Dissertationen zum Thema „Modèle de xénogreffe“
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Soquet, Jérôme. „Modulation médicamenteuse des calcifications valvulaires dans un modèle ovin de xénogreffe aortique“. Electronic Thesis or Diss., Université de Lille (2022-....), 2023. http://www.theses.fr/2023ULILS061.
Der volle Inhalt der QuelleAortic stenosis (AS) is the most frequent and the most lethal valvular heart disease in the elderly in high-income countries
Angioi, Duprez Karine. „La souris nude : un modèle d'études expérimentales des xénogreffes de tissus humains“. Nancy 1, 1993. http://www.theses.fr/1993NAN19430.
Der volle Inhalt der QuelleBousquet, Guilhem. „Transgénèse et xénogreffe : deux stratégies expérimentales pour les thérapies innovantes en cancérologie“. Paris 7, 2011. http://www.theses.fr/2011PA077142.
Der volle Inhalt der QuelleCancers are frequent diseases and leading causes of mortality in the world. They are a major health care problem. Despite a significant improvement in prognosis of patients since the last 20 years, the development of innovating therapeutical agents is highly required, challenging research in oncology. In addition, a preclinical knowledge of mechanisms of action and biomarkers of response is crucial for not missing the clinical development of these new drugs. The preclinical pharmacological models currently used since 30 years are clearly insufficient, as only 5% of tested agents finally succeed in being active in patients. I had the opportunity to use two different experimental murine models for the development of two innovating therapies : 1)The double transgenic model which develop colorectal tumors mimicking the human pathology. First, we demonstrated its pharmacological relevance regarding to cytotoxic currently used in patients. Second, we showed that Dbait, a DNA repair inhibitor, may be an effective additional treatment for increasing the efficacy of chemotherapy in colon or rectal cancer, independently of KRAS status. 2)Mice xenografted with human tumor cell lines with sequential cellular and molecular studies. We demonstrated that the specific effect of sunitinib, mainly a VEGFR inhibitor, differs according to the tumor type. This effect was first identified on neoangiogenic microvessels, but a direct effect on tumor cells was also found and related to sunitinib target expression
Ruellan, Anne-Lise. „Ciblage du syndecan-1 dans un modèle de xénogreffe de carcinome mammaire en radioimmunothérapie alpha et bêta“. Nantes, 2009. https://archive.bu.univ-nantes.fr/pollux/show/show?id=831fcdb6-7ee2-42c1-b1a0-650f5021b5c5.
Der volle Inhalt der QuelleRadioimmunotherapy has for principle to target the surface of cancer cells to destroy them. In most of the cases, the used vectors are spécific antibodies of tumoral antigens. The use of radionucleids presenting different physical characteristics allow to adapt the treatment to every type of tumors. So, bêta particles (β), of weak energy, possess a long scope and are adapted to the irradiation of bulky tumors. On the other hand, the alpha particles, very energetic, of wich is limited, would be better suited for the treatment of isolated cells or micrometastasis. In this frame, we developped a murin model of breast cancer to estimate the relevance particles, in this pathology, by targeting syndecan-1 (CD138) associated with Iodine 131. This antigen is over express on multiple myeloma cells and on several carcinomas including breast, prostate, colon, renal cell and hepatocellular carcinoma. In breast carcinomas the over expression of syndecan-I correlates with poor prognosis and an aggressive phenotype. We showed the efficiency of the targeting syndecan-1 in radioimmunotherapy β, with a regression of the tumoral volume. Besides, although the structure of solid tumor is little favorable to the treatment in RIT alpha, we showed that it was possible to obtain the regression of mammary tumor by this technique, using Bimuth 213, this independently of the specificity of the used antibody. This regression seems essentially due to the tumoral neo-vascularization targeting. We thus tried to validate this hypothesis or this model by targeting specifically the tumoral neo-vessels in RIT alpha
Capito, Carmen. „Développement du pancréas humain embryonnaire ex vivo / in vivo : La greffe musculaire : un nouveau modèle d'étude longitudinale et dynamique“. Phd thesis, Université René Descartes - Paris V, 2013. http://tel.archives-ouvertes.fr/tel-00862466.
Der volle Inhalt der QuelleBenomar, Abdeljalil. „Interactions macrophages - cellules tumorales : analyse dans un modèle de xénogreffe de lignées cellulaires de mélanomes humains chez la souris Nude“. Lyon 1, 1985. http://www.theses.fr/1985LYO1W033.
Der volle Inhalt der QuelleCoutier, Stéphanie. „Effet de l'irradiance sur la déplétion photochimique en oxygène après photosensibilisation de sphéroï͏̈des et de xénogreffes tumorales par la méta-tétra(hydroxyphényl)chlorine : activation par photosensibilisation de monocytes différenciés en macrophages“. Nancy 1, 2001. http://www.theses.fr/2001NAN11316.
Der volle Inhalt der QuelleThiollier, Clarisse. „Modélisation et caractérisation des leucémies aiguës mégacaryoblastiques pédiatriques“. Paris 7, 2013. http://www.theses.fr/2013PA077126.
Der volle Inhalt der QuelleAcute megakaryoblastic leukemia (AMKL) is a heterogeneous subtype of acute myeloid leukemia, more frequent in children and associated with a poor prognosis. Until recently, two distinct subgroups have been characterized in pediatric AMKL: 1-children with Down syndrome that acquire GATAI mutation in virtually ail cases and 2-children with a translocation t(l;22)(pl3;q!3), that leads to the expression of the oncogenic OTT-MAL fusion protein. I have developed xenotransplantation models of human AMKL cells in immunodeficient mice and have obtained murine models of human AMKL. High throughput sequencing of RNA from leukemic cells allowed to identify a third subgroup defined by a new ETO2-GLIS2 fusion resulting from an inversion of chromosome 16 and present in 31% of non-Down syndrome paediatric AMKL. The ETO2 transcription factor is expressed during normal haematopoiesis and controls the expression of genes implicated in terminal megakaryocytic differentiation. GLIS2 is similar to GLI factors controlling the response to Hedgehog pathway activation and is not expressed during normal haematopoiesis. The high expression of Hedgehog pathway target genes in patients with the ETO2-GLIS2 fusion in comparison to other patients suggests that aberrant activation of Hedgehog pathway is involved in leukemic transformation. A fourth subgroup is defîned by an HOX genes transcriptional signature sometimes associated with MLL-AF9 and NUP9§-KDM5a fusions. Finally, we have used these models to show the efficacy of Aurora A kinase inhibitors to inhibit the proliferation of patient cells in vivo that suggests the interest of these molecules as new therapeutic strategy
Mazzola, Clarisse. „Réalisation d'un modèle de xénogreffe rénale utilisant des embryons de poule permettant d'analyser en amont la sensibilité des cellules tumorales de chaque patient ayant un cancer du rein métastatique aux différents agents de thérapie ciblée“. Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS471.
