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Dekky, Bassil. "Micro-environnement et cancer : rôle des adamalysines dans la progression tumorale". Thesis, Rennes 1, 2018. http://www.theses.fr/2018REN1B046.
Pełny tekst źródłaTumor microenvironment plays a major role in tumor growth, invasion and resistance to treatments. Understanding the mechanisms that regulate communication between tumor cells and their microenvironment is essential to develop effective therapies. In this context, Adamalysin extracellular proteases play major role in tumor progression, by modulating the extracellular matrix (ECM) remodeling and the bioavailability of cell communication mediators such as cytokines, chemokines and growth factors. My work revealed a new interaction between ADAM12, a mesenchymal marker induced during the epithelial-mesenchymal transition (EMT) dependent on TGF-β and ZO-1, a scaffolding protein expressed in tight junctions of epithelial cells. Both proteins are redistributed in invadopodia-like structures to promote ECM degradation. In a second study, we carried out an in silico screening that allowed us to identify a cluster of Adamalysin genes co-expressed in patients with hepatocellular carcinoma. Among these Adamalysins we have studied the protein ADAMTS12 in more details, and shown that this protein plays a key role in the development of liver fibrosis involving an acute or chronic inflammatory response
Guillet, Pierre. "Infections nosocomiales et cancer : rôle des facteurs environnementaux". Aix-Marseille 2, 1992. http://www.theses.fr/1992AIX20655.
Pełny tekst źródłaBONNIER, PASCAL. "Aspects epidemiologiques et pronostiques recents des cancers du sein. La tumeur et son environnement". Aix-Marseille 2, 1997. http://www.theses.fr/1997AIX20667.
Pełny tekst źródłaEmeville, Elise. "Polluants Organochlorés et Risque de Survenue du Cancer de la Prostate. Interactions Gène-Environnement". Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1B016/document.
Pełny tekst źródłaProstate cancer (PCa) is the most frequent type of cancer in Western countries. Advanced age, ethno-geographic origin and the presence of a family history of CaP are the main clearly established risk factors. The effects of exposure to synthetic chemicals with hormonal properties, also called endocrine disruptors (EDCs), on PCa are also are suspected. The main objective of this thesis is to evaluate the relationships between plasma concentration of persistent organochlorine pollutants with hormonal properties, such as DDE (the main metabolite of DDT) and PCBs as well polymorphisms of selected genes involved in xenobiotic (GSTM1, GSTT1) and estrogens (CYP17, CYP19, CYP1B1, COMT, UGT1A1) metabolism, and the occurrence of PCa or its recurrence after treatment with radical prostatectomy. This project is based on data obtained from the population-based case-control study (KARUPROSTATE) in Guadeloupe and from cases treated by radical prostatectomy
Dumond, Aurore. "Les Neuropilines, des cibles pertinentes dans le traitement du cancer du rein à cellules claires". Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6033.
Pełny tekst źródłaClear cell Renal Cell Carcinoma (ccRCC) represent 80% of kidney cancers. Around 80% of ccRCC present an inactivation of the von Hippel-Lindau gene (VHL) gene, leading to the stabilization the Hypoxia Inducible Factors 1 and 2 alpha (HIF-1 and 2α) and to the overexpression of their targeted genes such as the « Vascular Endothelial Growth Factor (VEGF) », the principal angiogenic factor. Thus, ccRCC are one of the most vascularized cancers and represent a paradigm for anti-angiogenic treatments (AAT). Currently,15 different AAT have obtained FDA and EMA approval. They are divided in three different families:- antibodies targeting VEGF- tyrosine-kinase inhibitors (TKi) that target receptors involved in neo-angiogenesis such as the current reference therapy, sunitinib- decoy receptors that trap VEGFA and PlGF such as aflibercept.Overexpression of VEGF (involved in angiogenesis) and of the other member of the VEGF family, VEGFC (involved in lymphangiogenesis) is also a key phenomenon of immune tolerance. Therefore, immune-checkpoint inhibitors (anti PD-1, anti PD-L1 and anti CTLA-4) also obtained an approval for the treatment of ccRCC.However, relapse on TKi are frequently observed after a few months and immune-checkpoint inhibitors present a long-lasting effect only in 20% of patients. Hence, ccRCC is still an uncurable disease and new therapeutic strategies targeting concomitantly angiogenesis/lymphangiogenesis and immune tolerance are urgently needed. Neuropilins (NRP1 and NRP2) are co-receptors of VEGF and VEGFC and are expressed on vascular and lymphatic endothelial cells, on tumor cells and on immune cells. Hence, they may represent ideal targets to inhibit the drivers of ccRCC aggressiveness.My thesis describes the relevance of targeting the NRP1 and NRP2 signaling pathways in ccRCC by a genetic (invalidation of the two genes by CRISPR/Cas9) and by a pharmacological approach (development of a NRPs inhibitor). The preclinical results generated represent an essential first step for the initiation of early phase clinical trials for patients with treatment failure
Legendre, Claire. "Adaptation cellulaire et moléculaire des cellules d'hépatome humain HepaRG à un environnement hypoxique". Rennes 1, 2009. http://www.theses.fr/2009REN1S055.
Pełny tekst źródłaReduced oxygen level, or hypoxia, is frequently encountered in solid tumours and contributes to drug resistance. Hypoxia is also associated with invasive phenotype and correlated to poor prognosis and mortality. The role of hypoxia in hepatocellular carcinoma biology is not fully understood. Therefore, there is a need for developing in vitro models mimicking hypoxic conditions find within solid tumours using hepatic tumour cells. Highly differentiated human hepatoma HepaRG cells respond to hypoxia by a switch from aerobic to anaerobic glycolysis. Moreover, we showed that hypoxia also repressed drug-metabolizing enzymes expression. These repressions could therefore strongly compromise chemotherapy effectiveness on tumour cells within hypoxic environment. Furthermore, HepaRG cells cultured under hypoxic versus normoxic conditions might represent a new strategy to test different types of therapeutic molecules in order to predict their effectiveness
Clement-Colmou, Karen. "Impact du fractionnement de la radiothérapie sur le microenvironnement vasculaire tumoral". Thesis, Nantes, 2018. http://www.theses.fr/2018NANT1029/document.
Pełny tekst źródłaThe 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
Atieh, Youmna Marie Lyne. "Interplay between cancer cells and cancer-associated fibroblasts in tumor invasion and metastasis formation". Electronic Thesis or Diss., Paris 6, 2017. http://www.theses.fr/2017PA066140.
