Teses / dissertações sobre o tema "Microenvironnement tumoralal"
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Pavy, Allan. "Mécanismes cellulaires adaptatifs du microenvironnement tumoral exposé au plasma froid - Application au traitement du cholangiocarcinome". Electronic Thesis or Diss., Sorbonne université, 2024. http://www.theses.fr/2024SORUS267.
Texto completo da fonteCholangiocarcinoma (CCA) is a cancer with a poor prognosis and limited therapeutic options. Surgical resection is the only curative option available, but it is applicable to only a small number of patients and offers relatively low survival rates (5-year survival of 30%) due to the typically late diagnosis of this cancer. Palliative therapies, based on chemotherapy and immunotherapy, are generally ineffective, mainly because of the desmoplastic nature of CCA, which limits the entry of drugs into the tumor site. With an increasing incidence and accounting for 2% of global cancer mortality, it is crucial to develop new therapies, including local treatments targeting tumor cells and their microenvironment, for the treatment of this cancer. It is in this context that enthusiasm for the use of cold atmospheric plasma (CAP) in the treatment of CCA has emerged. Considered the fourth state of matter and generated by the partial ionization of a gas at low temperature, CAP has demonstrated promising antitumor effects in various preclinical cancer models over the past fifteen years. It is indeed capable of producing reactive oxygen and nitrogen species (RONS). A close collaboration between the Saint-Antoine Research Center (CRSA) and the Plasma Physics Laboratory (LPP) has highlighted significant antitumor effects in an immunodeficient murine model of CCA, as well as significant remodeling of the tumor stroma, a crucial element in tumor progression. Since then, a CAP device adapted for insertion into a duodenoscope has been developed, with the aim of enabling in situ treatment of CCA tumors via endoscopy in the future. The objective of this thesis was to explore the antitumor effects of this new plasma source on in vitro and in vivo models of CCA, distinguishing the direct effects of plasma on tumor cells from indirect effects on tumorigenesis, mediated by phenotypic modifications of stromal cells, including cancer-associated fibroblasts (CAFs) and tumor endothelial cells (TECs). After demonstrating the technical feasibility and biological applicability of this endoscopic source, it was observed that the oxidative stress induced by CAP altered the activation state and migratory phenotype of CAFs, while affecting the viability and angiogenic profile of TECs. The use of three-dimensional spheroid models also revealed immunogenic signatures triggered by cold plasma treatment. Indeed, it was proven in vivo, through prophylactic vaccination, that CAP could induce immunogenic cell death (ICD) of tumor cells, promoting the recruitment of immune cells to the tumor site. Preliminary results also showed that direct treatment of subcutaneous tumors slowed tumor growth while allowing the recruitment of antitumor immune cells. Finally, after elucidating the mechanisms of ICD in vitro, a new therapeutic approach combining CAP and vaccinations was proposed, demonstrating an antitumor effect accompanied by increased infiltration of immune cells. To make the use of CAP clinically accessible, tests on porcine models were conducted to verify the thermal and electrical safety of this endoscopic source, both for the patient and the clinician. Thus, CAP opens up promising new perspectives for the locoregional treatment of CCA, by modulating the immunogenicity of tumors and impacting their desmoplastic stroma
Leca, Julie. "Impact du dialogue entre microenvironnement intra-tumoral et cellules tumorales dans l'adénocarcinome pancréatique". Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4003.
Texto completo da fontePancreatic adenocarcinoma (PDA) is particularly resistant to current therapies. A concept suggests that its cellular composition participates in this process, limiting drugs access and affecting tumor cells behavior. Indeed, non-tumor cells, mainly mesenchymal (including Cancer Associated Fibroblasts, CAFs) and immune cells display over 70% of the tumor mass and form the intra-tumoral microenvironment or stroma. The impact of stroma in PDA development and progression is at the center of many clinical investigations. Firstly, we studied a neurogenic factor, Slit2, implicated in axon guidance pathway and secreted by CAFs. Slit2 increases Schawnn cells migration and morphologic changes of neural cells. Indeed, nerve size and density are increased in a tumor compared to a healthy pancreas, that is called, neural remodeling. Secondly, we worked on a multi-proteic complex (ANXA6/LRP1/TSP1), associated to vesicular trafficking, only expressed in stromal compartment, and mainly in CAFs. This complex is present in extracellular vesicles and confers proliferative and pro-migratory capacities to tumor cells. Data obtained during my thesis constitute an important rationale to target the crosstalk between tumor and stromal compartment, in order to sensitize tumor cells to chemotherapy and improve patient survival
Le, Nail Louis-Romée. "Caractérisation de cellules dérivées d'ostéosarcomes humains". Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1032/document.
Texto completo da fonteOsteosarcoma (OS) is the most frequent primitivemalignant bone tumor. We hypothesised that someMSC with cancer stem cell (CSC) characteristics maybe involved in OS development, chemotherapyresistance and metastatic progression.Adherent cells from six human OS samples wereisolated after tumor dissociation and culture. They werenamed OS derived cells (OSDC) and were compared toown patient bone marrow mesenchymal stem cells(BMMSC). We tested MSC characteristics, CSCcharacteristics, and tumor growth support capacities inan induced human OS mouse model.OSDC had the same morphologic aspect andmembrane expression profile as BMMSC. They keptdifferentiation capacities toward osteoblastic lineageand to less extend toward adipogenic and chondrogeniclineage, with variability between different OSDCpopulations. Karyotype was normal for all 6 BMMSCand for 4 OSDC. OSDC showed CSC characteristics,with sphere formations in semi solid conditions,decrease of mitochondrial metabolism in normoxiacondition. Some minimal karyotype abnormalities werefound in 2 OSDC populations. However, no tumorformation was induced in immunocompromised mice(SCID). In coinjection mouse model, 4 out of 6 OSDCincreased tumor growth compared to osteosarcomacells (MNNG-HOS) alone.OSDC that were isolated from human OS samples didnot demonstrate own tumor properties. They are highlysuspected to be part of tumor microenvironment, ratherthan the tumor origin, and to support and modulate thetumor growth. More studies are necessary to identifywhich CDOS factors influence tumor growth suggestingnew stromal targets for combined therapy
Yvonnet, Sarah. "Une approche épistémologique du microenvironnement tumoral". Thesis, Sorbonne université, 2021. http://www.theses.fr/2021SORUL163.
Texto completo da fonteCancer research has long been dominated by a genetic and molecular research approach of the disease. However, the accumulation of experimental data since 2000 also highlights the importance of another factor in carcinogenesis: the tumor microenvironment (TME). The study of the TME is accompanied by different assertions in the scientific literature: it would be an opportunity to improve therapies and enrich current knowledge or, on the contrary, it would be a new "paradigm" and would allow the development of new types of therapies.Our thesis proposes an analysis of the evolution of the field of oncology (and of the hypothesis of a potential scientific change) starting from the introduction of the study of the TME. We propose an original approach to this question by adopting two epistemological assumptions. First, we analyze both the scientific and medical communities. We study the continuum between fundamental research and clinical practice, articulating philosophy of biology and philosophy of medicine. Secondly, we conduct our philosophical analysis not only from a theoretical point of view but also as close as possible to the practices, behaviors, methods, and research organizations that participate in this scientific change. To do so, we will use methods rarely used in philosophy, such as semi-directive interviews or field observations.This approach aims to produce a philosophical analysis that contributes to both the philosophical and biomedical literature
Delorme, Solène. "Annexine A1 : dissémination et microenvironnement tumoral". Thesis, Université Clermont Auvergne (2017-2020), 2020. http://www.theses.fr/2020CLFAC042.
Texto completo da fonteAnnexine A1 (ANXA1) belongs to the annexin superfamily, which includes proteins capable of binding membrane phospholipids in a calcium dependent manner. This is a multifunctional protein initially described for its anti-inflammatory properties. ANXA1 can be nuclear, cytosolic, membrane and it can also be secreted and cleaved in surrounding environment. It presents a real interest in oncology due to its deregulation in many cancers. Depending on cancer types, ANXA1 is up- or down-regulated compared to normal tissues. It is overexpressed in triple negative breast cancer relative to other subtypes of breast tumors and in melanoma compared to melanocytes. In both pathologies, ANXA1 is associated with proliferation, migration and invasion processes, but the exact mechanism of its roles in tumors still unknown, especially those mediated by extracellular fraction. Studies carried out with Anxa1 null mice have shown the ANXA1 from stromal cells implication in tumor development and progression.The first objective of this work was to test the opportunity to block extracellular ANXA1 with a monoclonal patented antibody, VJ4B6, to decrease migration (in vitro) and dissemination (in vivo). Our results showed that VJ4B6 was unable to limit cellular migration of triple negative breast cancer (MDA-MB-231-luc) and melanoma (SK-MEL-28 and A375-MA2) cell lines presenting extracellular ANXA1. This antibody was also unable to decrease tumor development and dissemination of B16Bl6 melanoma in vivo. The second objective was to study the role of ANXA1 from tumoral and stromal cells in melanoma development and dissemination. Our results highlighted involvement of tumoral ANXA1 in proliferation of A375-MA2 and SK-MEL-28 melanoma cells in vitro. The use of Anxa1 null mice allowed to reveal that stromal ANXA1 promotes tumor development and metastases formation of murine B16Bl6 cells in vivo. Interestingly, studies of tumors showed that stromal ANXA1 absence limits both proliferation of tumor cells and angiogenesis. This could explain the decreased progression of tumors in Anxa1 null mice. Furthermore, tumors developed in these mice presented overexpression of lymphocyte markers (CD3, CD4, FoxP3, CD8a, NKp46) compared to those developed in wild-type mice. This lymphocyte influx concerned both pro- and anti-tumoral lymphocytes. Our hypothesis is that lymphocyte influx is a result of increased tumor vessels permeability in tumors from Anxa1 null mice
Castells, Magali. "Implication du microenvironnement dans la progression tumorale ovarienne". Toulouse 3, 2012. http://www.theses.fr/2012TOU30099.
Texto completo da fonteOvarian cancer is rare but has a bad prognosis due to a high level of chemoresistance to the reference treatment, carboplatin. We focused on the role of the microenvironment in ovarian cancer progression. The team previously demonstrated that Hospicells are able to potentialize tumour growth and angiogenesis in vivo. My aim was to determine how Hospicells interact with tumoral cells and other microenvironment partners to promote cancer proliferation. I showed that Hospicells alone cannot induce tumoral neoangiogenesis in vitro and they promote macrophage recruitment in tumours and enhance the synthesis of several cytokines involved in angiogenesis (IL-6, IL-8 and VEGF) through macrophages. Hospicells are also involved in chemoresistance acquisition via membrane exchange and efflux pumps transfer. This original mechanism working through direct contact between cells is probably not the only one responsible for this chemoresistance. Indeed, I showed that molecules secreted by Hospicells can also induce ovarian cancer cells chemoresistance. In order to identify the mechanism through which ovarian cancer cells can become chemoresistant under microenvironment stimulation, I studied the role of Hospicells in apoptosis protection after carboplatin treatment. Hospicells conditioned medium can partially inhibit apoptosis by apoptotic signalling pathway modifications and notably a decreased activation of effector caspases (caspases 3 and 7)
Duval, Stéphanie. "Imagerie du microenvironnement matriciel tumoral : les héparanes mimétiques". Thesis, Tours, 2014. http://www.theses.fr/2014TOUR3802.
