream of JAK1-binding receptors, such as IL-2 and IL-9 receptor, allowing for cytokine-independence of BAF3 cells. Moreover, 13 of the 18 identified mutants conferred hypersensitivity to the anti-proliferative effects of type I interferons.
The second part of this master thesis focuses on the study of the genetic factors promoting the apparition of spontaneous point mutations. JAK1 overexpression is a prerequisite for the selection of JAK1-mutated autonomous clones suggesting a favourable cellular context for further mutations. Therefore, we investigated systematically the different possible mechanism of JAK1 overexpression. Using transcription and translation inhibitors, we demonstrated that kinetics of JAK1 messenger RNA and JAK1 protein degradation were not altered by selection in IL-9 excluding post-transcriptional deregulation mechanisms. Treatment of cells with demethylating or acetylating agents and bisulfite sequencing ruled out the direct epigenetic regulations like modification of promoter methylation pattern or histones acetylation. Complementary experiments are needed in order to identify the mechanism underlying JAK1 overexpression in our model and to assess its impact on apparition of spontaneous activating mutations in JAK1 Le développement d’un cancer est le résultat d’un processus séquentiel qui implique une succession d’anomalies génétiques et de sélections clonales de cellules présentant un avantage de prolifération. Certaines de ces anomalies génétiques accroissent l’autonomie des cellules tumorales moyennant une signalisation aberrante des facteurs de croissance dont elles sont physiologiquement dépendantes.
Le modèle de tumorgenèse in vitro étudié dans ce travail met en scène des cellules au départ dépendantes de cytokines qui acquièrent la capacité de proliférer de façon autonome au terme d’un processus en deux étapes de sélection. Dans un premier temps, des cellules BaF3 exprimant un récepteur pour l’interleukine-9 (IL-9) non-fonctionnel développent une faculté de réponse à l’IL-9. Nous avons observé que cette adaptation s’accompagne systématiquement d’une surexpression de la protéine kinase JAK1 associée au récepteur à l’IL-9 et impliquée dans sa signalisation intracellulaire. Les cellules adaptées à l’IL-9 peuvent, dans un second temps, donner naissance à des clones totalement autonomes.
Dans le premier volet de ce mémoire, nous montrons que les clones autonomes présentent des mutations ponctuelles de JAK1. L’intérêt de ces mutations est illustré par le fait que récemment certaines d’entre elles ont également été identifiées chez des patients atteints de leucémies lymphoblastiques aiguës. Nous avons caractérisé fonctionnellement les différents mutants de JAK1. Ils activent constitutivement les molécules de signalisation en aval des récepteurs de cytokines tels ceux de l’IL-9 ou l’IL-2 assurant l’autonomie des cellules. Par opposition, 13 des 18 mutants identifiés confèrent une hypersensibilité aux effets anti-prolifératifs des interférons de type 1.
Le second volet de ce travail est l’étude des facteurs génétiques favorisant la survenue de telles mutations. La surexpression de JAK1 est un prérecquis à l’émergence de cellules autonomes évoquant un contexte propice à l’apparition de mutations. Nous avons entrepris l’examen systématique des divers mécanismes de surexposition envisageables. En faisant usage d’inhibiteurs de la transcription ou de la traduction, nous avons démontré que les cinétiques de dégradation de l’ARN messager et de la protéine n’étaient pas modifiées par la sélection en IL-9 écartant par conséquent une dérégulation post-transcriptionnelle. Le traitement des cellules par agents déméthylants ou acétylants ainsi que le séquençage d’ADN génomique traité au bisulfite excluent une régulation épigénétique telle qu’une modification dans la méthylation du promoteur ou l’acéthylation des histones. Des expériences complémentaires sont nécessaires afin d’élucider la cause de la surexposition de JAK1 dans notre modèle et de comprendre son éventuel impact sur l’apparition de mutations spontanées

Janus Kinase 1 --- Signal Transduction --- Angiogenic Proteins --- STAT Transcription Factors --- Neoplasm Proteins --- Smarcd3 protein, mouse --- Clone Cells