Pełny tekst źródłaCancer-associated fibroblasts (CAFs) are the most abundant cells of the tumor stroma. Their capacity to contract the matrix and induce invasion of cancer cells has been well-documented. However, it is not clear if CAFs remodel the matrix by other means (degradation, matrix deposition or stiffening). This project demonstrates that CAFs induce cancer cell invasion through assembly of FN into the matrix. CAFs assembled fibronectin (FN) mainly via integrin α5 but integrin αvβ3 was necessary for initial mechanosensing and fibrillar adhesion formation. In the absence of FN, contractility of the matrix by CAFs is preserved. When degradation is impaired, CAFs retain the capacity to induce invasion in a FN-dependent manner. In all cases, the levels of expression of integrin β3 and the amount of assembled FN was directly proportional to the invasion induced by fibroblast populations. Our results highlight FN assembly and integrin β3 as new hallmarks of CAFs. We also noticed that cancer cells migrate towards CAFs suggesting a possible chemotactic response. Using Dunn’s chemotaxis chamber, we found that cancer cells migrate along a gradient of CAF-conditioned media and a gradient of fibronectin. Finally, orthotopic injections of cancer cells and CAFs in the colon wall of mice revealed that CAFs stimulate metastasis of cancer cells to the liver. In conclusion, our data show that CAFs promote cancer cell invasion by depositing fibronectin that can guide cancer cells favoring metastasis formation
Tcheandjieu, Gueliatcha Catherine Ines. "Etude des facteurs de risque génétiques et des interactions gène-environnement dans les cancers différenciés de la thyroïde". Thesis, Université Paris-Saclay (ComUE), 2017. http://www.theses.fr/2017SACLS064.
Pełny tekst źródłaContext : Differentiated thyroid cancer (DTC) incidence is characterized by considerable geographic and ethnic variations. Particularly high incidence rates were observed in Melanesian women of New Caledonia. Except for the exposure to ionizing radiation in childhood and obesity, the role of other DTC risk factors is not clearly established. Genetic factors have been suggested to play an important role in DTC risk since epidemiological studies have shown that DTC has a higher familial relative risk than any other cancers. Linkage studies in multiple-case DTC families and candidate gene studies have identified polymorphisms in several genes but very few have been replicated so far. Genome-wide association studies (GWAS) also identified several DTC susceptibility loci with the most robust associations reported on the loci 9q22 and 14q13. Only few susceptibility loci were highlighted by GWAS and the identified variants were shown to account less than 10% of the DTC familial risk, emphasizing that much remains to be discoveredObjectives: The main objective of this work was to study the role of genetic risk factors and their interaction with environmental factors in DTC risk. More specifically, we aimed to: 1) replicate the association between DTC risk and polymorphisms reported in candidate gene and GWAS studies in 2 case-control studies conducted in Metropolitan France and New Caledonia; 2) identify potential causal variants of DTC risk in GWAS loci 9q22 and 14q13 using fine-mapping approach; 3) identify new genetic risk factors for DTC in women using pathway approach by pooling data from 2 case-control studies conducted in France and USA..Materials and methods: The analysis of the candidate genes and of the GWAS loci were based on a European population of 508 cases and 621 controls from 2 case-control studies conducted in metropolitan France (CATHY study) and in New Caledonia (NC study) and, a Melanesian population of 156 cases and 114 controls from the NC study. The pathway analysis was conducted in a first step on European women from the CATHY study (365 cases/376 controls) and from the Young-Thyr study (83 cases /93 controls) both conducted in metropolitan France. In a second step, we pooled the data from CATHY/Young-Thyr study and USRT/UTMDACC study (332 cases/443 controls) conducted in the United States.Results: In Europeans and Melanesians, we found no association with polymorphisms reported previously by candidate genes studies. However, we observed that among these genes, GSTM1 and GSTT1 may modulate the associations between DTC risk and obesity or alcohol consumption. Some polymorphisms identified in GWAS studies at loci 9q22, 14q13 and 2q35 were replicated in Europeans and in Melanesians. In the GWAS loci 9q22 and 14q13, we identify new variants that can be functionally related to DTC pathogenesis in Europeans and Melanesians. We also reported interactions between some of these variants and parity or tobacco smoking. The analysis of candidate pathways in European women showed interactions between alcohol consumption or tobacco smoking and genes involved in the metabolism of these compounds and, between age at first menarche or oral contraception and genes involved in biosynthesis and metabolism of sex steroid hormones
Masson, Olivier. "Cancer du sein et micro-environnement tumoral : rôle de la protéase cathepsine D adipocytaire et de son récepteur LRP1". Thesis, Montpellier 1, 2010. http://www.theses.fr/2010MON1T027.
Pełny tekst źródłaThe aspartyl protease cathepsin D, overexpressed and hyper-secreted by epithelial breast cancer cells is a poor prognosis factor in breast cancers and stimulates cancer cell growth and metastasis formation. It also affects the tumor microenvironment, inducing the fibroblasts invasive outgrowth. Our works have shown that the LDL receptor-related protein1, LRP1, is the fibroblastic receptor for cathepsin D. LRP1 is highly expressed in adipocytes. Clinical studies indicate that obesity is a risk factor in many cancers, including breast cancer in postmenopausal women.During this thesis, we studied the role of cathepsin D and LRP1 in adipocytes, which are the prominent cell type in the tumor microenvironment of breast cancers. Our results indicate that cathepsin D and LRP1 are overexpressed in human and mouse obese adipose tissue. Furthermore, the expression of cathepsin D is increased during adipocyte differentiation. Finally, the inhibition of the cathepsin D and LRP1 expression inhibits adipogenesis indicating their key role in this process.All these results suggest that cathepsin D and its receptor LRP1 could be potential therapeutic targets in the treatment of obesity
Tang, Alexandre. "Rôle des lymphocytes B dans l'immunité anti-tumorale dans un modèle murin de cancer lié au papillomavirus humain (HPV)". Sorbonne Paris Cité, 2015. http://www.theses.fr/2015USPCC248.
Pełny tekst źródłaEnhancing ante-tumor immunity and preventing tumor escape are efficient strategies to increase the efficacy of therapeutic cancer vaccines. However, the treatment of advanced tumors remains difficult, mainly due to the immunosuppressive tumor microenvironment. Regulatory T cells (Tregs) and myeloid-derived suppressor cells (MDSCs) have been extensively studied and their role in suppressing tumor immunity is now well established. In contrast, the role of B lymphocytes in tumor immunity remains unclear, since B cells can promote tumor immunity or display regulatory functions to control excessive inflammation, mainly through IL-10 secretion. Here, we demonstrate in a mouse model of HPV-related cancer that B cells play a detrimental role in anti-tumor immunity and participate in tumor promotion. Indeed, in B cell-deficient MuMT mice, the tumor growth was impaired and tumor rejection occurred due to a strong T cell dependent anti-tumor response. We show that B cells expressing PD-L1, CD39 and Ly6A/E markers accumulate in the tumor draining lymph node (dLN) which can directly impact T cell immunity. This inhibition is IL-10 independent since B cells from tumor-bearing mice did not show an increased ability to secrete IL-10 and deficiency in IL-10 production did not impair tumor growth. Furthermore, genetic analysis based on Single Nucleotide Polymorphisms (SNPs) also evidenced a relation between tumor rejection in MuMT mice and reactive oxygen species production and NK cell activity. Our results suggest that targeting B cell populations could enhance anti-tumor response and improve the efficacy of therapeutic cancer vaccines
Pourreyron, Céline. "Étude des interactions entre les cellules tumorales et leur environnement dans les tumeurs endocrines digestives : approche expérimentales in vivo et in vitro". Lyon 1, 2003. http://www.theses.fr/2003LYO10052.
Pełny tekst źródłaCruard, Jonathan. "Le Myélome Multiple et son environnement immunitaire à l’échelle de la cellule unique". Electronic Thesis or Diss., Nantes Université, 2023. http://www.theses.fr/2023NANU1033.