Texto completo da fonteHeparan sulfate proteoglycans (HSPG), like all proteoglycans (PG), consisting of a protein portion and a glycosaminoglycan (GAG), heparan sulphate (HS) for HSPG. They are part of the extracellular matrix (ECM). PG are able, through their GAG, to bind a number of partners such as growth factors, chemokines, cytokines or enzymes. They regulate the bioavailability of many soluble mediators and thus their biological activity. They are thus involved in the regulation of many processes such as proliferation, differentiation, tissue remodeling, angiogenesis... In addition, it was shown that the binding of proteins having a heparan binding site (HB) with HS of HSPG protect them from enzymatic degradation. However, HSPG are among the first components of the ECM to be digested by heparanase during cellular tissue damage. This digestion makes HB sites available and proteins are sensitive to proteolytic degradation. It is in order to protect the HSBP (heparan sulfate binding protein) that was developed technology heparan mimetics (HM) that will replace the degraded HS on available HB sites and protect proteins of middle injured. These HM, already used as a therapeutic agent of the ECM, are identified in this use under the symbol RGTA for regenerating agent because they increase the speed and quality of the tissue repair, potentially leading to a true tissue regeneration. During tumor development and metastasis, it has been shown that the enzymatic activity of heparanase is multiplied, leading to an increased degradation of HS. In this context, the HM will be able to fix this matrix injured hence the idea of their diagnostic use in oncology. Using labeled HM (HM*) with a radioisotope such as fluorine-18 (18F) and followed by molecular imaging PETScan (positon emission tomography with scanner associated) should allow a particularly efficient marking of the matrix surrounding metastatic and tumor cells. HM* could indeed target ECM involved, through its early degradation in the processes of tumor growth and tumor spread and become a new marker oncology in molecular imaging. To date, among the various studied cancer markers, none address the matrix compartment. The use of HM* should allow the detection of peri-tumor and find a place in the early diagnosis of cancer and the therapeutic monitoring
Papin, Antonin. "Rôle du microenvironnement tumoral dans l'expansion des lymphomes B". Thesis, Nantes, 2019. http://www.theses.fr/2019NANT1009/document.
Texto completo da fonteMantle cell lymphoma (MCL) is an aggressive non-Hodgkin lymphoma associated with poor prognosis, and despite recent improvements in the therapeutic strategies for treating MCL, its management remains challenging. While improvements in next generation sequencing technologyhave greatly increased our understanding of the intrinsic abnormalities of MCL, the role of extrinsic signaling remains largely unknown. Recent studies have highlighted the central role of the MCLmicroenvironment in tumor cell survival, drug resistance and proliferation. Characterization of the diverse MCL tumoral niches and comprehension of the crosstalk between tumor cells and surrounding cells within the MCL microenvironment are needed to increase treatment efficacy. In this work, we present a revue of MCL microenvironment and our results on the role of tumoral niches in B lymphomas. This knowledge could be rapidly translated into new therapeuticstrategies to overcome drug resistance during MCL treatment
Augustin, Jérémy. "Caractérisation du microenvironnement tumoral immunitaire des carcinomes hépatocellulaires réséqués". Electronic Thesis or Diss., Sorbonne université, 2021. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2021SORUS409.pdf.
Texto completo da fonteHepatocellular carcinoma (HCC) shows globally low response to immunotherapy and HCC immune microenvironment is not well characterized. Our objective was to connect immune, viral and morphologic aspects of HCC and understand how they intervene in sensitivity to immune checkpoint blockade. In this study, we performed a transcriptomic analysis of onco-immune genes to characterize the tumor microenvironment of 170 HCC: 23% hepatitis B (HBV), 29% hepatitis C (HCV), 16% metabolic syndrome, 17% alcohol consumption related, and 14% of undetermined etiology. We correlated gene expression profiles with clinical, morphological and viral features. We did not observe difference of immune microenvironment at a global scale, between etiologies. But within HBV group, we identified 3 Clusters. None of of these clusters expressed ϒ-interferon (compared to 25% of HCC of all etiologies combined). Cluster 1 showed an ambivalent « hot » and exhausted profile with higher expression of exhaustion markers but lower densities of T lymphocytes by immunostaining. This Cluster was associated with HBV transcription and patients from this Cluster showed higher recurrence. Cluster 2 was enriched with macrotrabecular massive subtype and was immunologically “cold” and was also associated with higher recurrence. At last, Cluster 3 was developed much more on cirrhotic liver and showed an intermediate level of immune cells infiltration, with no marker of exhaustion. It was associated with lower recurrence. In conclusion we highlight viral related specificities within HBV HCC, associated with prognostic significance
Bouakka, Ibrahim. "Ciblage thérapeutique de l’Hepatic Leukemia Factor (HLF) dans les cancers du sein triple négatifs". Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL017.
Texto completo da fonteThe intricate interplay between the immune response and tumor progression, particularly in the context of triple-negative breast cancer (TNBC), has been a focal point of oncological research over the last decade. Our preceding investigation highlighted the role of the HLF gene within a quartet gene signature, identifying its inverse association with the infiltration of immune cells within the tumor milieu. During my thesis, we investigated more precisely its implication in the immune response and TNBC tumor development. The bioinformatic analysis of clinical data from patients with TNBC demonstrated that low levels of HLF expression were associated with an overexpression of genes related to the mechanisms of attraction and activation of the immune system. The implication of neutrophils in cancer is contentious, as they can function either as active anti-tumoral partners or as pro-tumoral agents promoting immunosuppression and tumor growth. The duality of the immune system’s role in cancer, oscillating between antitumor action and support for tumor growth, reflects its great complexity within the tumor microenvironment. In this study, we employed CRISPR/Cas9 technology to inactivate the HLF gene in TNBC cell lines, enabling us to explore the repercussions on the chemokine network regulating the presence and activity of different immune populations in the tumor microenvironment. Finally, in vivo experiments conducted on immunodeficient mouse models demonstrated that reducing HLF in certain TNBC subtypes hindered tumor progression. Altogether, our results suggest that a reduction of HLF expression can lead in the early steps of tumor development to the awakening of the anti-tumoral function of the immune system to enforce the necessary immunological tone to tumor elimination. Thus, HLF emerges as a promising therapeutic target to promote the engagement and effectiveness of a competent immune response against aggressive subtypes of TNBC
Peyvandi, Sanam. "Les cellules Myéloïdes Dans le Microenvironnement Tumoral : Rôle de FasL". Phd thesis, Université Paris Sud - Paris XI, 2013. http://tel.archives-ouvertes.fr/tel-00968103.
Texto completo da fonteFoy, Pierre-Emmanuel. "Conséquences des infections virales respiratoires sur le microenvironnement tumoral pulmonaire". Electronic Thesis or Diss., Sorbonne université, 2024. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2024SORUS044.pdf.
Texto completo da fonteLung cancer is the world's leading cause of cancer-related death. Treatment is based on surgery, when the tumor is resectable, and adjuvant therapy, generally combining chemotherapy with radiotherapy, immunotherapy or targeted therapies.Patients with non-small cell lung cancer (NSCLC) are frequently exposed to viral infections such as Influenza A (IAV) or SARS-CoV-2. The tumor microenvironment (TME) is a complex, heterogeneous ecosystem that conditions tumor cell growth, treatment response and patient survival. Infection of the TME by a virus represents a disruption that can impact tumor progression. In the infected cell, viral RNA is recognized by viral sensors, including TLR7, leading to the production of type I interferon (IFN-I) and the expression of ISG (Interferon-Stimulated-Genes).Recently, our team demonstrated that IAV infection of lung tumor-bearing mice results in viral sensor-dependent acceleration of tumor growth. Furthermore, IAV induces the expression of a transcriptomic signature composed of genes involved in drug detoxification metabolism and associated with chemoresistance, which we have termed the "REVIS-DM signature".This finding suggests that IAV induces chemoresistance involving xenobiotic detoxification.In NSCLC patients, co-expression of the REVIS-DM signature and an ISG signature confers a poor prognosis. In-vitro, we confirmed that infection of NSCLC tumor lines induces specific resistance to platinum salts and expression of genes encoding drug metabolizing enzymes. In-vivo, we confirmed that IAV infection induces chemoresistance to Cisplatin. Furthermore, we found that IAV infection leads to increased invasion from a 3D culture model, in connection with EMT initiation. Our future work will focus on the mechanisms leading to chemoresistance and invasion by infected cells. A number of hypotheses have been put forward in the literature, including the involvement of oxidative stress, viral sensors and ISGs.In parallel, we investigated the consequences of SARS-CoV-2 on MET and whether infection with the virus induces changes in anti-tumor immunity. Indeed, COVID-19 has been associated with strong immune disturbances such as inflammation and lymphopenia. In the context of cancer, these phenomena could lead to altered anti-tumor immunity and hence tumor progression. To answer these questions, we conducted a MET study of NSCLC patients infected with COVID-19 using two technologies: RNAseq and multiplex immunohistochemistry. Finally, we performed ex-vivo infection of tumor fragments in culture to study the direct impact of the virus on the MET.The impact of respiratory viruses on pulmonary MET is poorly documented. Our study sheds new light on the links between tumor cells and environmental viruses
Dejean, Emilie. "Microenvironnement des lymphomes anaplasiques à grandes cellules : angiogenèse et dissémination tumorales". Toulouse 3, 2011. http://www.theses.fr/2011TOU30308.
Texto completo da fonteThe most frequent lymphoma in childhood is often charaterized by aberrant expression of oncogenes with tyrosine kinase activity: NPM- or TPM3-ALK (nucleophosmin- or non-muscular tropomyosin 3- anaplastic lymphoma kinase). In our laboratory, we developed and charatacterized a conditional mice model for ALK+ lymphoma (Tet-Off). With those models, my work highlighted the role of VEGF in ALK+ lymphoma angiogenesis. We show that VEGF mRNA can be negatively regulated by one microRNA, miR-16 which is underexpressed in thoses tumors, even in human samples. If miR-16 is reexpressed in ALK + cells, we can osbserve a dealy in tumor growth and a reduction of angiogenesis (Dejean et al. , Leukemia, 2011). Anaplasic large cell lymphoma is characterized by frequent extranodal dissemination (70% of cases) which is skin in most cases. We were then interested in identify solubles factors responsible of this epidermotropism. We show that ALK+ cells (cell lines and human samples) secrete a pro-inflammatory cytokine: HMGB1. Our results demonstrate that HMGB1 is able to induce hypersecretion of IL-8 by keratinocytes, via PAR2 and NF-?B activation. IL-8 is a chemokine which can attract cells with specific receptors (CXCR1 and CXCR2). ALK+ tumor cells, cell lines and human samples, express these two receptors. We also show that inhibition of HMGB1 lead to a drastic reduction of invasive abilities of ALK+ cells in vitro and in vivo. Skin, activated by soluble factors from primary tumor, would then constitute a favorable environment for lymphoma dissemination. This study would be the first to highlight the existence of a cutaneous premetastatic niche in anaplasic large cell lymphoma (Dejean et al. , manuscript in preparation). My thesis work demonstrates the importance of microenvironment and solubles factors from primary tumor to tumorigenesis. Lymphomatous cells are able to induce angiogenesis and distant inflammation to cause tumor growth and lymphoma dissemination
Fourré, Nicolas. "Microenvironnement cellulaire et réponse de la cellule tumorale au médicament : impact du microenvironnement sur les propriétés anti-migratoires des anthracyclines". Reims, 2007. http://www.theses.fr/2007REIMP209.