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This book is devoted to vascular endothelial growth factor A (VEGF or VEGFA), a secreted signalling protein of great significance for development and disease in vertebrates. VEGFA controls the proliferation, migration, specialisation and survival of vascular endothelial cells, and it is therefore essential for the establishment of a functional blood vessel circuit. In addition, VEGFA is emerging as a versatile patterning factor for several non-endothelial cell types in vertebrates. Thus, it plays a central role during organ development at multiple levels, including blood vessel growth, vessel-

Neovascularization. --- Vascular endothelial growth factors. --- Angiogenic factors --- Angiogenic proteins --- Endothelial growth factors, Vascular --- VEGFs (Proteins) --- Growth factors --- Angiogenesis --- Blood-vessels --- Growth --- Biochemistry. --- Biochemistry, general. --- Biological chemistry --- Chemical composition of organisms --- Organisms --- Physiological chemistry --- Biology --- Chemistry --- Medical sciences --- Composition

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Neovascularization --- Tissue engineering --- Angiogenic Proteins --- Cardiovascular Physiological Processes --- Culture Techniques --- Publication Formats --- Intercellular Signaling Peptides and Proteins --- Cardiovascular Physiological Phenomena --- Clinical Laboratory Techniques --- Publication Characteristics --- Investigative Techniques --- Circulatory and Respiratory Physiological Phenomena --- Biological Factors --- Peptides --- Proteins --- Amino Acids, Peptides, and Proteins --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Phenomena and Processes --- Chemicals and Drugs --- Tissue Engineering --- Vascular Endothelial Growth Factors --- Neovascularization, Physiologic --- Collected Works --- Human Anatomy & Physiology --- Health & Biological Sciences --- Physiology

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This volume of Studies in Mechanobiology, Tissue Engineering and Biomaterials describes the most recent advances in angiogenesis research at all biological length scales: molecular, cellular and tissue, in both in vivo and in vitro settings.  Angiogenesis experts from diverse fields including engineering, cell and developmental biology, and chemistry have contributed chapters which focus on the mechanical and chemical signals which affect and promote blood vessel growth. Specific emphasis is given to novel methodologies and biomaterials that have been developed and applied to angiogenesis research. .

Angiogenesis. --- Biomedical engineering. --- Engineering. --- Neovascularization. --- Biomedical engineering --- Neovascularization --- Intercellular Signaling Peptides and Proteins --- Cell Physiological Processes --- Cardiovascular System --- Biochemical Processes --- Cardiovascular Physiological Processes --- Biological Science Disciplines --- Chemical Processes --- Peptides --- Anatomy --- Proteins --- Cardiovascular Physiological Phenomena --- Cell Physiological Phenomena --- Biological Factors --- Natural Science Disciplines --- Biochemical Phenomena --- Chemical Phenomena --- Circulatory and Respiratory Physiological Phenomena --- Amino Acids, Peptides, and Proteins --- Disciplines and Occupations --- Phenomena and Processes --- Chemicals and Drugs --- Neovascularization, Physiologic --- Angiogenic Proteins --- Signal Transduction --- Physiology --- Blood Vessels --- Health & Biological Sciences --- Medicine --- Biomedical Engineering --- Cardiovascular Diseases --- Angiogenesis --- Biochemical engineering. --- Biochemistry. --- Biomaterials. --- Biomedical Engineering. --- Biological and Medical Physics, Biophysics. --- Biochemistry, general. --- Biochemical Engineering. --- Blood-vessels --- Growth --- Biomedical Engineering and Bioengineering. --- Bio-process engineering --- Bioprocess engineering --- Biochemistry --- Biotechnology --- Chemical engineering --- Biological chemistry --- Chemical composition of organisms --- Organisms --- Physiological chemistry --- Biology --- Chemistry --- Medical sciences --- Biocompatible materials --- Biomaterials --- Medical materials --- Materials --- Biocompatibility --- Prosthesis --- Clinical engineering --- Medical engineering --- Bioengineering --- Biophysics --- Engineering --- Composition --- Biophysics. --- Biological physics. --- Bioartificial materials --- Hemocompatible materials --- Biological physics --- Physics --- Biomaterials (Biomedical materials)