Pełny tekst źródłaMultiple myeloma (MM) is a hematological cancer in which the tumor cell is derived from the long-lived plasma cell. This pathology is characterized by strong heterogeneity at various levels. This heterogeneity includes alterations intrinsic and extrinsic to tumors, which have an impact on patient prognosis and response to treatment. The development of single-cell sequencing technologies has enabled us to explore new aspects of this diversity. The work presented here first explores the diversity of response to dexamethasone within the MM.1S cell line of MM. This work shows that within this homo- geneous tumoral population there is a diversity of response to treatment. Secondly, we worked on MM together with its immune environment at the single-cell level. In order to better understand how the immune environment evolves during the course of the disease, but also under the pressure of treatment. This as- pect is even more essential as the most recent treatments directly involve the immune environment by redirecting it against the tumor. A better characterization of the immune environment could therefore enable us to better predict the response to treatments, as well as their consequences for the immune environment
Lopès, Amélie. "Infection chronique par les souches Escherichia coli colibactine-positives : impacts sur le micro-environnement immunitaire colique dans le contexte du cancer colorectal". Thesis, Université Clermont Auvergne (2017-2020), 2018. http://www.theses.fr/2018CLFAS006/document.
Pełny tekst źródłaMultiple evidences show the role of microbiota in colorectal cancer (CRC) development and anti-tumor drug responses. Various independent studies demonstrated that Escherichia coli strains with specific invasive properties and virulence factors abnormally colonize CRC patient mucosa. More than half of these strains harboring the pks pathogenic island coding for the synthesis of a genotoxin named colibactin. This genotoxin can impair directly DNA synthesis or cellular cycle and provokes genomic instability. Many different studies highlighted others bacteria-associated mechanisms leading to colorectal carcinogenesis as crosstalk between immune responses, inflammatory events, and/or cell senescence induction. However, the mechanisms by which CRC-associated E. coli promote colorectal carcinogenesis are diverse and some-what specific to the animal models and the microbial status of the animals (germ-free or Specific Pathogen Free). However, modulation of immune response and inflammation seems to play a central role in these mechanisms.The aim of this work was to evaluate the impact of chronic infection by colibactin-positive E. coli in a CRC reference model, the APCMin/+ mice colon focusing on inflammation and immune cells. First, we developed and validated an innovative method to quantify immune cells in APCMin/+ mice, based on immunostainings and digital image analysis. Thanks to the machine learning approach, we succeeded to precisely discriminate, quantify and localize these cells in three regions of interest: mucosa, lymphoid follicle and tumor. After the complete validation of this new method, we accurately examined the impact of a chronic infection with a colibactin-positive E. coli strain isolated from a CRC patient, on the APCMin/+ colon immune microenvironment. Particularly, we demonstrated the induction of a pro-carcinogenic environment by these bacteria in vivo, in a colibactin dependent manner, with both an increase of the pro-inflammatory neutrophil enzyme (myeloperoxydase) and cells, and a decrease of anti-inflammatory cytokines. This carcinogenesis-associated context is emphasized by the decrease of anti-tumor T cells in colon mucosa and tumor. This phenomenon is equally observed in CRC patients, with a decrease of T cells in patient tumors, which are harboring the colibactin-positive E. coli. Finally, we demonstrated for the first time that colibactin-positive E. coli infection induce resistance to an anti-tumor immunotherapy treatment based on PD-1 immune checkpoint blockade. Our results suggest that the decrease of T cells induce by colibactin-positive E. coli chronic infection could lead to the impairment of an immunotherapy response. To conclude, this thesis work confirms the crosstalk between some specific bacteria from intestine microbiota and the immune system in carcinogenesis and anti-tumor drug efficacy. In longer term, these results suggest that the colibactin-positive E. coli presence could be used as a poor prognosis biomarker in CRC and particularly to predict response to anti-PD-1 immunotherapy
Thibault, Benoît. "Rôle des hospicells dans la progression et la dissémination tumorale ovarienne : implication particulière des macrophages". Toulouse 3, 2013. http://thesesups.ups-tlse.fr/2714/.
Pełny tekst źródłaOvarian cancer is the leading cause of death from gynaecological cancer in the world and is characterized by peritoneal dissemination, ascite development and a high rate of mortality. Advanced epithelial ovarian cancer is treated by a cytoreductive surgery and chemotherapy but most of patients experience a recurrence with the apparition of a chemoresistance. The microenvironment could be implied in this recurrence and the resistance to chemotherapies. Rafii et al. Isolated original cells, called Hospicells, from ascitic fluid of patients with a grade III ovarian cancer. Although their origin is unknown, these cells share homologies with mesenchymal stem cells (MSCs) or carcinoma associated fibroblasts (CAFs). Hospicells are able to enhance the chemoresistance of ovarian cancer cells via a membrane exchange of chemotherapeutic drugs efflux proteins. Moreover, Hospicells present immunosuppressive properties as the inhibition of proliferation and cytokine production of T lymphocytes. The research carried out in the laboratory showed that Hospicells can also enhance tumour growth by activating the angiogenesis. My PhD focused on the description of interactions between Hospicells and ovarian cancer cells or other stromal cells, responsible for the pro-tumoral effects described previously. I highlighted in vitro and in vivo (intraperitoneal xenograft of ovarian cancer cells in immunosuppressed mice) that Hospicells are able, by a secreted factor, to induce the production of IL-6, IL-8 and VEGF (pro-angiogenic cytokines) in ovarian cancer cells. However, while Hospicells always enhance tumor growth in vivo, the results obtained in vitro are ovarian cancer cell line specific. Complementary data obtained in the laboratory showed that the interactions between ovarian cancer cells and Hospicells in vitro are not sufficient to explain the activation of angiogenesis highlighted in vivo. Therefore, we looked for another potential cellular partner for Hospicells in the tumor microenvironment that could explain the pro-tumoral effects observed in vivo. I showed that Hospicells can activate the recruitment of macrophages toward ovarian tumors. Hospicells can, by a secreted factor, polarize monocytes/macrophages into a pro-tumoral phenotype of tumor associated macrophages (TAMs) and trigger the secretion by these cells of IL-6, IL-8, VEGF, GM-CSF, IL-1, MCP-1, etc. . . I also studied the cellular pathways potentially implied in the secretion of IL-6, IL-8 and VEGF by ovarian cancer cells or macrophages, induced by Hospicells. Although these pathways are still under study, I highlighted that the TNF-alpha, the IL-1alpha, estrogens, Fas Ligand, the S1P, the LPA and the NO are not implied in this secretion of cytokines. However, I showed an implication of the COX-2 pathway in the VEGF synthesis induced by Hospicells in macrophages. We thus make the hypothesis that Hospicells are able to establish interactions with ovarian cancer cells and tumor macrophages, resulting in a secretion of pro-tumoral cytokines. Hospicells allow the activation and polarization of monocytes/macrophages into a pro-tumoral phenotype enhancing the recruitment of new macrophages toward the tumor site. These interactions allow an enhanced tumor growth and angiogenesis, and can activate metastatic process and the acquisition of a chemoresistance. These results underline the importance of targeting the microenvironment, especially the Hospicells, in order to improve the management of patients with ovarian cancer
Masson, Olivier. "Cancer du sein et micro-environnement tumoral : rôle de la protéase cathepsine D adipocytaire et de son récepteur LRP1". Montpellier 1, 2009. http://www.theses.fr/2009MON1T029.