Texto completo da fonteThe @aim of our study was to evaluate the role of the microenvironment on the anti-migratory abilities of doxorubicin on HT-1080 cell line. In this context, two models of cell culture have been used: one on a 2D-coated substrate with extracellular matrix proteins (type I collagen or fibronectin) and the other one in a 3D collagen matrix mimicking an in vivo environment. Control experiments on plastic showed that subtoxic doses of doxorubicin exhibit a significant anti-migratory effect by totally disorganizing actin stress fibers and by modifying vinculin distribution. However, the anti-migratory effect of the drug is totally inhibited in presence of matrix proteins. This protection could be due to the preservation of the activation states of RhoA GTPase, which are necessary for the formation of actin stress fibers, and of FAK, implicated in the formation of focal adhesions. The study carried out in a 3D matrix demonstrates that this type of microenvironment can act as a physical barrier by delaying the biodistribution of doxorubicin. Long-term incubations, avoiding the barrier effect, show that the protectory effect to doxorubicin anti-migratory effect is less important and is not followed by a modification of FAK activation. In conclusion, the microenvironment is able to protect the tumor cell from the anti-migratory effect of a drug. However, this effect is very dependent on culture conditions, which underlines the extreme adaptability of the cell to its environment. In comparison to previous work on the cytotoxic effect of drugs, our results demonstrate that the microenvironment should be taken into account in the study of pharmacological properties of anti-tumor drugs
Fourré, Nicolas Jeannesson Pierre. "Microenvironnement cellulaire et réponse de la cellule tumorale au médicament impact du microenvironnement sur les propriétés anti-migratoires des anthracyclines /". S.n. : S.l, 2007. http://scdurca.univ-reims.fr/exl-doc/GED00000613.pdf.
Texto completo da fonteTrédan, Olivier. "Optimisation de la distribution des chimiothérapies pour contourner la résistance liée au microenvironnement tumoral". Thesis, Lyon 1, 2009. http://www.theses.fr/2009LYO10238.
Texto completo da fonteThere is a vast literature about mechanisms that lead to drug resistance of individual cancer cells, including drug export pumps, changes in expression of targets (such as topoisomerases) or alterations in apoptosis. A smaller number of publications has drawn attention to causes of drug resistance that depend on the solid tumour microenvironment. Drugs must penetrate the extra-vascular space to reach all of the cancer cells (including cells far from blood vessels in hypoxic condition) in sufficient concentration to cause lethal toxicity. Model systems such as multilayered cell cultures provide direct evidence of poor drug penetration through tumour tissue. In vivo techniques using quantitative immunohistochemistry allow studying drug distribution as a function of distance from the nearest blood vessel. We have evaluated the penetration of several topoisomerase inhibitors: topotecan, doxorubicine, mitoxantrone and banoxantrone (AQ4N). We have compared the distribution of these drugs through normal and tumour tissue, demonstrating the limited perivascular distribution of conventional chemotherapies in tumour. We have also showed the rapid and uniform penetration of banoxantrone. This pro-drug is reduced to AQ4 (a topoisomérase II inhibitor of similar structure to mitoxantrone) under hypoxic condition. The targeting of mitoxantrone to oxygenated regions and AQ4 to hypoxic tumour regions resulted in effective drug exposure over the entire tumour and increased tumour growth delay compared with either drug alone. Improving drug penetration and/or targeting hypoxic tumour cells may overcome chemoresistance due to the tumour microenvironment
Thomas, Audrey. "Effet sur le microenvironnement tumoral d’une modulation pharmacologique du stress oxydant". Thesis, Paris 5, 2012. http://www.theses.fr/2012PA05T086/document.
Texto completo da fonteSeveral reports have demonstrated the involvement of reactive oxygen species (ROS) in carcinogenesis, through promotion of cancer cell proliferation and invasion. But ROS could also have consequences on non cancerous cells which are part of the tumor microenvironment, such as immune cells. Therefore, a pharmacological modulation of oxidative stress can induce a cytotoxic effect on tumor cells but its consequences on microenvironment are unknown. The aim of our studies was to evaluate the effects of a pharmacological modulation of oxidative stress on immune cells from the tumor microenvironment. At low dose, Arsenic trioxide (As203), an oxidative stress modulator, was shown to exert antitumor effects in colon tumor-bearing mice. We observed that this effect was related to As203-induced regulatory T cells (Tregs) -selective depletion in vitro and in vivo and was mediated by oxidative and nitrosative bursts. The differential effect of As203 on Tregs versus other CD4 cells was related to difference in the cells’redox status. We also observed that vinorelbine, an anticancer agent, could interfere with the antitumor immune response. We showed that vinorelbine could alter the function of immune cells surrounding tumor cells by a bystander toxic effect against tumor effector cells. In vivo experiment in A549 tumor bearing nude mice showed that adoptive transfer of A549 immune splenocytes was not able to delay tumor growth when vinorelbine-pretreated A549 cells were used for immunization. This effect was mediated by ROS and was inhibited by an oxidative stress modulator, mangafodipir, which restored antitumor immune function. Therefore, our work showed that oxidative stress modulators can influence tumor microenvironment and more specifically, immune cells. They could be used to restore antitumor immune response
Sick, Emilie. "Rôle des mastocytes dans le microenvironnement inflammatoire tumoral : exemple des astrocytomes". Strasbourg, 2009. http://www.theses.fr/2009STRA6147.
Texto completo da fonteThis thesis aimed at studying the spatio-temporal reorganization of a remote spatial memory in the Rat, and more particularly the roles of the hippocampus and the medial prefrontal cortex in systems consolidation. We first showed, in the Morris water maze, that contextual cue saliency affected the precision and thus the quality of memories. This is important as the degree of trace degradation determined the outcome of extinction of a remote memory. Furthermore, we found that the degree of trace degradation determined the level of participation of the hippocampus and the anterior cingulate cortex during remote memory retrieval. Lastly, whereas most studies in the literature focused on the role of neocortical areas in systems consolidation, we demonstrated that the intralaminar/lateral thalamic nuclei may also participate in systems consolidation and/or retrieval of a remote memory. In conclusion, taken together, these results do not fully corroborate the main theories on systems consolidation. Instead, it seems that the way in which the spatio-temporal reorganization of a memory takes place could depend on the conditions in which memories are formed and subsequently recalled
Alamé, Melissa. "Intégration de données et caractérisation du microenvironnement tumoral de tumeurs rares". Thesis, Montpellier, 2020. http://www.theses.fr/2020MONTT046.
Texto completo da fonteThe development of high-throughput technologies, especially Next Generation Sequencing, has triggered considerable advances in tumor understanding and molecular classification. Patient subgroups for a same tumor have been defined and characterized. Those subgroups are typically associated with a particular prognosis or eligible to a specific targeted therapy. These progresses paved the way towards personalized medicine.The understanding of the contribution of the tumor microenvironment (TME) to disease aggressiveness, progression, and therapy resistance is another revolution in cancer biology and patient care. The contribution of the aforementioned high-throughput technologies was essential. At the era of immunotherapy, the sub-classification of tumors based on their TME composition identified patient subgroups correlated to survival and to their response to this particular class of drugs. Despite a formidable community effort, the molecular and immunological classification of tumors has not been completed for every cancer, some rare and aggressive entities still require thorough characterization. Moreover, most TME studies have focused on the cellular composition and they neglected the mapping of the intercellular communications networks occurring in neoplasms. The advent of single-cell technologies is filling this gap, but with a strong focus on the most frequent cancers.In my thesis, I have both deployed advanced data integration methods and a novel approach to infer ligand-receptor networks relied on a database (LRdb), which is developed by the Colinge Lab, to characterize the TME of two rare tumors, Salivary Duct Carcinoma (SDC) and Primary Central Nervous System Diffuse Large B-Cell Lymphoma (PCNSL). I have combined classical – yet advanced – bioinformatic and multivariate statistics methods integrating bulk transcriptomics and proteomics data, including fresh and TCGA data. Those computational techniques were supplemented with immunofluorescence and immunohistochemistry coupled with digital imaging to obtain experimental validations. To accommodate limited patient cohorts, I have searched for highly coherent messages at all the levels of my analyses. I also devoted important efforts relating our findings with the literature to put them in a clinical perspective. In particular, our approach revealed TME groups of tumors with particular prognosis, immune evasion and therapy resistance mechanisms, several clinical biomarkers, and new therapeutic perspectives
Clement-Colmou, Karen. "Impact du fractionnement de la radiothérapie sur le microenvironnement vasculaire tumoral". Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1029/document.
Texto completo da fonteThe tumour blood vessels are immature and dysfunctional, limiting the distribution and efficacy of anticancer drugs. Conventional radiotherapy (2Gy / day) improves their structure, reduces hypoxia and improves the biodistribution of concomitant treatments. However, hypofractionated radiotherapy, using higher doses per fraction, tends to replace conventional schedules. Their consequences on the tumour microenvironment are poorly understood. Our goal was to define the impact of different fractionation schedules on the tumour vascular microenvironment. A fractionation scale, ranging from 2 to 12Gy per fraction, was implemented on two cancer models (prostate and lung). Several phenotypical and functional aspects of the vasculature and anti-tumour efficacy were studied. A radiation-induced vascular maturation was observed, including an increased pericyte coverage and an improved distribution of doxorubicin. In both models, tumour control was better for hypofractionated schedules. Vascular pseudo-normalization was poorly sensitive to fractionation, but hypoxia was improved in a dose-dependent manner. The depth and duration of the improvement was greater in the slow-growing prostate cancer model: hypoxia seemed to depend as much on the kinetics of repopulation of the model as on the quality of the blood supply. Our results highlight the mutual influence of tumour and vascular responses to irradiation. They will be useful to optimize the future delivery schedule of anticancer treatments
Said, Georges. "Modélisation du microenvironnement tumoral : impact du collagène de type I sur la migration de la cellule tumorale et sur sa réponse à la chimiothérapie". Thesis, Reims, 2012. http://www.theses.fr/2012REIMP204.