Der volle Inhalt der QuelleObjective: Approximately 30% of patients with metastatic renal cancer are resistant to targeted therapy agents. The other patients will eventually develop long-term therapeutic resistances. An improvement in the clinician's ability to predict therapeutic response before treatment initiation could improve patients' prognosis. The aim of our projet was to develop a patient-derived xenograft models to be able to test the sensibility of each patient's renal tumor cells to the different available targeted therapy agent prior to treatment.Methods: The chicken embryo chorioallantoic membrane has been the base of our model. In a first phase of our work, a xenograft of human kidney tumor cells has been carried out in order to verify that the histologic and phenotypic characteristics of the original tumors were preserved in the xenografts performed on our model. As a second step, fragments of the kidney tumor speciments of 5 patients undergoing cytoreductive nephrectomy in our hospital center were grafted on our model (> 60/patient). Different targeted therapy agents were tested on the xenografts we performed.Results: The histopathologic and phenotypic characteristics of the original renal tumors were preserved in our xenografts. There was intra-tumor spatial heterogeneity in terms of sensitivity in different targeted therapy agents. There was also a nucleotide polymorphism within the different regions of each renal tumor.Conclusion: This patient-derived renal xenograft model could be useful prior to treatment for the evaluation of each patients'renal tumor cells to the different available targeted therapy agents. This model could make it possible to personalize the treatment of each metastatic kidney cancer patient, prior to systemic treatment. A prospective evaluation of our model could help assess the potential clinical benefits of its use
Van, Zoggel Johanna. „Dermaseptine B2 : un peptide antimicrobien issue des sécrétions de peau de Phyllomedusa bicolore avec des activités antitumorales et angiostatiques“. Thesis, Paris Est, 2010. http://www.theses.fr/2010PEST0051.
Der volle Inhalt der QuelleThe skin secretions of neotropical and South American frogs contains large amounts of a widerange of biological active molecules. Commonly studied are peptides with antimicrobialactivities. In this study we have postulated that the skin secretions from the South Americanfrog Phyllomedusa bicolor contain molecules with antitumor and angiostatic activities. Twowell known cationic alpha helical antimicrobial peptides of the dermaseptin (Drs) family wereidentified to have these activities: Drs B2 and Drs B3. Both peptides inhibited proliferationand colony formation of various tumor cell lines, and the proliferation and capillary formationof endothelial cell in vitro. Furthermore, Drs B2 inhibited tumor growth in a PC3 xenograftmodel in vivo.Research on the mechanism of action of Drs B2 on tumor cells PC3 demonstrated a rapidincreasing amount of cytosolic LDH, no activation of caspase-3, -9 or -8, and no changes inmitochondrial membrane potential. These data together indicate that Drs B2 does not act byapoptosis but possibly could fix to the tumor cell surface, disrupt the cellular plasmamembrane leading to its death by necrosis.In conclusion, Drs B2 could be an new interesting and promising pharmacological leadermolecule for the treatment of cancer. Its antitumor and angiostatic activities, especially itsselective targeting of tumoral cells with micro molar concentrations propose Drs B2 as anpotential candidate for the development of a new efficient targeting therapy against cancer
Mouawad, François. „Evaluation de combinaisons thérapeutiques ciblées en cancérologie des voies aérodigestives supérieures. Mise au point d’un modèle tumoral in vivo“. Thesis, Lille 2, 2014. http://www.theses.fr/2014LIL2S028/document.
Der volle Inhalt der QuelleHead and Neck Squamous Cell Carcinoma (HNSCC) is the sixth most common cancer worldwide. The treatment of advanced stages HNSCC is based on surgical treatment combined with radiotherapy and chemotherapy or concomitant chemo-radiotherapy. However, the 5-year survival remains poor for advanced stages HNSCC and the development of new targeted therapies is eagerly awaited. F14512 combines an epipodophyllotoxin core-targeting topoisomerase II with a spermine moiety introduced as a cell delivery vector. This spermine moiety facilitates selective uptake by tumor cells via the Polyamine Transport System (PTS) and reinforces topoisomerase II poisoning. Here we report the evaluation of F14512 toward HNSCC.Four cell lines representative of head and neck cancer localizations were used: Fadu (pharynx), SQ20B (larynx), CAL33 and CAL27 (base of the tongue). PTS activity and specificity were evaluated by confocal microscopy and flow cytometry using the fluorescent probe F17073 which contains the same spermine moiety as F14512. Cytotoxicity, alone or in association with standard chemotherapeutic agents (cisplatin, 5FU), and radio-sensitizing effects were investigated using MTS and clonogenic assays, respectively. F14512 efficiency and PTS activity were also measured under hypoxic conditions (1% O2).In all 4 tested HNSCC lines, an active PTS was evidenced providing a specific and rapid transfer of spermine-coupled compounds into cell nuclei. Interestingly, F14512 presents a 1.6 to 11 fold higher cytotoxic effect than the reference compound etoposide (lacking the spermine chain). It appears also more cytotoxic than 5FU and cisplatin in all cell lines. Competition experiments with spermine confirmed the essential role of the PTS in the cell uptake and cytotoxicity of F14512. Hypoxia had almost no impact on the drug cytotoxicity. The combination of F14512 with cisplatin, but not 5FU, was found to be synergistic and, for the first time, we demonstrated the significant radio-sensitizing potential of F14512. The spermine moiety of F14512 confers a targeted effect and a much better efficacy than etoposide in HNSCC lines. The synergistic effect observed in association with cisplatin and radiotherapy augurs well for the potential development of F14512 in HNSCC
Bordignon, Benoît. „Cibles thérapeutiques d'analogues de l'acide ascorbique“. Thesis, Aix-Marseille, 2013. http://www.theses.fr/2013AIXM5042.