Pełny tekst źródłaThe aspartyl protease cathepsin D, overexpressed and hyper-secreted by epithelial breast cancer cells is a poor prognosis factor in breast cancers and stimulates cancer cell growth and metastasis formation. It also affects the tumor microenvironment, inducing the fibroblasts invasive outgrowth. Our works have shown that the LDL receptor-related protein 1, LRP1, is the fibroblastic receptor for cathepsin D. LRP1 is highly expressed in adipocytes. Clinical studies indicate that obesity is a risk factor in many cancers, including breast cancer in postmenopausal women. During this thesis, we studied the role of cathepsin D and LRP1 in adipocytes, which are the prominent cell type in the tumor microenvironment of breast cancers. Our results indicate that cathepsin D and LRP1 are overexpressed in human and mouse obese adipose tissue. Furthermore, the expression of cathepsin D is increased during adipocyte differentiation. Finally, the inhibition of the cathepsin D and LRP1 expression inhibits adipogenesis indicating their key role in this process. All these results suggest that cathepsin D and its receptor LRP1 could be potential therapeutic targets in the treatment of obesity
De, Vlieger Paul. "Création d'un environnement de gestion de base de données "en grille" : application à l'échange de données médicales". Phd thesis, Université d'Auvergne - Clermont-Ferrand I, 2011. http://tel.archives-ouvertes.fr/tel-00719688.
Pełny tekst źródłaAtieh, Youmna Marie Lyne. "Interplay between cancer cells and cancer-associated fibroblasts in tumor invasion and metastasis formation". Thesis, Paris 6, 2017. http://www.theses.fr/2017PA066140/document.
Pełny tekst źródłaCancer-associated fibroblasts (CAFs) are the most abundant cells of the tumor stroma. Their capacity to contract the matrix and induce invasion of cancer cells has been well-documented. However, it is not clear if CAFs remodel the matrix by other means (degradation, matrix deposition or stiffening). This project demonstrates that CAFs induce cancer cell invasion through assembly of FN into the matrix. CAFs assembled fibronectin (FN) mainly via integrin α5 but integrin αvβ3 was necessary for initial mechanosensing and fibrillar adhesion formation. In the absence of FN, contractility of the matrix by CAFs is preserved. When degradation is impaired, CAFs retain the capacity to induce invasion in a FN-dependent manner. In all cases, the levels of expression of integrin β3 and the amount of assembled FN was directly proportional to the invasion induced by fibroblast populations. Our results highlight FN assembly and integrin β3 as new hallmarks of CAFs. We also noticed that cancer cells migrate towards CAFs suggesting a possible chemotactic response. Using Dunn’s chemotaxis chamber, we found that cancer cells migrate along a gradient of CAF-conditioned media and a gradient of fibronectin. Finally, orthotopic injections of cancer cells and CAFs in the colon wall of mice revealed that CAFs stimulate metastasis of cancer cells to the liver. In conclusion, our data show that CAFs promote cancer cell invasion by depositing fibronectin that can guide cancer cells favoring metastasis formation
Gobert, Michael. "Le cancer du sein, un environnement immunotolérant : émergence, mécanismes d'action des lymphocytes T régulateurs CD4+ CD25+ et relations avec les cellules dendritiques plasmacytoïdes". Lyon 1, 2008. http://www.theses.fr/2008LYO10271.
Pełny tekst źródłaDespite the infiltration of tumors by the immune competent cells, spontaneous rejection of breast tumors is rarely documented. Our work on CD4+CD25high regulatory T cells (Treg), cells inhibiting the immune response, might reconciliate this apparent discrepancy. Indeed, functional Treg are present in high proportions in primary breast tumors and have a negative impact on patient’s survival. This negative impact occurs only when Treg are present in the periphery of the tumor in the lymphoid aggregates in contact with mature Dendritic Cells (DC), where they are activated and proliferate, but not in the tumor area. Regarding their intra-tumoral recruitment, we have demonstrated the importance of the CCR4 receptor and one of its ligands CCL22. Plasmacytoid DC (pDC), circulating interferon-α producing cells during viral infection, are also present in breast tumors and their presence has a negative impact on patients’ survival as previously demonstrated by our team. Tumor-infiltrating pDC express activation markers, respond in vitro to activation signals, but their ability to produce interferon-α is strongly impaired. We showed that two cytokines, TGF-β and TNF-α produced within tumor microenvironment are involved in this inhibition. The perspectives of this work are to identify the mechanisms of Treg mediated suppression and the importance of their interaction with pDC. Our goal is to understand how to neutralize Treg and reactivate pDC in breast cancer in order to restore an anti tumor immune response
Eyraud, Daniel. "Environnement du cancer colorectal : étude conjointe des lymphocytes T régulateurs et du système IDO. Mise au point d’un modèle de croissance de cancer colorectal humain chez la souris immunodéprimée". Paris 6, 2013. http://www.theses.fr/2013PA066601.
Pełny tekst źródłaIn this thesis, we first assessed the cellular infiltrate of colorectal cancer (CRC) using computer-aided analysis of whole slide digital image derived from tissue microarray (TMA), at different sites, center (C) and front (F) of tumor, non metastatic draining lymph nod (N) and healthy mucosa (M). The proportion of IDO positive tissue area in epithelium was significantly higher in healthy mucosa of patients with cancer than without. The FOXP3+ tissue area was increased in healthy mucosa of CRC patients in comparison with healthy mucosa of patients with colorectal resection for disease other than cancer. The proportion of IDO+ tissue area in N was correlated with the proportion of FOXP3+ tissue area in N, F and M. Then, were measured concentrations of tryptophan (Trp) and kynurenin (Kyn) in the sera of patients with and without CRC prior surgery (D0) and 7 days after surgery (D7). The IDO activity was estimated by the serum Kyn/Trp ratio. At Day 0, serum Kyn concentration and Kyn/Trp ratio were higher in the CRC group than in Control group. At Day 7, serum concentrations of Kyn and IDO activity were not statistically different between the two groups. Then we elaborated a xenogenic model of CRC tumor growth in immunodeficient NSG mice using different types of implantation sites and cellular or tissular preparations. Then we monitored the growth with bioluminescence camera, before and after chemiotherapy
Le, Cornet Charlotte. "Évolution du cancer du testicule en Europe : expositions environnementales et professionnelles". Electronic Thesis or Diss., Lyon 1, 2014. http://www.theses.fr/2014LYO10277.
Pełny tekst źródłaTesticular germ cell tumours (TGCT) are the most common cancer diagnosed among young European men aged between 15 and 39 years. TGCT incidence rates have doubled in most European countries over the last 30 years. This rapid increase in incidence, the geographical variations and the studies in migrant populations suggest a role of environmental factors in TGCT aetiology. This thesis aims to contribute to the knowledge of TGCT evolution by studying the impact of environmental and occupational exposures, especially during the prenatal period. The objectives are: 1. To estimate the proportion of the increased incidence due to overall changes in risk patterns compared to the proportion due to demographic changes, by predicting the future testicular cancer trends in Europe 2. To summarize and evaluate the current knowledge on environmental and occupational exposures related to TGCT risk by means of a systematic literature review 3. To investigate the association between the prenatal parental occupational exposure to pesticides and TGCT risk in the offspring. The results show that the TGCT incidence continues to increase, supporting an environmental impact on TGCT evolution. From the epidemiological literature to date no specific environmental risk factors emerge; however, there have clearly been a lack of studies investigating prenatal exposures on TGCT risk. The NORD-TEST study, based on registry data from four Nordic countries, is the largest study to date. No association was found between parental occupational exposure to pesticides during prenatal period and TGCT risk
Salaud, Céline. "Reconstruction in vitro d'un glioblastome par techniques de bioimpression". Thesis, Nantes, 2020. http://www.theses.fr/2020NANT1032.