Texto completo da fonteThe tumor microenvironment via the extracellular matrix plays an important role in cancer cell response to chemotherapy by promoting their survival and proliferation. In this work, we studied the impact of collagen type I, a major matrix protein of tumor microenvironment, on the migration capacities of tumor cells and on their response to anticancer drugs such as doxorubicin and metformin. This approach was performed with the highly invasive human cell line HT1080,by means of 2D coating or 3D matrix cell culture systems. The effects of collagen posttranslational modifications such as carbamylation and glycation were also assessed. The results show that the 3D collagen inhibits the anti-migratory effect of doxorubicin. This protection is carried out through the preservation of the activation states of FAK and RhoA, which are involved in the formation of actin stress fibers and focal adhesions. On 2D coating, the glycated collagen and at a lesser extent the carbamylated one decrease the adhesion, the migration oftumor cells and, disorganize the actin cytoskeleton via a modified distribution of vinculine, FAK and beta1 integrins. This impact is also demonstrated by using 3D matrices, after adaptation of the glycation process. In addition, we reported that the glycated collagen protects against the antiproliferative and the anti-migratory effects of doxorubicin and metformin. In conclusion, we highlighted a new form of CAM-DR resistance that targets the drugs anti-invasive activity. This impact could be induced by the native form of matrix proteins or the modified one found inpathological situations which are associated to cancer
Vancauwenberghe, Eric. "Rôle du canal TRPA1 dans le microenvironnement tumoral des cancers prostatiques humains". Thesis, Lille 1, 2016. http://www.theses.fr/2016LIL10210.
Texto completo da fonteProstate cancer (PCa) is the second most common cancer in men. The tumor microenvironment (TME) plays an important role in prostate carcinogenesis and metastasis independently of androgens. There is a close communication between tumor epithelial cells and stroma through the secretion of soluble factors promoting survival and metastasis of cancer cells. Modulating the secretion of these factors could therefore be a potential therapeutic option in the treatment of prostate cancers. Ion channels and the intracellular calcium are known to modulate secretion. In this context, we have shown that the TRPA1 channel is expressed in fibroblasts associated to cancers (CAF) in human prostate. Here, we describe that the activation of TRPA1 channel by epithelial factors leads to an increase in intracellular calcium levels promoting expression and secretion of growth factors. Our data show that these latter induce the epithelial-mesenchymal transition, migration and resistance to chemotherapeutic agents in cancer cells. Finally, we identified polymorphisms and mutations in TRPA1 channel allowing its activation by environmental factors and secretion of growth factors inducing resistance to apoptosis of prostate cancer cells. All these data suggest that TRPA1 channel constitutes a potential target for future therapies of PCa to interrupt the epithelial-stromal interactions of TME and prevent the development of these cancers
Prat, Mélissa. "Les macrophages au sein du microenvironnement tumoral : étude et modulation des mécanismes moléculaires et cellulaires de la réponse anti-tumorale au cours de carcinoses péritonéales". Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30116.
Texto completo da fonteMacrophages, which are crucial effectors of innate immune response, exhibit a remarkable phenotypic and functional plasticity that allows them to adapt to the different stimuli present in their microenvironment. Within the tumor microenvironment, macrophages or TAMs (Tumor-associated macrophages) represent the major leukocyte population. During tumor development, secreted mediators produced by transformed cells « educate » TAMs which acquire properties favorable to tumor growth. Thus, it is now widely accepted that TAMs, initially of anti-tumor M1 phenotype, differentiate towards an M2 phenotype able to promote tumor cell proliferation, angiogenesis, metastases, resistance to chemotherapy treatments and suppression of the adaptive anti-tumor immune response. However, this functional M1/M2 dichotomy, while facilitating the description TAMs phenotype and their associated functions, is an oversimplification of the macrophage biology within tumor tissues which is actually more complex. Thus, in the first part of this work, we showed that treatment with IL-13, a Th2 cytokine well described to be involved in macrophage M2 polarization, inhibits tumor growth in two murine models of T-cell lymphoma and ovarian adenocarcinoma via the promotion of macrophage cytotoxic activity. Interestingly, we demonstrated the key role of Mannose (RM) and Dectin-1 C-type Lectin receptors, strongly expressed on IL-13-activated macrophages, in tumor cell recognition. We specifically identified the sialic acid expressed on transformed cell surface as a critical epitope for their recognition by IL-13-activated macrophages. Moreover, we showed that, following this recognition, RM and Dectin-1 trigger cytotoxic signaling pathways leading to the production of radical oxygen species and the amplification of arginase activity. We finally demonstrated that these two mediators produced by IL-13-activated macrophages induce tumor cell necrosis. In the second part of this work, we studied the impact of 15(S)-HETE, a natural ligand of the PPAR-γ nuclear receptor involved macrophage M2 polarization, on tumor development. We showed that this lipid inhibits tumor growth in an experimental murine model of ovarian adenocarcinoma. Interestingly, we demonstrated that 15(S)-HETE anti-tumor effect depends on the activation of PPAR-γ in macrophages. We showed that 15(S)-HETE modifies peritoneal macrophage population balance, likely by promoting the differentiation of Small Peritoneal Macrophages (SPM) into Large Peritoneal Macrophages (LPMs). These LPMs display a phenotype which contributes to the increase of effector/regulatory T lymphocyte ratio in tumor ascites, and thus counteracts tumor-induced immunosuppression. Finally, in the third part of our work, the analysis of circulating blood monocytes in ovarian adenocarcinoma patients revealed a strong increase in the proportion of the « intermediate » subset (CD14high CD16+), usually poorly represented in healthy subjects. Interestingly, we demonstrated a positive correlation between a high proportion of intermediate blood monocytes and the presence of an immunosuppressive microenvironment in the tumor ascites of these patients (↗ Tregs, TAMS CD163high CD206high CCR2high CD86low and ↘ NK and CD8 + cytotoxic). In addition, we showed a positive correlation between the expansion of these intermediate monocytes and tumor development within the peritoneum. Together, these data highlight the role of blood monocytes as a predictive signature of immune status and tumor development within the peritoneum in patients with ovarian cancer
Blondy, Thibaut. "Développement et caractérisation de NanoAssemblages aux propriétés théranostiques : Etude dans le microenvironnement tumoral". Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1035.
Texto completo da fonteMalignant pleural mesothelioma (MPM) is a cancer with a poor prognosis which arises from the pleura and mainly caused by occupational exposure to asbestos. Thus, there is a necessity to develop new therapeutic strategies to increase the lifespan of patients. My PhD project consisted in better understanding the interactions between mesothelioma cells and the tumor microenvironment and characterizing a new therapeutic approach, the vectorisation of active ingredients, in the MPM. The first part of my thesis project aims to study the macrophages present in the microenvironment of the MPM. It is now well established that the majority of macrophages present in the tumor have an immunosuppressive phenotype and play a role in tumor progression. Thus, I have shown that IL-34 and M-CSF, two cytokines involved in the survival and differentiation of these macrophages, are prognostic factors of MPM I also developed a 3D co-culture model of tumor cells with macrophages to study the role of the M-CSF / IL-34 / CSF1-R pathway in macrophage acquisition of an immunosuppressive phenotype under the influence of mesothelioma cells. Drug vectorization is a strategy that aims to improve the delivery of therapeutic agents in the tumor while preserving healthy tissue. In collaboration with the chemistry team of the Pr Elena Ishow from CEISAM lab of the Nantes University, I was able to evaluate the behaviour of different structures of nanoassemblies (NA) on cancer cells and on cells from the tumor microenvironment, notably the macrophages. This study allowed us to identify the best structure for transporting a drug and also to efficiently target MPM cells
Lailler, Claire. "Biomarqueurs du microenvironnement tumoral pour la stratification thérapeutique des cancers tête et cou". Thesis, Amiens, 2021. https://tel.archives-ouvertes.fr/tel-03881131.
Texto completo da fonteHead and Neck Squamous Cell Carcinomas (HNSCC) were the seventh most frequent tumors worldwide in 2020. Although therapeutic perspectives have evolved favorably over the last ten years, the search for useful biomarkers for therapeutic stratification remains a major challenge for these tumors. In addition, the induction of antitumor adaptive immunity seems to be an increasingly important mechanism for the efficacy of approved therapies in HNSCC. In this perspective, the study of the interactions between tumor cells and immune cells of the tumor microenvironment (TM) is essential. Several anticancer therapies have been reported for the induction of tumor cell death by ferroptosis, an iron-dependent regulated necrosis that occurs during unresolved oxidative stress in the cell. In the first part of our work we focused on the possibility of exploiting ferroptosis in Human Papillomavirus positive HNSCC (HPV+ve HNSCC), which usually show higher oxidative stress than HPV negative HNSCC (HPV-ve HNSCC). Using in silico analyses, we observed low expression of SLC7A11, an essential transporter in the cell for the synthesis of glutathione, an inhibitor of oxidative stress, in HPV+ve HNSCC compared to HPV-ve HNSCC. In vitro, HNSCC cell lines expressing HPV E6/E7 transforming proteins showed higher sensitivity to erastin-induced ferroptosis compared to their parental cell lines. In the second part of our work, we studied the regulation of PD-L1 (Programmed Death-Ligand 1) expression by different approved therapies in HNSCC. The expression of PD-L1 by tumor and inflammatory cells of the TM is indeed partly responsible for the frequent inactivation of cytotoxic T cells of the TM, and thus represents an obstacle for the induction of antitumor adaptive immunity. We observed a specific regulation of PD-L1 by 5-fluorouracil (5-FU) that was dependent on the DNA damage response and the JAK / STAT pathway
Ringuette, Goulet Cassandra, e Goulet Cassandra Ringuette. "Interactions entre les cellules tumorales et stromales dans le microenvironnement du cancer de la vessie". Doctoral thesis, Université Laval, 2019. http://hdl.handle.net/20.500.11794/36895.
Texto completo da fonteLes fibroblastes associés au cancer (CAF) constituent le type cellulaire le plus abondant du microenvironnement tumoral. In vivo, les tumeurs les plus agressives corrèlent avec un enrichissement en CAF et une matrice extracellulaire plus dense. En effet, les interactions dynamiques et réciproques entre les cellules cancéreuses et les CAF favoriseraient la progression tumorale. Cependant, les molécules impliquées dans ces interactions ainsi que leurs effets sur le devenir de la tumeur et sur le remodelage du microenvironnement sont mal connus. Or, mieux définir et comprendre les mécanismes moléculaires impliqués dans cette interaction est crucial afin de pouvoir développer de nouvelles cibles thérapeutiques. Ainsi, nous avons étudié les interactions entre les cellules cancéreuses et les cellules stromales dans le microenvironnement du cancer de la vessie. Les exosomes sont une classe de vésicules extracellulaires d’origine endocytique de 30 à 200 nm de diamètre. Ils sont sécrétés par tous les types cellulaires et constituent, entre autres, un moyen de communication intercellulaire en transportant protéines, lipides et ARN d’une cellule à l’autre. Les cellules cancéreuses sécrètent une grande quantité d’exosomes et ces derniers joueraient un rôle dans la modulation du microenvironnement tumoral, notamment en activant les fibroblastes sains en CAF. Les travaux présentés dans cette thèse ont permis de démontrer que les exosomes sécrétés par les cellules cancéreuses sont internalisés par les fibroblastes vésicaux sains et qu’ils favorisent la prolifération de ces derniers. De plus, les exosomes dérivés de cellules cancéreuses activent les fibroblastes sains en CAF grâce au TGFβ qu’ils contiennent. La neutralisation du TGFβ par des anticorps spécifiques confirme ces résultats. Une fois activés, les CAF augmentent la prolifération, la migration et l’invasion des cellules cancéreuses via une sécrétion soutenue de la molécule IL-6. D’ailleurs, le blocage de la voie de signalisation de l’IL-6 renverse les effets observés sur les cellules cancéreuses. Nous avons également démontré que les CAF diminuent la sensibilité des cellules cancéreuses à la mitomycine C. Enfin, les CAF remodèlent la matrice extracellulaire du microenvironnement tumoral notamment par une sécrétion accrue des protéines oncofétales ténascine C et EDA-fibronectine, ainsi qu’une activité LOX-1 et MMP augmentée. Par ailleurs, la matrice extracellulaire générée par les CAF favorise la transition épithéliomésenchymateuse des cellules urothéliales saines en inhibant le marqueur épithelial Ecadhérine au profit du marqueur mésenchymateux N-cadhérine. Ainsi, une communication étroite et complexe entre les cellules cancéreuses et les CAF favorise la progression tumorale. En secrétant des facteurs solubles à activité protumorale et des protéines de la matrice extracellulaire, les CAF favorisent la prolifération, l’invasion et la chimiorésistance des cellules cancéreuses. Globalement, nos travaux soutiennent l'idée que l’inhibition de la transdifférenciation des fibroblastes sains en CAF est une cible thérapeutique de choix dans le développement de nouveaux anticancéreux.
