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The development of cancer is a multistep evolutionary process. At each step, cells are submitted to a selective pressure. With a Darwinian dynamic, cells which develop a phenotype adapted to their environment are able to survive. Without adaptation, the majority of human tumors stays in a quiescent state, resulting from a balance between cell proliferation and death. Unbridled proliferation of tumor cells progressive/y creates hypoxic areas distant from functional blood vessels. To grow in this hostile environment, cancer cells undergo two essential adaptations: the "glycolytic switch ", which allows cells to produce energy in a hypoxic environment, and the "angiogenic switch "promoting the development of their own vascular network. In this study, we show that the "glycolytic switch" plays a central role in the angiogenesis process. In particular, we document that lactate, the end product of glycolysis, is a pro-angiogenic agent. Characterization of this pathway has led to discover a new therapeutic approach. Because the uptake of exogenous lactate by the cells requires the transporter MCTJ at the cell membrane, MCTJ inhibition allows to repress angiogenesis and to black tumor growth. Le développement d'un cancer est un processus évolutif comprenant plusieurs étapes. A chaque étape, les cellules sont soumises à une pression de sélection. Par une dynamique Darwinienne, les cellules qui développent un phénotype adapté à leur milieu sont capables de survivre. En absence d'adaptation, la majorité des tumeurs humaines persiste dans un stade de dormance, résultat d'un équilibre entre prolifération et mort cellulaire. La prolifération débridée des cellules cancéreuses génère progressivement des zones tumorales hypoxiques, éloignées de vaisseaux sanguins fonctionnels. Pour survivre à cet environnement hostile, les cellules cancéreuses procèdent à deux adaptations essentielles: le switch glycolytique qui permet de produire de l'énergie en absence d'oxygène et le switch angiogénique qui permet la néovascularisation du tissu. Dans cette étude, nous montrons que le switch glycolytique joue un rôle majeur dans le développement de l'angiogenèse tumorale. En particulier, nous documentons que le lactate, produit final de la glycolyse, est un agent pro-angiogénique . La caractérisation de cette voie signalétique a permis d'élaborer une nouvelle approche thérapeutique. Puisque l'entrée du lactate exogène dans la cellule requiert le transporteur membranaire MCTl, l'inhibition de ce transporteur permet de réprimer l'angiogenèse et de bloquer la croissance tumorale.

Glycolysis --- Angiogenesis Inducing Agents

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Cancer is a complex pathology in which several non-genetic factors such as hypoxia, inflammation and angiogenesis play a role in the disease progression. Although different anticancer modalities do exist, their use is often limited by important adverse effects. There is therefore a perpetual need to find new therapeutic molecules. The objective of this study was to characterize a potential anti-angiogenic activity from extracts of a plant named Schrankia leptocarpa, and if possible, to purify the active compound(s). Schrankia leptocarpa was selected because of its use as a treatment of diverse inflammatory pathologies in Benin. A screening test based on cytotoxicity measurements was used to determine the effect/dose relationship of extracts on different cell types. Quiescent and proliferating endothelial cells were used to reproduce the conditions of a healthy tissue and tumor vessels, respectively. The lack of cytotoxicity on healthy cells and an activity on tumor cells were chosen as additional filters to identify the most interesting extracts. Some experiments were also carried out under hypoxic conditions to mimic the tumor environment. Cytotoxic activity of a few extracts was identified both in proliferating endothelial cells and tumor cells. These extracts were also able to inhibit endothelial tube formation in an assay based on the capacity of endothelial cells to organize them into a network when cultured on extracellular matrix. Also, a slightly higher cytotoxicity of the extract was observed on endothelial cells maintained under hypoxic conditions. The dichloromethane extract was fractionated by liquid chromatography and fractions concentrating the activity could be isolated. The comparison of the LC-MS profile of the most active fraction with the chromatogram of known molecules indicated that besides lupeol which has a notorious antitumor activity, new molecules with an anti-angiogenic activity could be isolated from Schrankia leptocarpa Le cancer est une pathologie complexe dans laquelle interviennent divers facteurs tels que l’hypoxie, l’inflammation et l’angiogenèse. De plus en plus de traitements différents sont disponibles mais tous comportent des effets secondaires limitant souvent leur potentiel thérapeutique, d’où l’intérêt permanent de rechercher de nouvelles molécules. L’objectif de ce mémoire était de caractériser l’activité anti-angiogénique potentielle d’extraits d’une plante, le Schrankia leptocarpa, et le cas échéant d’entreprendre la purification du composé actif. Cette plante a été choisie pour son utilisation au Bénin dans le traitement de diverses pathologies à connotation inflammatoire. Un test de criblage basé sur la mise en évidence de la cytotoxicité a permis d’établir la relation dose /effet des extraits sur différents types cellulaires. Des cellules endothéliales quiescentes et proliférantes ont été utilisées afin de reproduire les conditions rencontrées respectivement dans un tissu sain et dans une tumeur sur des cellules tumorales ont constitué des filtres supplémentaires permettant d’identifier les extraits les plus intéressants. Certaines expériences ont également été réalisées en condition hypoxique de façon à mimer le microenvironnement tumoral. Une activité cytotoxique sur les cellules endothéliales proliférantes et tumorales a été identifiée sur certains extraits. Ces mêmes extraits se sont révélés capables d’inhiber la formation de tubes endothéliaux dans un test exploitant la capacité des cellules endothéliales à s’organiser en réseau lorsqu’elles sont cultivées sur une matrice extracellulaire. De plus, une légère augmentation de l’activité cytotoxique a été identifiée en condition hypoxique. Le sous-fractionnement par chromatographie liquide de l’extrait le plus actif a permis de démontrer que l’activité de celui-ci se concentrait dans certaines fractions. Le recours à la LC-MS et la confrontation aux profils de certaines molécules naturelles connues suggèrent qu’à côté du lupéol déjà identifié pour son activité anti-tumorale, des composés anti-angiogéniques nouveaux pourraient être isolés de l’extrait dichlorométhane du Schrankia leptocarpa.