Pełny tekst źródłaGlioblastomas (GBMs) are brain tumors with a poor prognosis, treatment is based on surgical removal followed by radiochemotherapy and the median survival is 15 months. The reason of therapeutic resistance is complex. GBMs are extremely heterogeneous in their composition. Tumor microenvironment (TME) is composed of numerous different populations including cancer-associated fibroblast (CAF) and plays an important role in survival, growth and resistance of the tumor. It is therefore necessary to find a pretherapeutic model closest to the in vivo conditions to improve our knowledge of tumoregenesis. Fist, we present a review of literature of resistance mechanisms. The quiescent cells, present in the TME, may have an important role. Second, we developed a 3D tumoroid model using patient-derived cultures. We determined optimal matrix composition and cell concentration. A mathematical model was developed to determine proliferation and form of tumoroids. Third, using our tumoroid models, we showed CAF protection to GBM cells to therapy. Fourth, we studied interaction between CAF and GBM cultures in co-culture. CAF transfer mitochondria by tunnelling nanotubes (TNT), extracellular vesicles or cannibalism. Mitochondrial transfer contributes to proliferation and resistance to treatment. These 3D tumor models are the first step to create personalized treatments based on tumor samples from patients
Delort, Laëtitia. "Facteurs de risque et de protection des cancers dans l'étude épidémiologique COSA (Cancers de l'Ovaire et du Sein en Auvergne) : étude des polymorphismes génétiques et des interactions gènes-environnement". Clermont-Ferrand 1, 2007. http://www.theses.fr/2007CLF1MM22.
Pełny tekst źródłaBreast and ovarian cancer incidence is increasing around the world. The great proportion of these cancers could be explained by polymorphisms in low penetrance genes involved in major biological pathways. These genes could also interact with environmental and lifestyle factors. Thus an efficient prevention and a reduction in cancer would be conceivable with the identification of these variants. We performed a case-control study in the Auvergne region consisted of 934 women who developed breast cancer, 54 women who developed ovarian cancer and 1000 healthy women. The aim of the study was to evaluate genetic and environmental risk and protective factors for these pathologies. We genotyped the whole population for eleven polymorphisms in seven low penetrance genes involved in xenobiotic and estrogen metabolisms (CYP1A1, CYP1B1, NAT2, GSTP1, COMT, ESR, PGR). Oral contraceptive (OC) use, age at first OC use and breastfeeding were risk factors for early age at breast cancer onset. We observed a major role of central adiposity in ovarian cancer risk. We investigated the roles of polymorphisms in a multigenic model and found that COMT played an important role in breast cancer. This gene seemed to interact with other genes such as CYP1B1, ESR, GSTP1, NAT2 and with waist-to-hip ratio factor by modifying the risk. Polymorphisms in the studied genes would modify detoxication and consequently women exposure to endogenous or exogenous carcinogens. This would change individual breast cancer susceptibility. A limited role of these polymorphisms was found in ovarian cancer risk. Thus the identification of gene-gene and gene-environment interactions will lead to an individualized prevention strategy by identifying high-risk individuals
Pujol, Jean-Louis. "L'annonce du cancer, entre corps - symptôme et langage traumatique". Phd thesis, Université Paul Valéry - Montpellier III, 2012. http://tel.archives-ouvertes.fr/tel-00755418.
Pełny tekst źródłaZaoui, Maurice. "Influence fonctionnelle de l’IMC, de la densité mammaire et du statut ménopausique sur le dialogue entre adipocytes et cellules tumorales mammaires". Thesis, Sorbonne université, 2018. http://www.theses.fr/2018SORUS325.
Pełny tekst źródłaBreast cancer is the most common and deadliest cancer in women. Body mass index (BMI), oestrogenic impregnation and breast density, factors known to influence breast adiposity are also risk factors. Our objective is to study the influence of adiposity in the mechanisms of initiation and mammary tumor progression. We compared the effects of differentiated adipocyte secretions from normal or isolated breast ASCs from mammary adipose tissue adjacent to the tumor. Both types of conditioned media were found to be equivalent in their effects on increased CD36 expression in tumor cells, AG capture and proliferation. In contrast, conditioned media of normal adipocytes showed greater chemoattractant potency on migration and invasion of aggressive tumor cells. In contrast, conditioned media of differentiated adipocytes from peritumoral ASCs showed a higher effect on normal mammary cell migration. These observed effects are dependent on the phenotype of the mammary tumor cells but independently of the level of adiposity. These data are particularly interesting in breast reconstruction strategies after lumpectomy or mastectomy
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.
Pełny tekst źródłaMelanoma 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
Azzazene, Dalel. "Cancer de l’ovaire et immunité anti-tumorale : rôle du Human Leukocyte Antigen-G (HLA-G)". Thesis, Paris 11, 2012. http://www.theses.fr/2012PA11T086.
Pełny tekst źródłaWith more than 15,000 deaths anticipated in 2012, ovarian cancer is the most deadly gynecologic malignancy. While approximately 80% of patients will respond to frontline chemotherapy, more than 60% of patients will experience disease recurrence and only 44% will be alive at 5 years. The role of the microenvironment in the process of carcinogenesis and tumor progression has been demonstrated in various studies. This original concept of initiation and tumor progression solicits a very varied conceptual and experimental approach. In this study, we demonstrate the important role of the immunosuppressive molecule HLA-G (Human Leukocyte Antigen-G), and its expression and regulation by cancer cells and tumor microenvironment cells. We studied the various factors involved in the mechanisms immune of tumor escape from the immune system and finally we analyse in vivo some chemotherapy protocols based on the immunomodulatory drugs
Joimel, Ulrich. "Étude de la contribution des monocytes/ macrophages dans la promotion tumorale : leurs rôles dans l'angiogenèse et les thromboses- essais de stratégies thérapeutiques". Rouen, 2012. http://www.theses.fr/2010ROUER012.
Pełny tekst źródłaThis PhD research investigated the development of experimental strategies whose aim was the attenuation of the pro-tumoral role of monocytes/macrophages. Macrophages can be classified into two subcategories, classically activated macrophages (or M1) and alternatively activated macrophages (or M2). M1 exibit anti-tumoral proprieties while M2 are involved in pro-tumoral activity. NF-KB was identified as a key regulator to switch from M1 macrophage towards M2 but the mechanisms of action remain not clearly understood. We showed that 1) the coculture supernatant from macrophages and cancer cells induced an increased angiogenesis in the chicken chorioallantoic membrane that could be associated with the increased expression of CXC/ELR+ chemokines; 2) coculture induced a M2 phenotype; 3) tetrathiomolybdate (TM), an anti-angiogenic agent and an NF-KB inhibitor inhibited the coculture-induced increase in angiogenic activity, but without altering macrophages phenotype. Cooperation between macrophages and cancer cells induces a reciprocal increase of tissue factor (TF) expression. Now, TF is involved in the folination of micro-thrombi by activating factor X (FX) and it's known that micro-thrombi protect cancer cells in the bloodstream. The effects of an indirect (fondaparinux) and a direct (rivaroxaban) activated FX inhibitor in pro-coagulant activity and cytokine release from activated monocytes were then compared. We showed that 1) only rivaroxaban reduced the pro-coagulant activity, 2) the two inhibitors decreased secretion of cytokines
Le, Joncour Vadim. "Étude du remodelage tumoral associé aux effets du peptide vasoactif urotensine II sur la néoangiogenèse et la croissance des glioblastomes". Rouen, 2015. http://www.theses.fr/2015ROUENR01.