Der volle Inhalt der QuelleAscorbic acid (AA) was long described as an antiproliferative agent. However, the molecule has to be used at very high concentrations, which necessitates intravenous injections. In addition, the tight regulation of in-blood and in-cell AA concentrations makes it impossible to hold very high concentrations for any substantial length of time.In collaboration with KaironKem, we undertook the creation of a focused chemical library of AA derivatives. The aim of this work was therefore to identify derivatives molecules with antiproliferative action higher than AA. Among these new molecules, we selected K873 that has cytotoxic and antiproliferative effects on different human tumor cells at tenth micromolar concentration, without being toxic for normal cells. We then tested in vivo the effect of treatment with K873's daily injections in xenografted immunodeficient mice with human cancer cells. K873 showed an antiproliferative effect on tumor growth similar to AA but at doses 100 to 200 times lower.Finally we studied the mechanism of action of K873. As AA, it decreases the expression of two genes families involved in cell cycle progression, i.e. initiation factor of translation and tRNA synthetases. Our results also showed that the specific intracellular transporter of AA (SVCT2) is not used for K873 entry in cells, thus bypassing saturation. Finally, as AA, K873 reduced cAMP intracellular level but without antioxidant activity. Our findings suggest that AA derivatives could be a promising new class of anti-cancer drugs
Poncet, Gilles. „Étude de la progression tumorale dans les tumeurs endocrines digestives : intérêt des modèles animaux de xénogreffe“. Lyon 1, 2008. http://www.theses.fr/2008LYO10195.
Der volle Inhalt der QuelleDigestive endocrine tumors are a rare and heterogeneous group of human tumors, and this is a major limitation for their study. In addition, many aspects of tumoral evolution, including molecular and cellular determinants are poorly understood at the present time. The aim of our experimental approach was to develop an animal model of digestive endocrine tumor, using heterotopic xenografts, reproducing all the different steps of tumoral progression: local invasion and metastatic dissemination. In particular, this model was used for the study of angiogenesis during the natural history of this specific kind of highly vascularized tumors. Recalling its human counterpart, our model is of great relevance for the identification of new diagnostic or prognostic markers, together with the development of new therapeutic approaches
Jego, Chloé. „Le rôle des cellules souches mésenchymateuses médullaires dans la leucémie myélomonocytaire chronique“. Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS377/document.
Der volle Inhalt der QuelleChronic myelomonocytic leukemia (CMML, is a rare myeloid hemopathy of the elderly. Clinical, genetic and molecular characteristics of the disease are well-known. The highly heterogeneous expression of the disease can’t be solely explained by genetic heterogeneity of the leukemic clone. Epigenetic alterations obviously play an important role. However, the role of extrinsic factors from the medullar microenvironment in CMML physiopathology is still poorly understood. The hematopoietic niche hosts a lot of bi-directionnal interactions between cells. Two non-exclusive schemes of primary and secondary alterations of the niche can be proposed. First postulate implies that the emergence of a hematopoietic clone alters its environment. The second one supposes that the first event causing the emergence of a clonal hemopathy is an alteration of the environment. My PhD work consisted of studying medullar alterations in patients and their impact on CMML physiopathology upon 2 axes: 1) to set up a murine model of human hematopoietic niche reconstitution 2) to caracterise mesenchymal stem cells from CMML patient ex vivo. During the first part of my PhD, I adapted a model published in 2016 to CMML. This model of human MSC graft in immunodeficient mice proved to be hardly reproducible. During the second part, I analysed of CMML patients MSC. I identified an excessive production of IGFBP2 (Insuline-like Growth Factor Binding Protein 2) probably secondary to an epigenetic disregulation. Single cell RNA sequencing revealed a restriction of MSC heterogeneity of which only a fraction produces IGFBP2. Finally, I showed that IGFBP2 favors myeloid progenitors differenciation towards monocytic lineage. IGFBP2 could therefore contribute to the amplification of CMML characteristic monocytosis.To conclude, CMML goes along with modifications of hematopoietic niche cells, some of which produce excessive amounts of IGFBP2. Investigation on the origin of this alteration and its significance in disease progression should allow to evaluate the potential interest of its neutralization for therapeutic strategies
Taillandier, Luc. „Un modèle de xénogreffes de gliomes humains et son utilisation en recherches pré-cliniques biologique et thérapeutique“. Nancy 1, 2003. http://www.theses.fr/2003NAN11309.
Der volle Inhalt der QuelleCoussy, Florence. „Identification de nouvelles thérapeutiques ciblées dans le cancer du sein à l’aide d’un large panel de tumeurs humaines xénogreffées“. Thesis, Université Paris-Saclay (ComUE), 2019. http://www.theses.fr/2019SACLS560.
Der volle Inhalt der QuelleTriple negative breast cancer (TNBC) accounts for 10-15% of breast cancers. Its prognosis is worse, particularly due to the rarity of targeted therapies adapted to this subtype. Its complexity of management is directly related to its high heterogeneity, both at the morphological and genomical levels.In this context, we developed Patient Derived Xenograft (PDX) models from TNBC. This robust model has the specificity of retaining the characteristics (histological, genotypic but also phenotypic) of the tumors observed in patients.In our cohort of 61 PDXs of TNBC, we confirmed the anatomopathological and genomical heterogeneity of this subtype. Majority of targeted alterations are of low frequency (<10%) but 88% of our models harbour a potential targetable alteration and more than half have at least 2 targetable alterations. We were particularly interested in 2 subtypes of TNBC: (i) the LAR subtype for which we have described the first PDX models: these models present frequent alterations of the PI3K pathway as well as major responses to PI3K inhibitors; (ii) the metaplastic subtype, of which 4 of our 9 models show double alterations in the PI3K and RTK-MAPK pathways and complete and durable responses to the combination of PI3K-MAPK inhibitors.In the other CSTN subtypes, we have also demonstrated significant response rates to PI3K and MAPK inhibitors. Biomarkers of response to these various targeted therapies tested are being studied, in particular by integrating the genomic and protein data from a higher number of PDX models
Vallerand, David. „Etude du stroma de tumeurs mammaires humaines xénogreffées et de modèles transgéniques murins“. Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T001.