Plants, Medicinal --- Plants, Medicinal --- Angiogenesis Inducing Agents

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To date, 13 live births have been reported worldwide that testify the promising future of cryopreservation and transplantation of human ovarian tissue. However, ischaemic stress post transplantation could affect the follicular population. It is therefore essential to ameliorate the angiogenic process following grafting with the aim of improving the experimental procedures. Xenografting of human ovarian tissue in immunodeficient mice is currently one of the best models to study vascularisation of ovarian tissue.
Recent studies in our laboratory has shown the presence of both murine host blood vessels and preexisting human vessels contributing to the progressive reperfusion of the graft following xenotransplantation of frozen-thawed human ovarian tissue.
The objective if this work is to characterize the human-murine vascular network established after xenografting of frozen-thawed human ovarian cortex. Our study therefore, aims to evaluate the relative contribution of the human and murine vessels to the formation of new vascular network, and their implication in the vascularisation process and follicular growth.
The kinetic analysis of the early revascularization of the graft shows that vascular density of the graft gradually increases from day 3 to day 21 post-transplantation. Double immunostaining of CD-34 specific for human and murine blood vessels showed a significant contribution of the human vessels following 21 days of ovarian xenotransplantation, implicating the presence of human angiogenic process. This specific study of human vessels indicates an increase of the proliferative index of human endothelial cells from day 5 till day 9 post-transplantation and a turnover of basal state by day 21. We observed a linear increase in pericytes from day 9 till day 21, indicating a stabilization of the human blood vessels.
Also after 6 months of grafting, the human-murine vascular network still persists and vascular density of the ovarian stroma is equivalent to that of a native ovary. Analysis of vascularisation in the theca layer of late secondary follicles showed the presence of both human and murine blood vessels from the stroma recruited by these growing follicles to ensure their vascularisation.
In conclusion, this study shows that vessels from the host but especiaaly preexisting vessels of the fragment are able to from a vascular network similar to that observed in an ungrafted ovary and this, un spite of the cryopreservation of the fragment and the hypoxia generated by the avascular graft. And also vascular network persists up to 6 months following grafting, recruiting by the late secondary follicles Les 13 naissances mondiales reportées à ce jour témoignent de l’avenir prometteur de la technique de cryopréservation et de greffe du cortex ovarien. Cependant, le stress ischémique lié à la greffe avasculaire présente un effet délétère sur la population folliculaire. Il est donc indispensable d’approfondir la compréhension des processus angiogéniques post-greffe pour le tissu ovarien dans le but d’améliorer les protocoles opératoires. Ces études de vascularisation utilisent classiquement la souris comme modèle de xénogreffe de tissu ovarien humain.
Les travaux récents du laboratoire de gynécologie ont démontré qu’après xénogreffe du cortex ovarien humain cryopréservé, les vaisseaux murins de l’hôte et les vaisseaux humains préexistants du tissu greffé prennent part tous deux au phénomène de reperfusion progressif du greffon.
L’objectif de ce mémoire est de caractériser le réseau vasculaire humain-murin établi après xénogreffe de cortex ovarien humain cryopréservé. Notre étude vise à évaluer la contribution relative des vaisseaux humains et murins à la formation du réseau vasculaire post-greffe, à étudier leur devenir et leur implication dans la vascularisation des follicules en croissance.
L’analyse cinétique de la revascularisation précoce du greffon montre que la densité vasculaire du greffon augmente progressivement du jour 3 au jour 21 post-transplantation. Le double marquage immunohistochimique anti-CD34 spécifique humain au 21ème jour post-greffe, suggérant dès lors l’implication d’un processus angiogénique humain. L’étude spécifique des vaisseaux humains indique une augmentation de l’index de prolifération des cellules endothéliales humaines à partir du jour 5 jusqu’au jour 9 post-transplantation pour retourner à un état basal au jour 21. A partir du jour 9 jusqu’au jour 21, une augmentation de la couverture péricytaire est observée, indiquant une stabilisation des vaisseaux humains.
Arpsè 6 mois de greffe, le réseau vasculaire humain-murin persiste et la densité vasculaire du stroma ovarien est équivalente à celle du tissu antif. L’analyse individualisée de la vascularisation thécale des follicules secondaires tardifs montre que tant les vaisseaux humains que murins du stroma peuvent être recrutés par ces follicules en développement pour assurer leur vascularisation.
En conclusion, cette étude montre que les vaisseaux de l’hôte mais surtout les vaisseaux préexistants du fragment sont capables de former un réseau vasculaire histologiquement similaire à celui de l’ovaire non greffé et ce, malgré la cryopréservation du tissu et l’hypoxie engendrée par la greffe avasculaire. De plus, ce réseau vasculaires persiste jusqu’à 6 mois de greffe et peut être recruté par les follicules secondaires tardif