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Angiogenesis and lymphangiogenesis have become attractive targets for drug therapy because of their key roles in a broad spectrum of pathological disease states ranging from macular degeneration to tumor growth and metastasis. A substantial increase in the research effort over the past decade has deepened our understanding of the basic mechanisms underlying angiogenesis and lymphangiogenesis, promoting the development of promising therapeutics for the clinical management of vascular-related diseases. These extraordinary advancements have been built upon a vast array of diverse analytical techniques developed globally throughout the field. Over the years, these methods have evolved to suit the specific needs of different researchers and experimental scenarios, resulting in a myriad of technical variants of basic assay approaches.  "The Textbook of Angiogenesis and Lymphangiogenesis: Methods and Applications" is an up-to-date comprehensive textbook on angiogenesis and lymphangiogenesis techniques and applications. This volume is designed to embody the collective works of experts in the clinical as well as the basic research arenas who have significantly contributed to the development and application of techniques in all areas of angiogenesis and lymphangiogenesis. Each chapter introduces and discusses one or a group of closely related techniques and convey step-by-step protocol information and detailed technical guidance to the reader. Emphasis has been placed on explanatory illustrations, critical technical steps as well as divulging information on the benefits and caveats of specific practices related to the methods discussed. This manual is intended to serve as a written guide for both newcomers and established professionals in the field.