Der volle Inhalt der QuelleTumor development is a multi-step process influencing by interactions between tumor cells and surrounding stroma. Breast cancer development involves a high level of communication between mammary epithelial cells, inflammatory cells, myofibroblasts and endothelial cells. So, the tumoral microenvironment appears as a prime target for anti-tumoral treatment. The use of preclinical models is a critical step in development and validation processes of new therapies. Nevertheless, the role of stroma in these models is poorly understood.In order to evaluate stromal cell populations in breast cancer preclinical models, we combined flow cytometry analysis and immunohistochemistry to identify, and then quantify, various stromal populations as hematopoietic cells (lymphocytes, monocytes/macrophages, polymorphonuclear leukocytes) and non-hematopoietic cells (myofibroblasts, endothelial cells). Twenty-one breast cancer patient-derived xenografts as well as 2 transgenic mouse models (MMTV-PyMT and MMTV-ErbB2), and their respective allografts, were studied.Analysis of human and murine tumors showed a strong heterogeneity between tumors regarding infiltrating stroma-cells, with a high proportion of macrophages. A significant amount of polymorphonuclear leukocytes was also detected in PDXs, indicating a local inflammation in these models. The phenotypic analysis of macrophages showed a variable expression of M1 and M2 markers in PDXs. Macrophages infiltrating transgenic mouse tumors, spontaneous or allografted, were mainly M1. Transcriptomic analyses of sorted macrophages, allowed us to validate previous results but also highlighted major differences in the expression of numerous genes implicated in various pathways as tumor growth, invasion and metastasis.Finally, this study highlighted the impact of tumor cells on their surrounding stroma. Indeed, we demonstrate that cancer cells are able to attract a specific panel of stromal cells and activate them in a specific way
M'Rabet, Manel. „Identification d'un nouveau biomarqueur, facteur pronostic et cible dans le cancer du sein triple négatif & développement préclinique d'une thérapie ciblée sur l'utilisation d'anticorps monoclonaux conjugués“. Thesis, Aix-Marseille, 2017. http://www.theses.fr/2017AIXM0204.
Der volle Inhalt der QuelleNectin-4 has been identified as a breast and ovarian biomarker at CRCM. Nectin-4 is a celladhesion molecule belonging to the immunoglobulin superfamily and is involved in ectodermaldevelopment in human. Nectin-4 has been recently identified as the epithelial receptor for themeasles virus. Together, this work has been rewarded by Inserm in 2012 (Prix del’Innovation). During my thesis, I have characterized nectin-4 as new prognosis biomarker andtherapeutic target in 63% of triple-negatif breast cancer (TNBC) . TNBCs represent 20% ofbreast cancer and are associated with poor prognosis as there is no exisiting targeted therapy.These results open the possibility for Antibody Drug Conjugate (ADC)-based targetedtreatment of primary and advanced TNBCs similar to trastuzumab-emtansine for HER2-positive breast cancers. We selected and validated a monoclonal antibody against nectin-4ectodomain and developed an ADC conjugated to monomethyl auristatin-E (MMAE). Weassessed the therapeutic efficiency of this ADC in vitro and in vivo in localised and metastaticTNBC Patient derived Xenografts (PDXs). In vivo, this ADC induced rapid, complete anddurable responses on nectin-4-positive xenograft TNBC samples including primary tumours,metastatic lesions, and local relapses. This antibody has been humanized, patented and iscurrently under clinical development by a pharmaceutical company testing toxicity and efficacyin cynomolgus monkeys
Potiron, Nicolas. „Xénogreffe d'îlots de Langerhans dans le diabète non autoimmun : intérêt du transfert de gène de molécules immunosuppressives dans les modèles porc/rat et rat/souris“. Nantes, 2002. http://www.theses.fr/2002NANT10VS.
Der volle Inhalt der QuelleFor diabetic patients, islet transplantation is a more physiological approach compared to insulin injections, however, despite its efficiency, widespread use is limited by donor shortage and immunosuppression related side effects. The use of pig islet xenografts would solve this problem. Futhermore, the possibility of in-vitro manipulation during islet purification makes it an interesting model for graft genetic engineering by adenoviral vectors for recombinant immunosuppressive molecules. Despite the use of immunosuppressive regimens, we were unable to evaluate this strategy via the pig-to-rat model due to the lack of graft finction. In the rat-to-mous e model, the inhibition of costimulatory signals (CTLA4Ig,CD40Ig) efficiently delayed rejection by systemic vector expression but not by islet transduction, although did not result in tolerance
Labussière, Marianne. „Impact du fractionnement du traitement sur les propriétés radiosensibilisantes du bortézomib sur deux modèles de gliome malin humain xénogreffés“. Thesis, Nancy 1, 2008. http://www.theses.fr/2008NAN10132/document.