Cancer-associated fibroblasts (CAFs) are the most abundant cell type of the tumor microenvironment. In vivo, aggressive tumors correlate with an enrichment of CAFs and a denser extracellular matrix. Indeed, the dynamic and reciprocal interactions between tumor cells and CAFs promote tumor progression. However, the molecules involved in these interactions, as well as their effects on the fate of the tumor and the remodeling of the microenvironment are poorly known. However, better define and understand the molecular mechanisms of this interaction is crucial to develop new treatments. Thus, we studied interactions between tumor cells and stromal cells in the microenvironment of bladder cancer. Exosomes are a class of extracellular vesicles with of endocytic origin measuring 30 to 200 nm in diameter. They are secreted by all types of cells and constitute, among others, a means of intercellular communication by transporting proteins, lipids and RNA from one cell to another. Cancer cells secrete a large amount of exosomes and these exert a role in the modulation of the tumor microenvironment, notably by activating healthy fibroblasts in CAFs. The work presented in this thesis has demonstrated that the exosomes secreted by cancer cells are internalized by vesical fibroblasts and promote their proliferation. In addition, exosomes derived from cancer cells activate healthy fibroblasts in CAFs using the TGFβ that they transport. The neutralization of TGFβ by specific antibodies confirms these results. Once activated, CAFs increase the proliferation, migration and invasion of cancer cells via a sustained secretion of the IL-6 molecule. Moreover, the blocking the IL-6 signaling pathway reverses the effects observed in cancer cells. We have also demonstrated that CAFs decrease the sensitivity of cancer cells to mitomycin C. Finally, CAFs remodel the extracellular matrix of the tumor microenvironment notably by an increased secretion of tenascin C and EDA-fibronectin oncofetal proteins, as well as a LOX-1 and MMP increased activity. In addition, the extracellular matrix generated by CAFs promotes the epithelio-mesenchymal transition of healthy urothelial cells by inhibiting the epithelial marker E-cadherin in favor of the mesenchymal marker N-cadherin. Thus, a close and complex communication between the cancer cells and the CAFs increases tumor progression. By secreting soluble factors with a pro-tumor activity and extracellular matrix proteins, CAFs promote the proliferation, invasion and chemoresistance of cancer cells. Overall, our work supports the idea that the inhibition of the transdifferentiation of healthy fibroblasts into CAFs is a therapeutic target of choice in the development of novel anticancer drugs.
Cancer-associated fibroblasts (CAFs) are the most abundant cell type of the tumor microenvironment. In vivo, aggressive tumors correlate with an enrichment of CAFs and a denser extracellular matrix. Indeed, the dynamic and reciprocal interactions between tumor cells and CAFs promote tumor progression. However, the molecules involved in these interactions, as well as their effects on the fate of the tumor and the remodeling of the microenvironment are poorly known. However, better define and understand the molecular mechanisms of this interaction is crucial to develop new treatments. Thus, we studied interactions between tumor cells and stromal cells in the microenvironment of bladder cancer. Exosomes are a class of extracellular vesicles with of endocytic origin measuring 30 to 200 nm in diameter. They are secreted by all types of cells and constitute, among others, a means of intercellular communication by transporting proteins, lipids and RNA from one cell to another. Cancer cells secrete a large amount of exosomes and these exert a role in the modulation of the tumor microenvironment, notably by activating healthy fibroblasts in CAFs. The work presented in this thesis has demonstrated that the exosomes secreted by cancer cells are internalized by vesical fibroblasts and promote their proliferation. In addition, exosomes derived from cancer cells activate healthy fibroblasts in CAFs using the TGFβ that they transport. The neutralization of TGFβ by specific antibodies confirms these results. Once activated, CAFs increase the proliferation, migration and invasion of cancer cells via a sustained secretion of the IL-6 molecule. Moreover, the blocking the IL-6 signaling pathway reverses the effects observed in cancer cells. We have also demonstrated that CAFs decrease the sensitivity of cancer cells to mitomycin C. Finally, CAFs remodel the extracellular matrix of the tumor microenvironment notably by an increased secretion of tenascin C and EDA-fibronectin oncofetal proteins, as well as a LOX-1 and MMP increased activity. In addition, the extracellular matrix generated by CAFs promotes the epithelio-mesenchymal transition of healthy urothelial cells by inhibiting the epithelial marker E-cadherin in favor of the mesenchymal marker N-cadherin. Thus, a close and complex communication between the cancer cells and the CAFs increases tumor progression. By secreting soluble factors with a pro-tumor activity and extracellular matrix proteins, CAFs promote the proliferation, invasion and chemoresistance of cancer cells. Overall, our work supports the idea that the inhibition of the transdifferentiation of healthy fibroblasts into CAFs is a therapeutic target of choice in the development of novel anticancer drugs.
Travert, Marion. "Modulation des propriétés anti-tumorales de TRAIL dans les lymphomes folliculaires : rôle du microenvironnement ganglionnaire". Rennes 1, 2008. http://www.theses.fr/2008REN1S040.
Texto completo da fonteFollicular Lymphomas (FL) are indolent non-Hodgkin lymphomas derived from germinal centers. There are characterised by a t(14,18) chromosomal translocation responsible for the overexpression of the oncoprotein, Bcl-2. In this pathology, tumor B cell survival is linked to the microenvironment of the lymph node (LNM). None of standard therapies are curative against FL, especially in case of a multi-recurrent disease. Then, innovative approaches are urgently needed. The TNF family member, TRAIL, is emerging as a promising cytotoxic molecule for antitumor therapies. In consequence, the aim of this work was to investigate TRAIL-mediated apoptosis in FL B cells of the LNM in this response. We show with clear evidence that stromal cells and TFH lymphocytes, which correspond to key cellular partners of the LNM, protect tumour B cell from TRAIL-induced. This protection is mediated by NFkappaB and COX-2 activation. It is then crucial to take impact of the stromal, haematopoietic and cytokinic microenvironment present in germinal center in new anti-lymphoma treatments
Lopez, Sara. "Destruction du microenvironnement tumoral par application de forces mécaniques exercées par des nanoparticules magnétiques". Thesis, Toulouse 3, 2019. http://www.theses.fr/2019TOU30202.
Texto completo da fonteEfficiency of anti-cancer treatments is limited by development of resistance to treatments, which has long been considered to depend solely on the genotype of cancer cells. However, these past few years, researchers proved that cancer progression and resistance are not only determined by the inherent characteristics of cancer cells, but also by their interactions with tumor microenvironment. Among other components of the tumor microenvironment, cancer-associated fibroblasts (CAFs) promote tumor growth and cancer cell resistance to treatments. CAFs modify the components and properties of tumor microenvironment (blood vessels, extracellular matrix or tumor immunity) and interact with cancer cells; those actions take a great part in the loss of treatment efficacy. Thus, as CAFs seem to be key players in cancer cell resistance to treatment, their eradication is an interesting strategy to inhibit cancer progression. While magnetic nanoparticles (MNPs) under a high frequency magnetic field produce heat, they generate a mechanical torque in response to low frequency rotating magnetic fields (RMF) Here, we chose this last property to elaborate a nano-therapeutic strategy directed against CAFs. The principle of this strategy is to target CAFs using vectorised MNPs and then apply a RMF that generates enough mechanical stress to induce cell death. The first objective was to target pancreatic CAFs that express the type 2 cholecystokinin receptor (CCK2R). For this, we synthesized gastrin-decorated MNPs (MNP@Gastrin). We showed that MNP@Gastrin bind to the CCK2R on the cell membrane of CAF-CCK2R, then internalize and accumulate in the lysosomes. Then, we tested different amplitudes and frequencies of RMF and demonstrated that RMF exposure induces the death of CAFs having accumulated MNP@Gastrin into their lysosomes. The optimal effect on cell death, namely the death of about 40% of CAFs, was obtained with 40mT and 1Hz RMF. Moreover, we investigated the cell death mechanism involved and we showed that cell death occurs through lysosomal damage. Lysosomes undergo membrane permeabilization, releasing their content, including cathepsin B which are involved in the observed cell death process. On top of that, the engaged cell death pathway seems to be caspase-1 dependent. Finally we used a magnetic setup under a confocal microscope in order to observe real-time cell reaction to RMF. We noticed cellular retraction, lysosomal movements towards the nucleus, and changes in cellular adhesion. This study establishes the proof-of-concept that targeted MNPs can disrupt tumor microenvironment through mechanical forces upon RMF exposure, and thus open new opportunities for cancer therapy
Nehar-Belaid, Djamel-Eddine. "Approche immunologie des systèmes pour l'étude du microenvironnement tumoral et de l'interface foeto-maternelle". Thesis, Paris 6, 2014. http://www.theses.fr/2014PA066206/document.
Texto completo da fonteThere are striking similarities between fetus and tumor development. They both require intense cell division, invasion of host tissues and sustained vascularization. Moreover, despite that fetus and tumor express foreign antigens - paternal allo-antigens for fetuses and modified auto-antigens for tumors, they are not rejected by the immune system. Among others, regulatory T cells (Tregs), which are key players in tolerance, appear to play a significant role in both processes. We showed that tumor emergence as well as embryo implantation elicit a strikingly similar brisk Treg response, which functional relevance is supported by the fact that and Treg depletion leads to fetus or tumor immune rejection. Comparison of fetal and tumor microenvironments through transcriptomics revealed strikingly similar and dramatic decrease in expression of multiple immune-related pathways, including antigen presentation and T cell response. Unsupervised analyses highlighted the co-evolution in time of downregulated immune signatures, from the very first days after tumor or embryo implantation. Treg depletion, which leads to fetus or tumor rejection, converted the very same down-modulated immune signatures to up-regulated ones. We propose that means selected during evolution to protect mammalian fetuses are hijacked to license tumor development
Ollion, Vincent. "Caractérisation des cellules dendritiques humaines BDCA3high et de leur modulation par le microenvironnement tumoral". Thesis, Lyon 1, 2015. http://www.theses.fr/2015LYO10163/document.