Pełny tekst źródłaGhiabi, Pegah. "Implication du microenvironnement sur la survenue de la maladie métastatique et l’apparition d’une maladie résiduelle dans les adénocarcinomes sein séreux". Thesis, Paris 11, 2013. http://www.theses.fr/2013PA11T063.
Pełny tekst źródłaBreast cancer is a heterogeneous disease, which is characterized by distinct morphological features and clinical behaviors and is the most commonly diagnosed cancer among women in the United States and worldwide and the second cause of cancer-related mortality in women. Several years of investigation have demonstrated that tumor initiation, progression and metastasis are closely regulated by the adjacent non-neoplastic tissues that are collectively referred to as tumor microenvironment (stroma). The components of tumor stroma such as mesenchymal stem cells have been shown to enhance cancer stem cell population in breast tumor. Also, the endothelial cells (ECs) conventional role in tumor angiogenesis is crucial in determining the tumor fate as microscopic and asymptomatic versus aggressive. This outstanding characteristic of ECs has set them as promising targets in cancer therapy. However, failure of anti-angiogenic therapies despite vessel disruption suggests the blood flow-independent ability of ECs to facilitate tumor growth. In this study, we show that ECs promoted breast cancer cell self-renewal, stemness, migratory characteristic and lung metastasis through Jagged1/Notch dependent Id1 modulation. ECs with Jag1 knock down (ECsJag1-) failed to sustain breast cancer cell proliferation and stemness in vitro and during xenografted tumor growth. Furthermore, we established a breast tumor mouse model with EC specific Jag1 mutation, by crossing the MMTV-PyMT mice with Cdh5-Cre+/-Jag1loxP/loxP mice. It demonstrated significant decrease in primary tumor growth and dramatic reduction in lung metastasis in Cdh5-Cre+/-Jag1loxP/loxPPyMT+ mice. Transcriptome sequencing analysis of the sorted primary tumor cells identified Notch downstream targets, specifically, Id1, which was reported to be essential for lung metastasis of breast tumors. Additionally, we were interested in determining the mechanisms that derive the activation of ECs toward supporting tumor growth and expansion. Previous studies have shown that ECs show tremendous degree of plasticity when placed under different conditions. Here, we showed that ECs show EndMT phenotypes upon having contact with tumor cells. Interestingly, the EndMT transforms the ECs into activated entities with increased proliferation, migration and angiogenesis properties. Our results demonstrated that the EndMT was reversible and dependent on EC-tumor cell contacts. Moreover, we were able to show that the tumor-induced EndMT in ECs is synergistically regulated by TGFβ and notch signaling pathways. Overall, our findings implicate the significance of endothelial-tumor cells perfusion-independent interaction in cancer progression, stemness, and metastasis. Besides, this study might have determined novel targets in combating cancer in a more effective way
Nerriere, Eléna. "Distribution de l'exposition de la population urbaine à des polluants particuliers et gazeux génotoxiques et évaluation du risque de cancer". Nancy 1, 2004. http://www.theses.fr/2004NAN11304.
Pełny tekst źródłaDesmet, Cloé. "Systèmes de détection multiparamétrique de marqueurs biologiques ou de polluants, appliqués au diagnostic et au contrôle environnemental". Thesis, Lyon 1, 2013. http://www.theses.fr/2013LYO10149/document.
Pełny tekst źródłaThe work reported in this thesis focuses on the development of new multiplex analytical devices on biochip or electrode microarray format, dedicated to diagnosis and environmental monitoring. The objective of the first research axis is diagnosis, thanks to the detection in patients’ serum of a panel of antibodies, biomarkers of a pathological state. For that purpose, two immunotests have been developed, enabling the multiparametric detection of specific antibodies by automated and high-throughput analysis of serum samples. This approach is based on the antibodies capture by antigens probes immobilized in a matrix of spots on a membrane surface composing the wells bottom of a micro-titer plate. Enzyme-labeled antibodies have been used, providing a colorimetric detection. This device enabled the achievement of the analysis of 96 samples in less than three hours and has been applied to different applications. The first one consists of allergy diagnosis, and the second focuses on cancer diagnosis. The second part of this work is applied to environmental monitoring, through water analysis. Different types of pollutants have been defined as targets: pesticides, toxins and explosives. In order to integrate them in a matrix of probes, different conjugates have been synthesized with these haptens. After screening and optimization of the conjugates through their reactivity and cross-reactivity with the specific antibodies, the developed device demonstrated his analytical performances in terms of sensitivity and selectivity. Finally, for the European Project BONAS, a last sensor based on water analysis has also been developed. This electrochemical microarray aims to detect explosives precursors, used in improvised explosive devices, for the localization of hidden bomb factory. The chip was designed as a screen-printed electrode network, which was modified by different metals electrodeposition
Toulet, Aurélie. "Dissémination du cancer de la prostate : un chemin pavé de gras". Thesis, Toulouse 3, 2018. http://www.theses.fr/2018TOU30237.
Pełny tekst źródłaProstate 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. [...]
Becht, Etienne. "Transcriptomic analysis of the immune microenvironment of non-hematopoietic human tumors". Thesis, Sorbonne Paris Cité, 2015. http://www.theses.fr/2015PA05T029/document.
Pełny tekst źródłaTumors grow within a complex microenvironment composed of immune cells, fibroblasts, endothelial cells and other non-malignant cells. The study of the composition of tumor microenvironments has led to classifications with prognostic and theranostic values, as well as the discovery of treatments modulating the composition and the functional orientation of the microenvironment. Concurrently, molecular classifications of tumors have proposed taxonomies within cancers that define groups of patients with different prognoses and are associated with response to treatments. Recent evidence suggest that the phenotype of the malignant cell is a critical determinant in the shaping of its microenvironment, suggesting potential correlations between immune and molecular classifications. The goal of this PhD project was therefore to analyze the microenvironment of molecularly-classified human tumors. Colorectal cancer represents a paradigm for tumor immunology, as it is the humancancer in which it was exemplified that an adaptive immune response can control tumor Growth and metastasis. Conversely, clear-cell renal cell carcinoma represents an exception in tumor immunology, as an extensive adaptive immune response is associated with more aggressive diseases. Molecular transcriptomic classifications were recently proposed for both of these apparently immunologically contrasted cancers. In this work, I propose a methodology that enables the characterization of the tumor microenvironment using transcriptomic data, and apply it to describe the immune contexture of molecular subgroups of colorectal and clear-cell renal cell carcinomas. These analyses argue in favor of the unification of molecular and immune classifications of human cancers, challenge our current views of the relationship between the composition of the tumor microenvironment and patient’s prognosis, and suggest immunotherapeutic approaches that could benefit subgroups of patients in these two cancers
Clatot, Florian. "Expression et valeur pronostique du couple CXCL 12/CXCR 4 dans les carcinomes épidermoïdes de la sphère ORL chez l'homme". Rouen, 2014. http://www.theses.fr/2014ROUES041.