Der volle Inhalt der QuelleMalignant gliomas are the most common neoplasm of the central nervous system and patients prognosis remains dismal, despite aggressive surgery, radio- and chemotherapy. Radiotherapy is a major treatment modality in this tumoral type but its usefulness is limited by normal brain tissue toxicity. The concomitant administration of a radiosensitizing agent is an innovative strategy to improve ionizing radiations efficacy. Bortezomib (Velcade®) belongs to a new class of anticancer agents, i.e. the proteasome inhibitors, and this molecule has been approved for the treatment of multiple myeloma. Our objectives are to study the radiosensitizing properties of bortezomib on two human malignant glioma models xenografted onto nude mice. Our work was designed to evaluate the impact of treatment fractionation on the antitumor activity of the concomitant association of bortezomib and radiotherapy. Our results show that bortezomib is a potent radiosensitizer on our two malignant glioma models but these properties are lost when treatments are fractionated according to a typical clinical schedule. In conditions of fractionated treatment, we demonstrate that bortezomib reduces the radio-induced apoptosis. This may be linked to the loss of the inhibitory properties of bortezomib secondary to consecutive infusions. We also evaluate the importance of the transcription factor NF-?B in the radioresponse of the malignant glioma xenografts used. Finally, our work emphasizes on the importance of performing preclinical studies using doses and therapeutic schedule mimicking the clinical settings to provide more predictive results of treatment response in Humans
Joalland, Noémie. „Immunothérapie anti-tumorale par transfert adoptif de LT Vγ9Vδ2 : utilisation préclinique de LT Vγ9Vδ2 humains allogéniques en immunothérapie anti-tumorale dans des modèles murins de xénogreffes orthotopiques“. Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1031/document.
Der volle Inhalt der QuelleCancer is a pathology characterized by uncontrolled proliferation of tumor cells. Despite many technological advances in terms of screening, medical imaging, surgery and treatments, cancer is still a therapeutic challenge. In recent years, development of immunotherapies, such as adoptive cell transfer, has been the aim of many studies. Vγ9Vδ2 T lymphocytes are interesting immune effectors because of their numerous effector functions and their nonalloreactivity. In fact, their targets recognition is not restricted to the major histocompatibility complex, so it is possible to create allogeneic Vγ9Vδ2 T cell banks that could be used to treat patients without risk of allogeneic reaction against the host. Moreover, this recognition can be induced by pharmacological molecules such as zoledronate. The aim of this thesis was to evaluate the therapeutically efficacy of allogeneic human Vγ9Vδ2 T lymphocytes in preclinical mouse models of orthotopic xenografts. Two models have been developed: (i) a model of epithelial ovarian cancer including standard treatment of patients by surgery and chemotherapy, followed by relapse with peritoneal carcinosis ; (ii) a model of glioblastoma multiforme based on intracranial injection of primary tumor cells. Thus, the therapeutically efficacy of adoptive transfer of allogeneic human Vγ9Vδ2 T lymphocytes, whether or not associated with zoledronate, has been demonstrated in several preclinical models, paving the way for clinical transfer
Berrabah, Sofia. „Etude de nouvelles cibles thérapeutiques dans les lymphomes compliquant la maladie cœliaque“. Electronic Thesis or Diss., Université Paris Cité, 2021. http://www.theses.fr/2021UNIP5201.
Der volle Inhalt der QuelleRefractory coeliac disease type II (RCDII), also called intraepithelial lymphoma, is a rare but severe complication of coeliac disease characterized by the clonal expansion of a small subset of innate intraepithelial lymphocytes (IEL), present in the normal human and murine intestine. Our lab has shown that this population displays shared features between T and natural killer (NK) cells. These so-called iCD3+ innate IEL are mainly characterized by intracellular expression of CD3, which is not detected at the cell surface, expression of NK receptors as well as DNA rearrangement of T cell receptor genes. Our lab has also shown that iCD3+ innate IEL originate from bone marrow precursors through coordinated NOTCH1 and interleukin (IL)-15 signals. During lymphomagenesis, iCD3+ innate IEL of most RCDII patients were shown to have acquired somatic gain-of-function mutations in JAK1 and/or STAT3 that confer increased sensitivity to interleukin-15, a cytokine overexpressed in the intestine of coeliac patients, thereby promoting their clonal expansion. Thus, our hypothesis is that JAK1/STAT3 mutations play a key role in initiating lymphomagenesis associated to coeliac disease in an IL-15-rich environment and that they could represent an attractive therapeutic target.The first objective of my thesis was to study the interest of JAK/STAT inhibitors for RCDII treatment. First, we have tested in vitro different JAK/STAT inhibitors on IL-15-dependent RCDII or normal IEL-T cell lines. We have shown that these inhibitors decrease the proliferation and phosphorylation of STAT3 and increase cellular apoptosis in both RCDII and normal T cell lines. Secondly, we have established a xenograft model based on the injection of cells derived from biopsy or blood from one RCDII patient into immunodeficient mice overexpressing the human IL-15 transgene in their gut epithelium (Rag-/-Gc-/- IL-15TgE; IRGC) to test the efficacy of JAK/STAT inhibitors in vivo. Treatment of xenografted mice with ruxolitinib, a potent inhibitor of JAK1/JAK2 decreased the frequency, number and cytotoxic potential of human tumoral cells and allowed clinical restoration. These preliminary results are encouraging but need to be confirmed. The second objective of my thesis was to test whether the Stat3 pD661V mutation is sufficient to induce the intraepithelial lymphoma in an IL-15-rich context in IRGC mice. We have successfully generated murine iCD3+ innate IEL in vitro, resembling their human counterparts from common lymphoid precursors by combining NOTCH and IL-15 signals. We then transduced CLP with a retroviral vector containing wild-type or mutated Stat3 pD661V. The transduced cells were injected into IRGC mice that subsequently were followed-up during a period of 8 weeks. In vitro generated iCD3+ innate IEL preferentially homed to the intestine. However, no development of intraepithelial lymphoma was observed suggesting that the Stat3 pD661V variant alone is not sufficient to induce the intraepithelial lymphoma. These preliminary results need to be reproduced and confirmed. The murine model used to test the role of STAT3 will now be used to evaluate the respective contribution of canonical mutations in JAK1 and STAT3 and of other recurrent mutations identified in RCDII
Devaud, Christel. „Etude in vivo du potentiel anti-tumoral des lymphocytes Tγδ Vδ2 négatifs humains dans un modèle murin“. Thesis, Bordeaux 2, 2009. http://www.theses.fr/2009BOR21684/document.