Texto completo da fonteDendritic cells {DC) play a major role in the induction of antigen {Ag) specific anti-tumoral immunity. Recently, human BDCA3high DC appeared to be homologous with CD8a+ DC known to activate very efficiently T CD8 lymphocyte by Ag cross-presentation in mice. Moreover, those two DC populations are the main producers of interferon-λ {IFN-λ), a recently discovered cytokine family with antiviral, anti-proliferative and anti-tumoral properties. My works participated to better characterize cell derived Ag cross-presentation by BDCA3high DC using an in vitro model and enlightened the role of NK cells in its induction. This works also end up in revealing the presence of BDCA3high DC in breast tumors and the inhibition of their IFN-λsecretion by soluble factor from tumor microenvironment. Altogether, those results should allow designing new anti-tumoral immunotherapeutic strategies based on BDCA3high DC targeting
Fouet, Morgane. "Modulation du microenvironnement tumoral et de la réponse immunitaire par des virus oncolytiques modifiés". Electronic Thesis or Diss., Nantes Université, 2024. http://www.theses.fr/2024NANU1008.
Texto completo da fonteViruses exhibiting a tropism for tumor cells and an ability to induce their lysis, are called oncolytic viruses. They are used in the context of virotherapy and make it possible to stimulate the anti-tumor immune response by recruiting and activating innate and adaptive immune cells. The work resulting from my thesis made it possible to deepen the understanding of the role of ϒ9δ2 T cells in the context of oncolytic infections, in particular by highlighting their specific activation by the Schwarz strain of the Measles virus. | then developed an oncolytic virus capable of encoding an antibody designed to specifically activate ϒδ T cells. Therapeutic evaluation of this virus in a mouse model revealed promising results, particularly on the control of tumor growth. Furthermore, | developed a therapeutic strategy aimed at promoting the formation of tertiary lymphoid structures within the tumoral microenvironment. Using an oncolytic virus to vectorize key proteins in tertiary lymphoid structures neogenesis, | observed that the combination of three distinct viruses facilitates the infiltration of not only T cells, but also B cells into the tumoral microenvironment. This approach offers a promising prospect for improving the antitumor immune response and deserves further exploration to confirm its clinical potential
Molière, Sébastien. "Modulation du micro-environnement tumoral par la MMP-11". Electronic Thesis or Diss., Strasbourg, 2023. http://www.theses.fr/2023STRAJ094.
Texto completo da fonteBackground : The tumor microenvironment plays a crucial role in cancer progression, especially in breast cancer. While high-throughput transcriptomic and genomic analyses provide an overview, understanding tumor-stroma interactions remains incomplete. Metalloproteinase- 11 (MMP-11) stands out for its role in breast cancer progression, with its stromal expression linked to poor prognosis. Research Focus: a) investigating the prognostic role of MMP-11 in a breast cancer cohort, b) exploring the role of MMP-11 in tumor progression and metabolism using a murine model, c) identifying and characterizing MMP-11 substrates, with a particular focus on IGFBP proteins. Conclusion: The findings indicated that stromal expression of MMP-11 has an interesting prognostic value in early stages of breast cancer. Experiments revealed an autocrine anti- adipogenic action of MMP-11 secreted by adipocytes, but the expected paracrine pro-tumoral effect was not confirmed. Additionally, it was discovered that MMP-11 can cleave the majority of human IGFBPs, suggesting a potentially novel mechanism through which MMP-11 might influence cancer, including unique intracellular actions
Gaud, Guillaume. "Impact d'un inhibiteur de protéases à sérine, le TFPI-2, sur le microenvironnement tumoral pulmonaire". Thesis, Tours, 2009. http://www.theses.fr/2009TOUR4007/document.
Texto completo da fonteTFPI-2 (Tissue factor pathway inhibitor-2), an inhibitor of serine proteinases, particularly plasmin, can indirectly regulate the activation of MMPs, thus regulating ECM degradation and tumour cell invasion. Our results demonstrated that TFPI-2 silencing was associated with a 2 and 3-fold increase in invasive ability through basement membrane components, for clones NCI-H460 miRNA-1b and -2 respectively, associated with an increased in the relative attachment towards laminin and collagen IV and MMP-1 and MMP–3 overexpression. In direct coculture with fibroblasts, an increase in MMP-3, -7 and -13 transcriptional expression was observed when CCD19-Lu cells were cocultured with both miRNA-1b or -2b clones. In indirect coculture, allowing contact between fibroblasts and NCI-H460 clones conditioned media, an increase in MMP-1, -3 and -7 fibroblastic expression was measured. This study has demonstrated that TFPI-2 can influence ECM remodelling-associated genes and then act as a pericellular proteolysis inhibitor, particularly at the tumour-stroma interface
Fernandes, Julien. "Etude de la formation d'agrégats multicellulaires de carcinomes ovariens et du remodelage du microenvironnement tumoral". Cergy-Pontoise, 2010. http://biblioweb.u-cergy.fr/theses/2010CERG0457_diff.pdf.
Texto completo da fonteThe ovarian adenocarcinomas derive from the malignant process of the epithelium ovarian surface, and develop and propagate within various microenvironments. The transformed cells can exfoliate from the ovarian surface form multicellular aggregates called “spheroids”. Their dissemination involves the “physical” interaction of the ovarian cancer cells between them, allowing them to survive “in suspension” within the ascite, but also, the interaction of cells with a matrix microenvironment during their reimplantation on healthy tissue. The work of this thesis contributes to a better understanding of the molecular mechanisms involved during the interactions within tumoral multicellular aggregates as well as during their dissemination. The role of the adhesive system consisted of the vitronectine and his receptor, integrin αv, as well as that of the fibronectine were more particularly studied
Saifi, Majda. "Etude du microenvironnement cellulaire non tumoral sur des ganglions de patients atteints de lymphome folliculaire". Montpellier 2, 2008. http://www.theses.fr/2008MON20225.
Texto completo da fonteHilmi, Marc. "Microbiote intra-tumoral et hétérogénéité de l'adénocarcinome du pancréas". Electronic Thesis or Diss., Université Paris sciences et lettres, 2024. http://www.theses.fr/2024UPSLS017.
Texto completo da fontePancreatic ductal adenocarcinoma (PDAC) is one of the cancers with the poorest prognosis, and its incidence is increasing. Treatment options remain limited. PDAC is characterized by an abundant stroma composed mainly of extracellular matrix, fibroblasts (CAFs) and immune cells. The heterogeneity of this cancer may partially explain the failure of the various therapeutic strategies (including immunotherapy) evaluated to date in PDAC. PDAC presents a uniquely favorable environment for bacterial colonization due to the permeable vascularity of tumor vessels, frequent immunoexclusion and intratumoral hypoxia containing nutrient-rich necrotic regions for bacteria. Furthermore, the characteristics of tumor and stromal cells condition the localization of bacteria within tumors. The hypothesis is that the intratumoral microbiota plays a part in the complexity of PDAC, with mutual interactions between bacteria, tumor cells and stromal cells. Firstly, several methods for bacterial analysis in replicates of human PCA samples were developed and compared. The Qiagen amplification kits targeting one or more variable regions of the 16S ribosomal RNA gene are relatively similar. Use of the Qiagen amplification kit was deployed in an ancillary study of the SHIVA01 trial, showing the link between bacterial diversity, the immune component and survival in patients with different types of cancer, reinforcing the hypothesis of a microbiota-immunity-cancer axis. The development of a personalized capture kit proved inconclusive, at least in part due to the lack of specific capture of bacteria compared with human genes. A pipeline based on ribo-depleted RNA sequencing using several filter techniques and read alignment was developed on several types of formalin-fixed and paraffin-embedded samples. The heterogeneity of tumor and stromal cells was studied using image analysis techniques. For tumor cells, a multi-step process was used to rigorously select markers in immunohistochemistry capable of differentiating molecular subtypes of PDAC, and to easily assess tumor heterogeneity using a stacked slide tile-based approach. This panel revealed the limitations of the binary basal-like/classical classification by highlighting a major intermediate group. A high degree of intratumoral and intertumoral heterogeneity was revealed. The presence of a minor basal-like component was the most important prognostic factor. Analysis of preneoplastic lesions within the tumors gave important insights into the evolutionary process of pancreatic carcinogenesis, from a classical phenotype through an intermediate phenotype to a basal phenotype. For CAFs, a multiplex immunofluorescence technique based on 5 of their markers (aSMA, FAP, periostin, podoplanin, myosin 11) was used to assess the different types of CAFs, their interactions and their proportions within the tumor. The multidimensional study of bacteria, tumor cells, immune cells and fibroblasts within the same PDAC samples was finally carried out to link these different components
Almairac, Fabien. "Plasticité des cellules tumorales de glioblastomes : inter-conversion d’un phénotype différencié et souche en fonction du microenvironnement". Electronic Thesis or Diss., Nice, 2016. http://theses.unice.fr/2016NICE4045.
Texto completo da fonteThere is great interest but little understanding in how cancer stem cells arise. Here we show that tumor cells exhibiting stem-like properties and expression of stemness(CD133) and pluripotency markers (SOX2, NANOG, OCT4), can arise from differentiated tumor cells that are isolated from human glioblastomas. These cells could transit from a more differentiated state that cannot self-renew to a self-renewing stem-like state upon EGF/EGFR signaling. This dedifferentiation process induced expression of pluripotency markers, and restored clonal and tumorigenic properties as well as resistance to temozolomide, the chemotherapy of reference. EGF/EGFR signaling including ERK activation was crucial for this cellular reprogramming. Interestingly, expression of pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating that the cells have the capacity to change and reprogram before the cell division starts. Our findings support a model of tumor homeostasis in which tumor cells driven by environmental cues such as EGF, can spontaneously acquire stem-like properties contributing thus to the enrichment in tumor propagating cells
Almairac, Fabien. "Plasticité des cellules tumorales de glioblastomes : inter-conversion d’un phénotype différencié et souche en fonction du microenvironnement". Thesis, Nice, 2016. http://www.theses.fr/2016NICE4045/document.
Texto completo da fonteThere is great interest but little understanding in how cancer stem cells arise. Here we show that tumor cells exhibiting stem-like properties and expression of stemness(CD133) and pluripotency markers (SOX2, NANOG, OCT4), can arise from differentiated tumor cells that are isolated from human glioblastomas. These cells could transit from a more differentiated state that cannot self-renew to a self-renewing stem-like state upon EGF/EGFR signaling. This dedifferentiation process induced expression of pluripotency markers, and restored clonal and tumorigenic properties as well as resistance to temozolomide, the chemotherapy of reference. EGF/EGFR signaling including ERK activation was crucial for this cellular reprogramming. Interestingly, expression of pluripotency markers occurred before the cells re-entered the cell cycle, demonstrating that the cells have the capacity to change and reprogram before the cell division starts. Our findings support a model of tumor homeostasis in which tumor cells driven by environmental cues such as EGF, can spontaneously acquire stem-like properties contributing thus to the enrichment in tumor propagating cells
Camus, Matthieu. "Etude des paramètres immunologiques du microenvironnement tumoral associés au pronostic des patients atteints de cancers colorectaux". Paris 6, 2008. http://www.theses.fr/2008PA066020.