Pełny tekst źródłaThe CXCL 12 chemokine and its receptors CXCR 4 and CXCR 7 are involved in many models of metastatic spread in cancer. Based on a cohort of patients treated for a curative intent for a head and neck cancer, we assessed the expression and the prognostic value of the CXCL 12/CXCR 4 axis in this setting. In our cohort of 71 patients we showed that the intratumoral level of expression of CXCL 12 assessed by quantitative PCR was a strong and independent prognostic factor. Using a high-throughput qRT-PCR, we performed an unsupervised clustering analysis based on the expression of 42 genes (involved in hypoxia, metabolism, matrix interactions, inflammation and angiogenesis) for 61 patients. We identified 2 groups of genes that were related to metastatic evolution. Next, we established a 9-gene model that was capable of classifying the samples into the 2 clusters with 90% accuracy. At the tissue level, the analysis of 23 samples after microdissection confirmed that the stroma is the main provider of CXCL 12. It also showed in a pioneering way that CXCR 4 was mainly produced by the stroma instead of the tumor. CXCR 7 expression did not differ between the 2 compartments. Finally, the methylation of the CXCL 12 promoter assessed by pyrosequencing could only explain the low intra-tumoral expression of this gene in 20% of cases. Taken together, these results suggest that CXCL 12 may be a tumor suppressor gene in head and neck cancers. A prospective evaluation of the CXCL 12 prognostic value is needed
Petitprez, Florent. "Integrated analysis and clinical impact of immune and stromal microenvironments in solid tumors Quantitative analyses of the tumor microenvironment composition and orientation in the era of precision medicine Transcriptomic analysis of the tumor microenvironment to guide prognosis and immunotherapies Tumor microenvironment quantification tool draws a comprehensive map of the tumor microenvironment of non-hematologic human cancers The mMCP-counter method to estimate abundance of tissue-infiltrating immune and stromal cell populations using gene expression in murine samples Immune sub-classes in sarcoma predict survival and immunotherapy response Intra-tumoral tertiary lymphoid structures are associated with a low risk of hepatocellular carcinoma early recurrence Association of IL-36γ with tertiary lymphoid structures and inflammatory immune infiltrates in human colorectal cancer Immune-based identification of cancer patients at high risk of progression Tumor-infiltrating and peripheral blood T-cell immunophenotypes predict early relapse in localized clear cell renal cell carcinoma PD-L1 expression and CD8+ T-cell infiltrate are associated with clinical progression in patients with node-positive prostate cancer Intratumoral classical complement pathway activation promotes cancer progression". Thesis, Sorbonne Paris Cité, 2018. http://www.theses.fr/2018USPCB104.
Pełny tekst źródłaTumors are composed not only of malignant cells but also contain a vast variety of non-malignant cells, notably immune cells forming the tumor microenvironment (TME). The composition of the TME was shown to be associated with clinical outcome for cancer patients, in terms of survival and therapeutic responses. With the relatively recent development of immunotherapies targeting specific elements of the TME, tumor immunology has risen a strong interest and holds a strong therapeutic potential. Several methodologies have been developed to study the composition of the TME with an increased precision. Notably, some methods such as MCP-counter enable the use of the tumor bulk transcriptome to quantify cell populations composing the TME. The methodological aspect of this PhD project consisted in setting up an enhanced version of MCP-counter that can be readily applied to RNA-Seq data, as well as propose an adaptation of the method for mouse models. Using MCP-counter, the TME of large series of tumors can be easily analyzed. The application part of this PhD work consisted of applying MCP-counter to establish an immune-based classification of soft-tissue sarcoma, a rare, aggressive and heterogeneous cancer type. The immune classification notably allowed to identify immune low and high groups, and a group characterized by a strong vasculature. Interestingly, the classification was notably found to be predictive of the patients' response to immunotherapies. It also highlighted an important role of tertiary lymphoid structures (TLS). TLS are lymph-node-like structures composed of T and B cells that form within the tumor or in close proximity. They are a site of formation and maturation of antitumoral immune responses. TLS are raising a growing interest in many malignancies. In most cancer types, a strong infiltration by T cells, in particular CD8+ T cells, is associated with a favorable clinical outcome. However, clear-cell renal cell carcinoma and prostate cancer are exceptions to this general rule. Indeed, in these urological cancers, an increased infiltration by T cells is associated with a decreased patient survival and with earlier relapse and disease progression. In a third part of this thesis, these exceptions are investigated with more details by scrutinizing the TME, and questioning the implication of the complement system. Overall, this thesis presents how the combination of several analysis methods, in silico, in situ and in vivo, can help achieve an extremely precise description of the TME. Knowing accurately what cell populations and what their functional orientation can help guide patients care and improve clinical outcome. Complete description of the TME opens the way towards personalized medicine for cancer patients
Roussel, Lucas. "Diagnostiquer le cancer de l'ovaire grâce à la technologie SpiderMass". Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2023/2023ULILS121.pdf.
Pełny tekst źródłaOvarian cancer (OC) is the deadliest gynecological cancer, causing over 200,000 deaths worldwide every year. Diagnosis of OC is extremely difficult and late diagnosis leads to delays in patient management thus reducing the chances of survival. Against this backdrop, we have developed a real-time diagnostic and prognostic tool: SpiderMass. Initially, to enable early diagnosis and preventive action, we focused on the origin of the most aggressive OC subtype: high-grade serous cancer (HGSOC). Following the discovery of lipid and protein markers specific to pre-neoplastic lesions of the fimbria, we highlighted the underlying mechanisms linked to these lesions and confirmed that they were at the origin of HGSOC. Secondly, we studied all the lipid molecular signatures specific to the different OC subtypes to build a classification model using SpiderMass technology for diagnostic. This model, combining both molecular and patient morphological data, was able to recognize all subtypes in real time ex vivo. We have also developed a new mass spectrometry imaging model enabling direct visualization of different immune cells within tissues. This model provides an accurate diagnosis of the different types of ovarian cancer, and can associate a prognosis with them, given that patient survival is closely linked to the infiltration of immune cells within the tumor. We have demonstrated that this imaging model is applicable to several types of cancer, including ovarian cancer and glioblastoma. Combined with these innovative models, SpiderMass guides the surgeon during the operation to reduce excision margins and provides a reliable diagnosis and prognosis to propose the best treatment to the patient
Bonneau, Claire. "Étude des mécanismes de récidive métastatique dans les cancers du sein luminaux de stade précoce : impact du microenvironnement tumoral Caractérisation moléculaire des cancers du sein en pratique clinique A subset of activated cancer associated fibroblasts is associated with distant relapse in early luminal breast cancers". Thesis, Sorbonne Paris Cité, 2018. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=2365&f=17162.