Der volle Inhalt der QuelleGamma delta (?d) T lymphocytes contribute to host immune competence uniquely especially during stress immune responses to infections and tumors. Because ?d T cells colonize epithelial surfaces, where they can exert rapid and pleiotropic effector functions, they are critical protagonists in anti-cancer response. During my Phd project we explored the anti-tumor potential of Vd2 negatives (neg) ?d T lymphocytes, in vivo using a mouse xenograft tumor model. A few years ago, studies in our laboratory showed an increase of peripheral blood Vd2neg ?d T lymphocytes in allograft recipients infected by cytomegalovirus (CMV). Interestingly, Vd2neg ?d T clones isolated from these patients showed a cytotoxic activity against CMV infected fibroblast in vitro. Moreover, they were able to kill colon cancer cells (HT29) in vitro, in contrast to normal epithelial cells. Cancer cell- as well as CMV infected cell- killing involved T cell receptor (TCR) engagement, independently of major histocompatibility complex (CMH) recognition, probably with a common ligand. The first part of my Phd project was undertaken to evaluate the in vivo tumor reactivity of anti-CMV Vd2neg clones, including their ability to inhibit tumor growth as well as their migratory potential toward colon cancer cells. In immunodeficient mice, we showed that systemic intraperitoneal (i.p) injections with human Vd2neg clones inhibited the growth of HT29 hypodermal tumors xenografts. Furthermore, our results demonstrated that Vd2neg T cells had an early and specific anti-tumor effect, and that such activity could be hampered in vivo using an anti-CCR3 antibody. Our study suggest that Vd2neg T cells with an anti-viral potential are able to reach a tumor site in vivo, and inhibit tumoral growth exercising a cytolytic activity. The second part of my Phd project proposed to get further insights on the role of Vd2neg T cells in the immune surveillance against colon cancer. To this aim, we tested, the involvement of human Vd1+ T lymphocytes, a substantial fraction of T cells in intestinal epithelia, in limiting tumor spread in vivo, using a mouse model of colorectal carcinoma (CRC). We sat up a physiological mouse model of CRC by orthotopic microinjection of HT29 colon cell, which mimics the natural history of human CRC. Indeed, primary colic tumors and pulmonary and hepatic distant metastases grew in mice. Furthermore, bioluminescence imaging was used to follow the outcome of luciferase expressing cancer cells. We showed that systemic treatment with human Vd1+ T lymphocytes could inhibit the growth of intracaecal HT29 tumors and led a substantial reduction of distant metastases. Our results are the first arguing for a crucial role of ?d T cells against CRC, specially in preventing the dissemination of colon cancer cells. Taken together, our results underline the role of of ?d T cells in theimmune response against colorectal cancer. Our findings put forward Vd2neg T cells as attractive candidates for novel anti-tumor immunotherapy protocols
Duconseil, Pauline. „Le décryptage omique de l'hétérogénéité de l'adénocarcinome pancréatique : de la paillasse au lit du patient“. Thesis, Aix-Marseille, 2018. http://www.theses.fr/2018AIXM0108/document.
Der volle Inhalt der QuelleHeterogeneity of Pancreatic Ductal AdenoCarcinoma (PDAC) has become the majorimpediment to the effective treatment of patients. Clinical outcome and sensitivity to treatments are associated with a given phenotype and associated at a transcriptomic level. Recent data indicate that studying the expressionof a selected gene set could inform selection of the most appropriate treatments.We areoptimizing this approach by analysing transcriptome of Patient-Derived Xenografts (PDX)from surgical as well as endoscopic ultrasound-guided fine needle aspiration (EUS-FNA)biopsies of tumors, as a source of RNA. We have found a molecularsignature capable of dividing patients into two groups, function of theirsurvival.Independently, we have shown that treatment response pattern can also be foundat a transcriptomic level. We thenanalysed tumors and their stromas, and have found two sub-types of stromas and two sub-types of tumors. These wereindinstinctly defined by RNAseq-based transcriptomics, or DNA methylation. We also studied response to treatments administered alone or incombination to routine chemotherapies. All these results are encouraging, but not yetapplicable in clinical pratice. We are now developing the PDAC Biopsy DerivedPancreatic Cancer Organoids (BDPCO): BDPCO culture represents an excellent source of “exvivo” material. Unlike PDX, which take many months to grow, BDPCO allow us to obtainexploitable material rapidly useful for clinical application. We are convinced that in the near future, the treatment ofpancreatic cancers will be preceded by an extensive molecular characterization of cancercells in order to select the most appropriate treatments
Walter, Thomas. „Métastases hépatiques de tumeurs endocrines digestives : développement de modèles animaux pour l’étude des mécanismes biologiques et l’évaluation préclinique des thérapeutiques“. Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10241.
Der volle Inhalt der QuelleLiver metastases of digestive endocrine tumors are hypervascular and heterogeneous. The mechanisms of development of these metastases, especially the role of angiogenesis, are complex. This explains the difficulty to predict the natural history of these tumors and to find predictive factors of response to medical treatments. Our aim was to evaluate: the role of angiogenesis in the development of liver metastasis from digestive endocrine tumors; mechanisms of action, especially antiangiogenic activity, of two drugs (somatostatin analogues and mTOR inhibitor). We were able to demonstrate through an in vitro and in vivo experimental approach that: (a) the regulation of VEGF synthesis and secretion is complex, with different roles according to the cell studied; (b) there is a dissociation between VEGF expression and angiogenic capacities, on one hand, and invasive and metastatic properties, on the other hand; (c) the inhibition of angiogenesis may contribute to the anti-tumoral effect of several drugs of therapeutic interest in digestive endocrine tumors
Verhoest, Grégory. „Développement et mise au point de modèles murins de xénogreffe de carcinome rénal à cellules claires, et évaluation de la réponse de l'association d'un antagoniste des récepteurs à l'angiotensine-II au sunitinib“. Phd thesis, Université Rennes 1, 2014. http://tel.archives-ouvertes.fr/tel-01057292.
Der volle Inhalt der QuelleVerhoest, Grégory. „Développement et mise au point de modèles murins de xénogreffe de carcinome rénal à cellules claires, et évaluation de la réponse de l’association d’un antagoniste des récepteurs à l’angiotensine-II au sunitinib“. Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1B005/document.