Texto completo da fonteLe, Rochais Marion. "Cancer colorectal : apport pronostique de l’étude pathomique du microenvironnement tumoral. Focus sur les structures lymphoïdes tertiaires". Electronic Thesis or Diss., Brest, 2024. http://www.theses.fr/2024BRES0044.
Texto completo da fonteColorectal cancer has become a major challenge for healthcare systems today due to its increasing prevalence and its impact on patients' quality of life. The anatomopathological analysis of colorectal cancer specimens, now enriched with molecular pathology data, is crucial for guiding patient treatment. However, despite advances in prognostic tools and treatments, interactions between tumor and immune cells in the tumor microenvironment are often not thoroughly evaluated in daily diagnostic practice. This thesis addresses the importance of studying the tumor microenvironment in colorectal cancer, particularly the need to better understand the role of residing structures, tertiary lymphoid structures (TLS). New techniques such as digital pathology and multiplex immunostaining offer perspectives for a more in-depth and accessible analysis of this microenvironment. Therefore, this thesis focused on characterizing TLS through multiplex imaging, developing pathomic analysis strategies, and exploring their clinical correlations to propose a clinically applicable score. This work aims to provide robust diagnostic and prognostic criteria, implementable in digitized pathology services to guide therapeutic decisions in colorectal cancer, thereby contributing to better patient management
Sulpice, Laurent. "Rôle du microenvironnement dans la progression du cholangiocarcinome intrahépatique : mécanismes moléculaires impliqués et recherche de biomarqueurs pronostiques". Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1B001/document.
Texto completo da fonteThe aim of this study was to specifically determine through a translational approach combining basic and clinical research, the role of the microenvironment in the tumor progression of intrahepatic cholangiocarcinoma (ICC). By gene expression profiling, we identified a signature that significantly discriminate the tumor stroma from non-tumor fibrous tissue, and the functional analysis of differentially expressed genes showed an enrichment in genes of the extracellular matrix , the cell cycle, the TGFb pathway and stem cell markers. Tissue microarray analysis using an independent cohort of ICC patients validated at a protein level the increased expression of selected candidate genes. Statistical analysis between basic and clinical data demonstrated that the stromal expression of Osteopontin was an independent prognostic marker for overall and disease-free survival. We also demonstrated that the preoperative serum level of Osteopontin was significantly higher in ICC patients than in healthy subjects. Our results identified the best diagnostic threshold to 57,8 ng/ml, associated with a sensitivity and specificity reaching to 80 and 100%, respectively. Moreover, we showed that level expression of stem cell markers such as EpCAM and CD44 in tumor stroma as well as in the fibrous non tumor liver tissue was correlated with recurrence, suggesting the pivotal role of cancer stem cells in ICC prognosis. In conclusion, our study confirmed the major involvement of the microenvironment in the progression of CCIH, allowed to identify two new prognostic tumor biomarkers, and highlighted new pathways for targeted therapeutics
Lazar, Ikrame. "Les exosomes, acteurs clés de la progression du mélanome : transfert entre cellules tumorales et rôle des exosomes adipocytaires dans un contexte normopondéral et d'obésité". Thesis, Toulouse 3, 2015. http://www.theses.fr/2015TOU30151.
Texto completo da fonteMelanoma is a skin cancer derived from the malignant transformation of melanocytes, cells involved in the skin pigmentation. It is now clearly established that tumor progression results in a dynamic interaction between tumor cells and their microenvironment. Among the different modes of cell communication, the secretion of nanovesicles called exosomes has been extensively studied in the last twenty years and they appear to be major actors in this communication. Indeed, they enable the transport of complex biological material that may impact the behavior of recipient cells. Whereas melanoma exosomes have been implicated in tumor progression and chemoresistance, the mechanisms associated with these processes are little known. The first part of my thesis consisted in the identification of the protein content of melanoma cell exosomes. We identified the exoproteome of seven melanoma lines with various degrees of agressivity using mass spectrometry. The obtained results highlighted the presence of a specific signature in the exosomes secreted by the most aggressive cells. Moreover, this signature was correlated with functional properties of the vesicles. Indeed, incubation of less aggressive cells with these vesicles promoted their migratory abilities. These results show the role of melanoma exosomes in cancer cell communication and in tumor progression. Among the cells composing the microenvironment of invasive melanoma, adipocytes, present in the hypodermis, represent an emerging actor in tumor progression. The group in which I did my PhD was one of the first to highlight the importance of fat cells in breast cancer aggressiveness. Whereas different studies have shown the role of adipocytes in melanoma progression, the mechanisms associated are little known. The second aim of my thesis therefore consisted in the study of the role of adipocytes in melanoma progression. We have shown that adipocytes stimulate the migratory abilities of melanoma cells and that this effect is mediated by exosomes secreted by adipocytes. Interestingly, we observed that these vesicles contain proteins involved in every step of fatty acid metabolism and induce a metabolic reprogramming of cancer cells. The increase in tumor cell migration induced by adipocyte exosomes is dependent on this metabolic remodeling. These results show that adipocyte exosome are actors of the deleterious dialogue between melanoma and adipocytes. This dialogue could be amplified in obese conditions and could explain the poor prognostic of this subtype of patients. We have shown that in obese conditions, exosome secretion by adipocytes is increased. In addition, at equal concentrations in exosomes, the effect of the vesicles secreted by adipocytes from obese mice on cancer cell migration is amplified. Adipocyte exosomes could therefore participate in the poor prognosis of obese patients. In conclusion, we have shown that exosomes represent a major player in melanoma progression. The specific pattern contained in the exosomes from aggressive cells could be used as prognostic biomarkers in melanoma. On the other hand, adipocyte exosomes induce a metabolic reprogramming of cancer cells and this leads to an increase in their migratory abilities. Understanding the role of adipocyte exosomes in tumor progression could help to stop the deleterious dialogue between adipocytes and tumor cells, particularly in obese individuals
Camus, Duboc Marine. "Chimiosensibilisation de l’adénocarcinome canalaire du pancréas par la perturbation du microenvironnement tumoral et l’augmentation de la biodisponibilité dans la cellule tumorale : effets de la cavitation ultrasonore et de l’inhibition de nrf2". Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCB113.
Texto completo da fontePancreatic ductal adenocarcinoma (PDAC) has increased in incidence over the past decade, leading it to be the fourth lethal cause of cancer in the world with a very poor prognosis, since less than 5% of patients are alive at 5 years. Many advances in the understanding of pancreatic tumorigenesis, notably on the genetic, immune and cellular stroma interactions of the tumor, have led to the development of new treatment strategies in the last decade. However, despite very encouraging pre-clinical results, none of these strategies has yet led to the emergence of a truly effective treatment in comparison with standard chemotherapy. This thesis focused on two innovative therapeutic modalities in the treatment of PDAC at a preclinical stage by studying in vitro (2D and 3D cell cultures) and in vivo (ectopic, orthotopic xenografts) the effects on the tumor growth of an inhibitor of the Nrf2 pathway (involved in oxidative stress), on the first hand, and of a physical element, ultrasound cavitation associated with liposomal chemotherapy, on the second hand. Ultrasound cavitation is a mechanical effect of ultrasound to increase the uptake of molecules or genes in cells. The feasibility and effectiveness of the combination of liposomal chemotherapy targeted by ultrasonic cavitation was evaluated in murin orthotopic models of PDAC. An ultrasound delivery system has been adapted to apply focused inertial cavitation to PDAC xenografts created after the injection of liposomal doxorubicin (L-DOX) according to a preliminary pharmacokinetic study carried out in the murine model. L-DOX, designed on unsaturated phospholipids of dioleoylphosphatidylethanolamine, was known to be stable in the bloodstream and to maximize its accumulation and release of the active drug during ultrasound delivery. This thesis shows that this therapeutic combination (L DOX and inertial cavitation) makes it possible to reduce the tumor volume in vivo in a nude mouse orthotopic model of PDAC. Inertial cavitation may be generated to increase the therapeutic effect of chemotherapybearing liposomes accumulated in the tumor with minimal mechanical effect on the surrounding tissue. Recent studies strongly suggest that Nrf2 is an ideal target against chemoresistance of PDAC. In vitro and in vivo methods were combined to examine the effect of brusatol associated with chemotherapeutic agents on cell death in addition to its impact on oxidative stress (reactive oxygen species and gluthation levels). This thesis demonstrates that the inhibition of the Nrf2 pathway via brusatol, a natural compound derived from Fructus Bruceae, potentiates the effects of chemotherapy and allows the inhibition of tumor growth in vitro on PDAC cell lines. This inhibition is accompanied by a modulation of oxidative stress by brusatol, with increasing ROS and decreasing GSH. In vivo, the combination of brusatol and oxaliplatin reduced tumor volume in two mouse models of PDAC xenograft. These results suggest the efficacy of using brusatol to combat chemoresistance and reinforce the idea that brusatol could be developed as an adjuvant to chemotherapy in PA. Clinical work was also carried out in parallel on an innovative physical treatment modality, endobiliary radiofrequency, in the management of adenoma of the ampoule of Vater, a rare tumor located between the digestive and the bilio-pancreatic systems. The results of this work will also be presented in this thesis
Jary, Marine. "Analyse du microenvironnement et de l'oncogenèse des cancers colorectaux surexprimant l’Angiopoiétine 2". Thesis, Bourgogne Franche-Comté, 2019. http://www.theses.fr/2019UBFCE016.
Texto completo da fonteColorectal cancer (CRC) is a severe and frequent disease, with important survival improvement due to therapeutic new approaches and surgical methods, even in metastatic setting. It is an heterogeneous entity, and personalized strategies are mandated, whereas few predictive and prognostic biomarkers are available in practical care. Molecular classifications are useful to better understand CRC biological characteristics, but they do not have predictive values, and seem to be inadequate for metastatic setting. Seric biomarkers are attractive since they could recapitulate tumor features, while being simpler and less expansive. There is a need to investigate surrogacy biomarkers illustrating intra tumoral microenvironment, in order to adapt treatment strategies.This thesis is about the clinical and molecular characterization of Angiopoietin 2 (ANGPT2) associated colorectal cancer. Assessment of microenvironment and peripheral immune Th1 response are performed and correlated with this entity.Prognostic value of ANGPT2 in metastatic colorectal cancer was studied in the first part of the manuscript. We described that ANGPT2 plasmatic levels were associated with a worst overall survival in metastatic setting. In the second part, using the open source transcriptomic tools, we decided to define the specific molecular signaling pathways correlated to ANGPT2 expression in CRC and its prognostic value in localized CRC. A specific signature was drawn, combining genes associated with stroma, invasion, angiogenesis, and chemo-resistance. Looking for associated secreted proteins, we could identify a seric signature (combining STC1, CD138 and ANGPT2), predictive for chemo-resistance. An negative correlation was observed between ANGPT2 signature and immune response. The last part of the thesis then explored the prognostic value of anti TERT peripheral immune Th1 response in metastatic colorectal cancer (Epitopes-CRC02 study), and validated its beneficial role for predicting OS. A negative correlation was confirmed, in seric measurement between CD4 immune response and ANGPT2.This work paves the way for individualized treatments in tumors harboring ANGPT2 associated characteristics', targeting the stromal and immune microenvironment. This immune and stromal biomonitoring is feasible and have to be associated to futures clinical studies. Future prognostic scores should probably assess the place of these biomarkers in order to improve their discriminant values
Schwenzer, Anja. "Mécanisme et conséquences de la répression de DKK1 par la ténascine-C, une molécule du microenvironnement tumoral". Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ086/document.