Angiogenesis. --- Heart -- Diseases -- Treatment. --- Medicine. --- Neovascularization --- Publication Formats --- Epithelial Cells --- Animal Diseases --- Organogenesis --- Models, Animal --- Angiogenic Proteins --- Models, Biological --- Cardiovascular Physiological Processes --- Intercellular Signaling Peptides and Proteins --- Embryonic and Fetal Development --- Investigative Techniques --- Diseases --- Publication Characteristics --- Cells --- Models, Theoretical --- Cardiovascular Physiological Phenomena --- Analytical, Diagnostic and Therapeutic Techniques and Equipment --- Anatomy --- Peptides --- Biological Factors --- Circulatory and Respiratory Physiological Phenomena --- Proteins --- Morphogenesis --- Amino Acids, Peptides, and Proteins --- Growth and Development --- Phenomena and Processes --- Chemicals and Drugs --- Physiological Processes --- Physiological Phenomena --- Endothelial Cells --- Vascular Endothelial Growth Factors --- Laboratory Manuals --- Disease Models, Animal --- Lymphangiogenesis --- Neovascularization, Physiologic --- Human Anatomy & Physiology --- Health & Biological Sciences --- Physiology --- Angiogenesis, Physiological --- Neovascularization, Physiological --- Physiologic Angiogenesis --- Physiologic Neovascularization --- Angiogenesis, Physiologic --- Physiological Angiogenesis --- Physiological Neovascularization --- Lymphangiogeneses --- Lymphatic Vessels --- Animal Disease Model --- Animal Disease Models --- Disease Model, Animal --- VEGFs --- Capillary Endothelial Cells --- Lymphatic Endothelial Cells --- Vascular Endothelial Cells --- Capillary Endothelial Cell --- Cell, Capillary Endothelial --- Cell, Endothelial --- Cell, Lymphatic Endothelial --- Cell, Vascular Endothelial --- Cells, Capillary Endothelial --- Cells, Endothelial --- Cells, Lymphatic Endothelial --- Cells, Vascular Endothelial --- Endothelial Cell --- Endothelial Cell, Capillary --- Endothelial Cell, Lymphatic --- Endothelial Cell, Vascular --- Endothelial Cells, Capillary --- Endothelial Cells, Lymphatic --- Endothelial Cells, Vascular --- Lymphatic Endothelial Cell --- Vascular Endothelial Cell --- Physiological Concepts --- Physiological Phenomenon --- Physiological Process --- Concept, Physiological --- Concepts, Physiological --- Phenomena, Physiological --- Phenomenas, Physiological --- Phenomenon, Physiological --- Physiological Concept --- Process, Physiological --- Processes, Physiological --- Development and Growth --- Gene Products, Protein --- Gene Proteins --- Protein Gene Products --- Proteins, Gene --- Circulatory and Respiratory Physiological Phenomenon --- Physiology, Circulatory and Respiratory --- Circulatory and Respiratory Physiology --- Biologic Agents --- Biologic Factors --- Biological Factor --- Factor, Biologic --- Factor, Biological --- Factors, Biological --- Biological Agents --- Agents, Biologic --- Agents, Biological --- Biologic Factor --- Factors, Biologic --- Polypeptides --- Anatomies --- Cardiovascular Physiological Concepts --- Cardiovascular Physiological Phenomenon --- Cardiovascular Physiological Process --- Physiology, Cardiovascular --- Cardiovascular Physiologic Processes --- Cardiovascular Physiology --- Cardiovascular Physiological Concept --- Cardiovascular Physiological Phenomenas --- Concept, Cardiovascular Physiological --- Concepts, Cardiovascular Physiological --- Phenomena, Cardiovascular Physiological --- Phenomenon, Cardiovascular Physiological --- Physiologic Processes, Cardiovascular --- Physiological Concept, Cardiovascular --- Physiological Concepts, Cardiovascular --- Physiological Phenomena, Cardiovascular --- Physiological Phenomenon, Cardiovascular --- Physiological Process, Cardiovascular --- Physiological Processes, Cardiovascular --- Process, Cardiovascular Physiological --- Processes, Cardiovascular Physiologic --- Processes, Cardiovascular Physiological --- Cardiovascular System --- Experimental Model --- Experimental Models --- Mathematical Model --- Model, Experimental --- Models (Theoretical) --- Models, Experimental --- Models, Theoretic --- Theoretical Study --- Mathematical Models --- Model (Theoretical) --- Model, Mathematical --- Model, Theoretical --- Models, Mathematical --- Studies, Theoretical --- Study, Theoretical --- Theoretical Model --- Theoretical Models --- Theoretical Studies --- Cell --- Investigative Technics --- Investigative Technic --- Investigative Technique --- Technic, Investigative --- Technics, Investigative --- Technique, Investigative --- Techniques, Investigative --- Prenatal Programming --- Embryo and Fetal Development --- Programming, Prenatal --- Growth Factors --- Paracrine Peptide Factors --- Paracrine Protein Factors --- Peptide Factors, Paracrine --- Biological Model --- Biological Models --- Model, Biological --- Models, Biologic --- Biologic Model --- Biologic Models --- Model, Biologic --- Experimental Animal Models --- Laboratory Animal Models --- Animal Model --- Animal Model, Experimental --- Animal Model, Laboratory --- Animal Models --- Animal Models, Experimental --- Animal Models, Laboratory --- Experimental Animal Model --- Laboratory Animal Model --- Model, Animal --- Model, Experimental Animal --- Model, Laboratory Animal --- Models, Experimental Animal --- Models, Laboratory Animal --- Diseases, Animal --- Disease --- Adenomatous Epithelial Cells --- Columnar Glandular Epithelial Cells --- Cuboidal Glandular Epithelial Cells --- Glandular Epithelial Cells --- Squamous Cells --- Squamous Epithelial Cells --- Transitional Epithelial Cells --- Adenomatous Epithelial Cell --- Cell, Adenomatous Epithelial --- Cell, Epithelial --- Cell, Glandular Epithelial --- Cell, Squamous --- Cell, Squamous Epithelial --- Cell, Transitional Epithelial --- Cells, Adenomatous Epithelial --- Cells, Epithelial --- Cells, Glandular Epithelial --- Cells, Squamous --- Cells, Squamous Epithelial --- Cells, Transitional Epithelial --- Epithelial Cell --- Epithelial Cell, Adenomatous --- Epithelial Cell, Glandular --- Epithelial Cell, Squamous --- Epithelial Cell, Transitional --- Epithelial Cells, Adenomatous --- Epithelial Cells, Glandular --- Epithelial Cells, Squamous --- Epithelial Cells, Transitional --- Glandular Epithelial Cell --- Squamous Cell --- Squamous Epithelial Cell --- Transitional Epithelial Cell --- Epithelium --- Angiogenesis --- growth & development --- physiology --- veterinary --- cytology --- Angiogenic Peptides --- Cancer research. --- Angiology. --- Cell culture. --- Biomedicine. --- Biomedicine general. --- Cancer Research. --- Cell Culture. --- Oncology. --- Angiography. --- Blood-vessels --- Diagnosis, Radioscopic --- Radiography, Medical --- Tumors --- Cultures (Biology) --- Cytology --- Clinical sciences --- Medical profession --- Human biology --- Life sciences --- Medical sciences --- Pathology --- Physicians --- Radiography --- Technique --- Health Workforce --- Neovascularization. --- Biomedicine, general. --- Cancer research