Der volle Inhalt der QuelleBackground: Clear cell renal cell carcinoma (ccRCC) are agressive tumors, with a bad prognosis when metastatic. Antiangiogenic treatments and especially tyrosine kinase inhibitors (TKI) have increasingly improve patients’ survival, but those drugs often present side effects like hypertension. Angiotensin-II stimulates tumor cell development and VEGF secretion via the type-1 receptor. In different types of cancer, angiotensin-II type 1 receptor antagonists (ARA-2) used as antihypertensive drugs can reduce tumor cell proliferation and inhibit neoangiogenesis. Objective: Develop different xenograft animal models of ccRCC, and test the efficacy of sunitinib (TKI) combined with telmisartan (ARA-2).Material & Methods: Nude mice have been injected sub-cutaneously with 786-O cells. Mice have been divied into 4 groups and received orally every day during 4 weeks: DMSO, telmisartan , sunitinib or the combination of sunitinib and telmisartan. Then animals were sacrified and their tumor was analyzed. In a second part using primary cell lines, a new mouse model was developed and tested.Results: In the first model, combined treatments (TKI+ARA-2) increased tumor necrosis, reduced microvascular density and circulant VEGF secretion. In the model developed with primary cell lines, there was a reduction in tumor growth but without increasing tumor necrosis. Conclusion: In this work, 2 different animal models of ccRCC have been developed. Sunitinib combined with telmisartan seems to potentiate anti-tumoral effects in these animal models. Further analyses are warranted to understand the different mechanisms implicated
Cottu, Paul-Henri. „Caractérisation moléculaire de la résistance à l’hormonothérapie et au ciblage de la voie PI3K/mTOR dans des modèles murins de cancers du sein luminaux“. Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS114/document.
Der volle Inhalt der QuelleLuminal breast cancer (ER+, HER2 negative) accounts for 65-75% of all breast carcinomas. Current guidelines strongly recommend endocrine treatment at both the early and advanced stages. However, more than 20% of early stage patients, and all advanced patients will eventually develop endocrine resistance.As most preclinical models (MCF7, T47D) do not recapitulate tumor biology, we have chosen to develop murine models derived from fresh tumors, hence called patient derived xenografts (PDX). We show that these models, although difficult to generate, faithfully exhibit the morphological and biological features of their parental counterpart, with high long term stability. These models have also been evaluated for their sensitivity to various endocrine treatments.In the next step, we developed from these initially endocrine sensitive models new tumors rendered resistant to endocrine therapies. We show that there is no unique biological pattern associated with endocrine resistance, although ER functional reprogramming appears to be critical. We also show that PI3K/mTOR pathway activation, may not be always related to endocrine resistance, and suggest that fulvestrant, an ER down regulator, may be highly synergistic with everolimus in specific cases.Several PI3KCA inhibitors are currently being evaluated in this setting
Colombo, Pierre-Emmanuel. „Nouveaux vecteurs polymères et modèles expérimentaux en vue de la délivrance intrapéritonéale prolongée d’agents anti tumoraux dans le traitement des cancers de l’ovaire“. Thesis, Montpellier 1, 2012. http://www.theses.fr/2012MON1T003.
Der volle Inhalt der QuelleOvarian carcinoma is the most lethal gynecologic malignancy. The aim of this PhD thesis was to develop new therapeutic approaches based on novel synthetic macromolecular drug delivery systems for intraperitoneal chemotherapy. These objectives were limited by the requirement of reliable tumor models for experimental studies. After a concise review of knowledge published in the literature, the potential interest of the establishment of a collection of tumor grafts derived from samples of human tumors is examined in a second chapter. Data show that the major phenotypic and genotypic features of the original tumors are maintained in the xenografts. They also confirm the importance of this tumor model to test new drugs and to analyze intratumoral heterogeneity and oligoclonality in primary ovarian carcinoma. The collection will be also helpful to study the mechanisms leading to disease recurrences and resistance to chemotherapies. An example of drug delivery system based on the different associations of a model chemotherapeutic drug (doxorubicin) with a bioresorbable macromolecular vector, namely poly(L-lysine citramide), is addressed in a third chapter. Direct amid linkage in the first conjugate was too stable with respect to antitumoral cytotoxicity desired after in vivo administration and different systems were generated subsequently to increase drug release in tumor deposits. The best results were obtained with a hydrazone cleavable spacer containing an ester group. To overcome the complexity of these conjugates, a novel strategy based on doxorubicin entrapment in a synthetic gelatin made of (poly(N-acryloyl glycinamide) is developed. This strategy should allow physical temporary entrapment of different drug molecules in a adhesive gel and could provide new solutions to the therapeutic challenges of intraperitoneal administration
Cikankowitz, Annabelle. „Evaluation de la radiothérapie vectorisée à l’aide de nanocapsules lipidiques chargées en rhénium-188 pour le traitement du glioblastome : investigation des modalités d’administrations locales“. Thesis, Angers, 2015. http://www.theses.fr/2015ANGE0057/document.
Der volle Inhalt der QuelleHigh grade glial brain tumors are defined as glioblastomas. Nowadays, they are incurable. The current therapeutic purposal (surgical resection, external radiotherapy and chemotherapy) doesn’t extend the patients median survival time up to a few months. Newstrategies as nanomedicines loaded with a radionuclide( or emitter) have been evaluated in clinical trials. As tate of the art of this domain’s technologies is described in a first part which analyses the important criteria to take account in vectorized radiotherapy like the radionuclides, the route of administration and the vectors used. Then, it is concluded with a presentation of preclinical on going studies as the use of nanovectors loaded with a radioisotope : the LNC188Re-SSS. The second part illustrates the therapeutical strategy application on a xenograft mice model. The data showan eradication of the tumor mass of treated mice withthe personalized convection-enhanced delivery offractionated radiotherapy. Furthermore, it describes the LNC distribution and the direct radiation effects on tumor cells (atypical giant cells, polyploïdy) supported by an inflammatory infiltration (innate immune effectors). An evaluation on the GL261 mice model has been realized and concerns the third part of this thesis. In perspectives, the transfer of these data to clinical trials could be facilitated thanks to the dog spontaneous glioma model. This tumor share characteristics with the human neoplasma. Finally, this work will aim to validate the automated intracranial injection procedures
Rouillé, Thomas. „Modèles d'étude pour l'évaluation préclinique de thérapies ciblées dans le nævus congénital mélanocytaire humain Clonogenic Cell Subpopulations Maintain Congenital Melanocytic Nevi Varying proliferative and clonogenic potential in NRAS-mutated congenital melanocytic nevi according to size“. Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS593.