Fetal Tissue Transplantation --- Transplantation, Heterologous --- Cryopreservation --- Ovarian Follicle --- Angiogenesis Inducing Agents

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Chemokine Receptors in Cancer summarizes the growing body of evidence that several chemokine receptors contribute to tumor behavior. Chemokine receptors were first identified on leukocytes and mediate directed migration of many host cells to sites of ligand expression. It is now well established that most malignant cells also express one or more chemokine receptor. This book describes our current understanding regarding how chemokine receptors contribute to tumor cell migration as well as cell survival and proliferation. The function of chemokine receptors expressed on host cells including antitumor immune effector cells as well as angiostatic and angiogeneic functions of chemokines acting on endothelial cells are described. The role of chemokine receptors that act as decoy receptors is also summarized. The therapeutic potential and challenges of targeting chemokine receptors or cognate ligands is also addressed.

Cancer cells --- Chemokines --- Receptors, Cytokine --- Antigens, CD --- Receptors, G-Protein-Coupled --- Diseases --- Angiogenesis Modulating Agents --- Growth Substances --- Receptors, Immunologic --- Antigens, Differentiation --- Receptors, Cell Surface --- Membrane Proteins --- Biological Markers --- Antigens, Surface --- Physiological Effects of Drugs --- Pharmacologic Actions --- Proteins --- Antigens --- Biological Factors --- Amino Acids, Peptides, and Proteins --- Chemicals and Drugs --- Chemical Actions and Uses --- Angiogenesis Inducing Agents --- Neoplasms --- Receptors, Chemokine --- Biology --- Health & Biological Sciences --- Medicine --- Pharmacy, Therapeutics, & Pharmacology --- Oncology --- Microbiology & Immunology --- Growth --- Regulation. --- Receptors --- Effect of drugs on. --- Effect of drugs on --- Regulation --- Chemokines. --- Drug receptors. --- Drugs --- Receptors, Drug --- Chemotactic cytokines --- Inflammatory peptides --- Intercrines --- Medicine. --- Cancer research. --- Oncology. --- Biomedicine. --- Cancer Research. --- Cell receptors --- Cytokines --- Inflammation --- Peptides --- Mediators --- Oncology  . --- Tumors --- Cancer research

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The book presents  the overview of the current knowledge in some fields of vascular biology, addressing cellular and molecular aspects of blood-vessel formation and their role in health and disease. The major factors involved in the formation of blood vessels are presented by scientists actively involved in this area of research. Special emphasis is put on the presentation of various molecular mechanisms not addressed in similar works to date. The book is divided into three parts. The first part describes the cells and mediators in angiogenesis.  The significance of various populations of potential endothelial progenitors is particularly highlighted. The chapters of the second part focus on molecular mechanisms, with special emphasis on the role of hypoxia, gasotransmitters and reactive oxygen species as well as microRNAs in regulation of angiogenic processes. In the third part, the pathological aspects of disturbed – aggravated or impaired – vascularization are discussed and new modalities for potential therapies are presented. The book is intended for scientists and PhD students in the fields of vascular biology and cancer research. It may be of interest for medical professionals in the fields of cardiovascular disease, diabetes, oncology and rheumatoid arthritis.

Angiogenesis Inducing Agents. --- Neovascularization, Physiologic. --- Neovascularization. --- Neovascularization --- RNA, Antisense --- Metaplasia --- Epithelial Cells --- RNA, Small Untranslated --- Cells --- RNA, Untranslated --- Antisense Elements (Genetics) --- Pathologic Processes --- RNA --- Anatomy --- Nucleic Acids --- Pathological Conditions, Signs and Symptoms --- Nucleic Acids, Nucleotides, and Nucleosides --- Diseases --- Chemicals and Drugs --- Endothelial Cells --- MicroRNAs --- Neovascularization, Pathologic --- Human Anatomy & Physiology --- Health & Biological Sciences --- Physiology --- Immunology. --- Cancer --- Research. --- Cancer research --- Immunobiology --- Angiogenesis --- Medicine. --- Cancer research. --- Oncology. --- Cell biology. --- Biomedicine. --- Cancer Research. --- Cell Biology. --- Blood-vessels --- Life sciences --- Serology --- Growth --- Cytology. --- Oncology  . --- Tumors --- Cell biology --- Cellular biology --- Biology --- Cytologists