Texto completo da fonteTenascin-C (TNC) is a major component of the tumor specific extracellular matrix and its expression has been linked to tumor angiogenesis and metastasis. I demonstrated that TNC downregulates the expression of the Wnt signalling inhibitor DKK1 and by that enhances Wnt/-catenin signalling. Reduced stress fibre formation in the presence of TNC was identified as a major mechanism contributing to DKK1 downregulation. The activity of the actin-regulated SRF co-transcription factor MKL1 was found to be reduced in the presence of TNC. My results indicate that TNC-regulated MKL1 function maybe one, but not the major mechanism of DKK1 regulation by the actin status and that other factors, presumably regulated by actin stress fibres, are involved. Enhanced Wnt signalling activity downstream of TNC-induced DKK1 downregulation might be a major mechanism by which TNC promotes tumor progression. Furthermore, this study discovered a novel mechanism of regulating the Wnt inhibitor DKK1 by the integrity of the actin cytoskeleton
Chatelain, Camille. "Rôles des cellules myéloïdes du microenvironnement tumoral lors d’une infection par le virus oncolytique de la rougeole". Electronic Thesis or Diss., Nantes Université, 2023. https://archive.bu.univ-nantes.fr/pollux/show/show?id=f16e2a89-845b-4d19-88b8-e1cecfa63242.
Texto completo da fonteAll nucleated cells can detect, signal and limit viral infections to their neighboring cells and to the immune system through the secretion of type I interferons (IFN). Attenuated measles virus (MV) replicates preferentially in tumor cells of malignant pleural mesothelioma (MPM) rather than in healthy cells, as they often have defects in this pathway. However, non-tumoral cells in the microenvironment possess functional antiviral pathways and can produce IFN upon infection. In this study, we aimed to determine the role of monocyte-derived myeloid cells on MV oncolytic activity and their contribution to anti-tumor immunity. We cultured MPM tumor cells with monocytes previously differentiated, or not, into macrophages or dendritic cells. These co- cultured cells were then infected with MV. Our results show that monocyte-derived cells can limit the oncolytic action of MV in a patient- specific manner. By producing IFN, these cells compensate for the lack of IFN expression by tumor cells, protecting them from the oncolytic action of MV. However, in response to the virus, these myeloid cells also generate an inflammatory response, which could stimulate the patient's antitumor immune response. In conclusion, this study highlights the importance of taking non-tumor cells into account when assessing the oncolytic activity of MV
Lauriol, Jessica. "Agressivité du mélanome liée à l'expression du complexe majeur d'histocompatibilité de classe II et à la plasticité cellulaire induite par le microenvironnement". Paris 7, 2010. http://www.theses.fr/2010PA077033.
Texto completo da fonteThe rising incidence of cutaneous melanoma and the low effectiveness of treatments of metastatic forms imply alternative therapies should be developed and that knowledge of its development should be improved. This thesis aims first to explain the known association between MHC class II abnormal constitutive expression by melanoma cells and unfavorable clinical outcome. This study shows that, although necessary, MAPK signalling activation is not sufficient to induce MHC class II expression and that this expression is correlated to but not regulated by NFKB activity. Moreover, MHC class II expression coincides with expression and production of chemokines associated with angiogenesis and metastasis, which provides a rationale for its association with poor prognosis. Secondly, we wondered to which extent microenvironment influences melanoma aggressiveness. In that purpose, we chose to study tumor initiating potential, invasive and differentiation abilities of melanoma cells cultured under three-dimensional condition in stem cell media. We provide evidence that this culture method increases invasive abilities of melanoma cells and directs them toward dedifferentiated phenotype marked by embryonic stem cell transcription factor expression and by an increase in differentiation potential. Finally, we put forward that the expression of embryonic stem cell transcription factors might be responsible for the observed alterations in aggressiveness properties of melanoma cells. This thesis supports actual concerns about the cancer stem cell concept and the actual hypothesis that proposes to define stem ness not as an entity but rather as a state, responding to environmental cues
Gourdin, Nicolas. "Biologie des lymphocytes T CD4+CD73+ et sensibilité à l’immunosuppression médiée par les Treg dans le microenvironnement tumoral". Thesis, Lyon, 2016. http://www.theses.fr/2016LYSE1101.
Texto completo da fonteRegulatory T cells (Tregs) play a key role in the immune system tolerance. In pathophysiology, a quantitative or functional defect in Treg promotes development of autoimmune diseases while their presence involved in tumor development. In particular, the presence of Treg in the immune stromal tumor environment (Ti-Treg) is associated with a poor prognosis for survival of patients suffering from breast cancer and ovarian cancer. Treg are recruited in the tumor through the CCL22 / CCR4 axis and are activated and amplified through their interaction with pDC expressing costimulatory axis ICOS-ICOSL and promoting their suppressive capacity. This project contributes to the efforts made in recent years to understand suppressive mechanisms of Treg operating in human tumors. Indeed, this project demonstrates that humans Ti-Treg strongly express the membrane ectonucleotidase CD39. This extracellular enzyme catabolizes Adenosine-triphosphate (ATP) to adenosine-monophosphate (AMP) which can then be degraded through the ectonucleotidase CD73 into Adenosine (Ado). While ATP is an Alarmine (extracellular danger signal) that particularly contributes to the inflammasome activation, Ado has strong immunosuppressive effect which is illustrated in patients with deficiency of the enzyme Adenosine Deaminase (ADA), which cannot degrade Ado into Inosine (Ino) and develop an Immunodeficiency Syndrome Severe. Unlike murine Treg, human Treg do not express CD73. However we could identify a non-regulatory population of CD4+ T cells (Tconv) expressing CD73, and thus cooperating with CD39+ Treg for Ado generation. This population has an increased capacity of secretion of inflammatory cytokines (IFNgamma, IL-17A, IL-22, GM-CSF) and the expression of molecules (CXCR3, CCR6, MDR1) characteristics of Th1/17 profile. Moreover, these cells appear to be less sensitive to regulation mediated by the immunocheckpoints (ICPs), such as PD-1, CTLA-4, TIM-3, TIGIT. Nonetheless CD73+ Tconv are sensitive to Ado generated in cooperation with CD39+ Treg which induce the inhibition of their proliferation and their secretion of IFNgamma and GM-CSF but not IL-17A . Ado acting locally, can also inhibit the Tconv CD73neg in the surrounding environment. All these results show that the expression of CD73 characterizes a population of multifunctional effector T CD4 Th1/17, which is a specific and cooperative target of Treg immunosuppression in the tumor environment. In addition the action of Ado transforms this potent anti-tumor effector to potentially pro-tumor cells which only secret IL17
Toulet, Aurélie. "Dissémination du cancer de la prostate : un chemin pavé de gras". Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30237.
Texto completo da fonteProstate cancer (PCa) is the most common cancer in men in Western countries. It is a heterogeneous disease ranging from indolent to very aggressive, life-threatening forms. The molecular mechanisms implicated in tumor progression have not been clearly identified yet. The aim of my thesis was to characterize the role of one of the main components of prostate cancer microenvironment, the periprostatic adipose tissue (PPAT), an adipose depot surrounding the prostate. Indeed, PPAT invasion by tumor cells is recognized as a poor prognosis factor in PCa, suggesting that PPAT (and more specifically their main cellular component, adipocytes) could be a key player in tumor progression. First, we focused on the paracrine role of this PPAT in the context of obesity, which is known as a poor prognosis factor for PCa. We have shown that a chemokine secreted by adipocytes (CCL7), by binding to its receptor CCR3 on the surface of tumor cells, is able to chemoattract these cells outside of the prostate gland, thus favoring the local dissemination of PCa, this phenomenon being amplified in the context of obesity. Once tumor cells have crossed the prostatic capsule, they come into direct contact with PPAT adipocytes and a bidirectional crosstalk between the two cell types is established. Our results show that this crosstalk begins with an increased lipolysis in adipocytes, that release free fatty acids (FFA) then taken up by tumor cells. Those FFA activate a signaling cascade in tumor cells, by stimulating the expression of pro-oxidant enzymes, especially NOX5 (NADPH-oxidase 5), that leads to an increase in intracellular ROS (Reactive Oxygen Species). This accumulation of ROS leads to an increase in the expression of some MMP (Matrix Metalloproteinases) participating in tumor invasion. We have also shown that all this signaling pathways is upregulated in a context of obesity. Aside from obesity, recent studies suggest that some patients could present an unusual accumulation of PPAT, independently from BMI (Body Mass Index), those abundant PPAT being correlated with more aggressive prostate cancers. We have shown, by measuring PPAT volume on the MRI of 147 patients with prostate cancer, that PPAT abundance is dissociated from BMI and the accumulation of other adipose depots. [...]
Bod, Lloyd. "Rôle de l'enzyme IL4-induced gene 1 (IL4l1) en contexte tumoral et sur la physiologie des lymphocytes B". Thesis, Sorbonne Paris Cité, 2016. http://www.theses.fr/2016USPCB107/document.
Texto completo da fonteImmunotherapy is one of the most promising advance in cancer treatments. It remains essential to identify new targets to maximize the anti-tumor immune response. Enzymes involved in amino acid metabolism have been described to impede these responses and thus promote tumor progression. They became good therapeutic targets. IL-4-induced gene 1 (IL4I1) is a phenylalanine oxidase which, over the last decade, was unveiled as a real tool for peripheral tolerance. However its functions remain largely unexplored. During my PhD thesis, I studied the immunoregulatory properties of IL4I1 in a tumoral context involving a spontaneous melanoma model (Ret mice), but also in the B cell physiology. First, my results highlight that the IL4I1 enzymatic activity is positively correlated with disease aggressiveness in the spleen of Ret mice. Interestingly, genetic inactivation of IL4I1 in this model (RetIL4I1KO) delayed the development of both primary tumor and metastatic dissemination. We demonstrate that IL4I1, mainly expressed by myeloid cells, has the ability to shape the immune compartment within the tumor microenvironment, through recruitment of myeloid cells instead of activated T cells. Furthermore, my data in mice deficient for IL4I1 (IL4I1KO) have emphasized a crucial role of IL4I1 in regulating many steps of B cell biology. Indeed, IL4I1KO mice exhibit an accelerated B cell egress from the bone marrow, resulting in the accumulation of peripheral follicular B cells. These mice have a high serum level of natural immunoglobulins and auto-reactive antibodies. We also demonstrate that IL4I1 controls the germinal center reaction, plasma cell differentiation and specific antibody production in response to a T-dependent antigen immunization. In vitro, the absence of IL4I1 in B cells increases their proliferation and the activation of signaling pathways upon B cell receptor (BCR) engagement. Thus, our results reveal a key role of IL4I1, which negatively controls the BCR-dependent activation. Regarding these effects of IL4I1 on B cell biology, it remains important to evaluate whether the BCR-dependent hyperreactivity in IL4I1KO mice contributes in the tumor control