Der volle Inhalt der QuelleCongenital melanocytic nevi (CMN) are benign cutaneous tumors resulting from melanocytic proliferation during fetal development. CMN of more than 20cm in diameter are associated with socio-aesthetic issues and an increased risk of malignant transformation into melanoma. Most lesions are characterized by a single mutation affecting the oncogene NRAS, which leads to the expression of a constitutively active protein. For patients harboring CMN, the only validated treatment is surgical resection, though they are often incomplete and do not prevent the risk of melanoma emergence. Our objective was to characterize the molecular pathways deregulated downstream of NRAS, and to validate in vitro as well as in two innovative preclinical models of CMN (ex vivo CMN explants and xenografts on immunocompromised mice Rag2-/-) the effects of inhibitory molecules of those pathways. Fourteen patients harboring NRAS mutated CMN were prospectively included in our study. Our in vitro experiments reveal an overactivation of MAPK and PI3K-AKT signaling pathways in CMN cells. In vitro, MEK and AKT inhibitors (respectively Binimetinib and GSK690693) induce a decrease of proliferation and survival. Ex vivo and in vivo, inhibitors induce a decrease in nevocytic cells Sox10+ and Melan-A+ as well as a decrease in proliferative cells Ki67+, especially when combined. The associated goal of our study is to develop an intra-tumoral therapy, to be used as an adjuvant or neo-adjuvant therapy, and adapted to the genetic profile of these tumors, in order to decrease tumor volume and avoid repeated and mutilating surgeries, and potentially decrease the risk of malignant transformation
Moustafa, Tarek Mohamed Mohamed. „Microencapsulation de cellules chromaffines bovines dans le traitement des douleurs chroniques rebelles : étude de faisabilité in vitro et in vivo“. Toulouse 3, 2007. http://thesesups.ups-tlse.fr/45/.
Der volle Inhalt der QuelleAdrenal medullary chromaffin cells secrete a combination of pain reducing neuroactive substances including catecholamine and opioid peptides that alleviate both acute and chronic pain not only in several animal models but also in some clinical applications. But, the xenografts can not maintain their survival in central nervous system for a long period without the implication of immunosuppressive drug. In this context, the concept of immune-isolation by cell encapsulation seems to have a great interest in the field of cell therapy in order to protect the transplant from the host’s immune system. In the present study, we report the viability and functionality of bovine chromaffin cells (BCC) encapsulated in microcapsules of alginate/poly-L-lysine/alginate (APA) with a liquefied inner core both in vitro and in vivo in rats. The microencapsulation of BCC not only allows the cells to keep their viability and functionality but also to retain their pharmacological integrity as indicated by expression of tyrosine hydroxlase, met-enkephalin and secretion of catecholamine. The in vivo study concerning the implantation of both microencapsulated chromaffin cells and empty microcapsule in the central nervous system of rats aimed to evaluate the cellular viability and functionality of microencapsulated cells and to determine the host reaction against the implanted microcapsules. This study showed that the microencapsulated cells maintain their viability and their functionality three weeks after implantation in sub-arachnoid space of rats. In addition, this study gave us an account very interesting concerning the absence of immunological response against the implanted microcapsules. This approach may offer a useful potential for cell transplantation in the management of many clinical problems including intractable pain and degenerative diseases. However, other investigations are still necessary before application of this strategy in human clinics
Chenau, Jérôme. „Le secretome, un modèle adapté à l'étude des protéines sécrétées par les tumeurs.Application à l'analyse du rôle joué par p53 sur la sécrétion de protéines par des cellules du cancer du poumon“. Phd thesis, 2009. http://tel.archives-ouvertes.fr/tel-00402098.
Der volle Inhalt der QuelleBrodeur, Melica. „Predictive carboplatin treatment response models for epithelial ovarian cancer : comparison of 2D, 3D and in-vivo models“. Thesis, 2021. http://hdl.handle.net/1866/25659.
Der volle Inhalt der QuelleEpithelial ovarian adenocarcinoma (EOC) is the most lethal gynecological cancer. The drug discovery pipeline is heavily based on preclinical models. Typically, 2D cell line (CL)-based models are used to screen compounds followed by validation in animal models to generate the evidence needed to design clinical trials. This process incurs a high cost to the research pipeline and still results in high drug attrition rates. This may in part reflect the poor translation of preclinical to clinical results and points to deficiencies in modeling. Previous work from our laboratory shows that the sensitivity of our EOC CLs to carboplatin therapy varies between 2D and 3D in vitro models, however it is unclear how these differences align with the in vivo response. We hypothesize that 3D models will more closely reflect therapeutic in vivo response. The objective of this study was to characterize the carboplatin sensitivity of EOC CLs in 2D and 3D-spheroids and compare them to in vivo response using mouse xenografts. We injected mice with 6 different EOC CLs that were treated with 3 different carboplatin concentrations. Tumor volume measurements and immunofluorescence viability stains were used to categorize CLs by their sensitivity. The same CLs were seeded in low attachment plates to form, and thereafter treat, spheroids. Flow cytometry analysis was used to classify CLs by their 50% inhibitory response (IC50). The 2D response (IC50) for these CLs has previously been published. Our results show that therapeutic response changes significantly for a single CL between different systems, and the 3D model was most concordant with the in vivo model. Our ultra-resistant CL in 2D became more sensitive in 3D/mouse models. In contrast, the highly 2D sensitive CL became more resistant in our xenograft/spheroid models. The results are important to consider when investing time/funds in drug screening and therapeutic response prediction studies.