Pełny tekst źródłaPurpose: Early luminal breast cancers (BC) represent 70% of newly diagnosed BC. Their prognosis is generally favorable but some patients (around 5 to 10% at 10 years) will relapse with distant metastases and most of them will die. Because this dismal prognosis concerns a small number of patients, T1N0 BC have been rarely studied. The aim of this work was to identify the mechanisms of metastatic recurrence in luminal breast cancers T1b-cN0M0 at diagnosis by deciphering characteristics of both epithelial cancer cells and their surrounding tumor microenvironment (TME). Experimental Design: We constituted a cohort of luminal T1b-cN0 BC patients with metastatic recurrence (defined as "cases”) and corresponding "controls" (i. e. patients without metastatic relapse) matched (1:1) to cases on the main known prognostic factors: age, tumor grade and tumor proliferation (assessed by Ki67). Results: We found that properties in both epithelial compartment and TME are indicative of relapse in early luminal breast cancers. In univariate analysis, the loss of differentiation (assessed by the reduced expression of CDH1/E-cadherin) in cancer cells is associated with recurrence, as also predicted by high ROR score using ProsignaTM test. In TME, quantitative and qualitative immunohistochemical analyzes reveals that “cases” are characterized by a significant decrease in CD4+ T lymphocytes and an accumulation of a particular subset of Cancer Associated Fibroblasts (CAF-S1) compared to “controls”, without any other association of T lymphocyte subtypes, B lymphocytes, macrophages or dendritic cells. In multivariate analysis, TME features, in particular CAF-S1 enrichment, remain significantly associated with recurrence, which demonstrates their biological and clinical relevance. Finally, by performing functional analyses, we demonstrated that CAF-S1 pro-metastatic properties are -at least in part- mediated by CDH11/Osteoblast cadherin, consistent with the fact that the bones are a major site of metastases in these patients. Conclusions: Distant recurrence in early luminal BC is strongly associated with TME features, such as the presence of CAF-S1 and their expression of CDH11. This is independent of tumor cells and represents a new prognostic factor of distant relapse in early luminal BC patients. This could justify targeted therapies against CAF-S1 or CDH11 in these cases
Vales, Simon. "Impact des cellules gliales entériques sur les cellules souches cancéreuses coliques et processus de carcinogenèse associés". Thesis, Nantes, 2017. http://www.theses.fr/2017NANT1033.
Pełny tekst źródłaCancer stem cells (CSC) are a subset of tumor cells thatpossess increased tumorigenic and metastatic abilities,as well as enhanced resistance to chemotherapy andradiotherapy. Thus CSC are considered as responsiblefor tumor initiation, metastasis and relapse. Compellingevidence have shown that the tumor microenvironmenttightly controls CSC functions. Among the cells of thecolorectal tumor microenvironment are enteric glial cells(EGC) that are potent regulators of barrier functions in ahealthy intestine. However, little is known about theimpact of EGC on colorectal carcinogenesis. Thereforethe main objective of my PhD project was to exploreEGC impact on CSC functions and associatedcarcinogenesis processes. Using in vitro and in vivoapproaches, we demonstrated that tumor cells activateEGC to acquire a pro-tumorigenic phenotype via therelease of IL-1. We also showed that tumor-activatedEGC increase CSC ability to initiate the formation of atumor via the production of PGE2 and the activation ofEP4/EGFR-dependent pathways in CSC. In a secondstudy, we demonstrated that EGC increase CSC abilityto give rise to tumors in the presence of 5- fluorouraciland oxaliplatin via an ATM-dependent pathway.Altogether our data demonstrate that EGC are a keycomponent of the tumor microenvironment that, onceactivated by the tumor, stimulates CSC and thuspromotes associated carcinogenesis
Berrandou, Takiy Eddine. "Gènes du métabolisme des xénobiotiques : rôle prédictif dans les niveaux de contamination biologique par les polluants environnementaux et implication dans le risque de cancer du sein. Analyse de l’étude CECILE". Thesis, Université Paris-Saclay (ComUE), 2018. http://www.theses.fr/2018SACLS598.
Pełny tekst źródłaThe xenobiotic metabolism (XM) genes involved in the activation and elimination of environmental carcinogens may modulate breast cancer risk, but their effects in breast cancer have been little studied and are poorly understood. The objectives of the PhD were to study the role of XM genes in breast cancer on the one hand, and in the biological levels of suspected breast carcinogens on the other. The analyses were based on a population-based case-control study on breast cancer (CECILE study). We investigated the association of breast cancer (1) with NAT2 gene variants that determine the type of slow or rapid acetylator in each individual; (2) with polymorphisms of XM genes that were studied jointly at the gene and at the XM pathway level using a gene set method. In each of these approaches, interactions with tobacco consumption were studied. In a final section, we sought to identify polymorphisms of XM genes that predict blood concentrations of persistent organochlorine pollutants (p,p'-DDE and PCB153) among the controls of the CECILE study.The risk of breast cancer was increased in women with a NAT2 genetic profile of rapid acetylators compared to women with a profile of slow acetylators. Among slow acetylators, current smokers had an increased risk of breast cancer compared to non-smokers, indicating an interaction between tobacco smoking and NAT2 genotype. The gene set approach showed that polymorphisms at the level of some XM genes and at the level of the entire pathway were collectively associated with breast cancer. The association between breast cancer and all pathway XM polymorphisms was observed in female smokers, indicating a role for tobacco smoking in this association. Finally, we have shown that CYP2B6 gene was a determinant of blood levels of p,p'-DDE and PCB153. Our results highlight a role of XM genes in breast cancer that is explained by their function in the metabolism and elimination of environmental carcinogens
Cohen, Charlotte. "La Fractalkine (FKN) comme traitement des métastases osseuses de CNPC au sein d’une stratégie multimodale : une étude préclinique sur un modèle murin". Electronic Thesis or Diss., Université Côte d'Azur, 2020. http://www.theses.fr/2020COAZ6030.
Pełny tekst źródłaIn France, about 50 000 new cases of lung cancer are diagnosed every year. Sixty percent of them are already metastatic. Bone localizations are described in 20 to 40% of cases and they are associated with poor survival (5 to 10 % at 5 years) and impaired quality of life. New therapeutic options are mandatory to improve survival and functional prognosis.A chemokine, the fractalkine (FKN), represents a promising one. It is known for its capacity of leukocytes recruitment and its impact on the bone metabolism. It could be able to restore anti-tumor immunity and to act on osteolysis, when delivered locally. The impact on tumor development is highly complex and depends on the expression of its receptor by tumor cells, its molecular form, the location of the lesion, and the tumor type.We first planned to determine the impact of the FKN on the tumor development within a syngeneic murine model of bone metastasis of lung cancer, using either LL2 lung cancer cell line expressing a low (LL2-FKNlo) or a high level of FKN (LL2-FKNhi).FKN had an anti-tumoral effect, able to reduce the tumor-weight by 73% in the LL2-FKNhi groups, compared to LL2-FKNlo one, at day 14. High level of expression of FKN was associated with an increase in the recruitment of inflammatory monocytes, natural killer cells, and more specifically B lymphocytes (LB). Together, they formed an immunopermissive tumoral microenvironment. We also noted significant modification of expression level of genes involved in osteoformation and regulation of immunity.The FKN anti-tumor effect tended to decrease after day 14. At the same time, we quoted a high level of infiltration of LL2-FKNhi tumors by T regulatory lymphocytes (LTreg). We suspected their implication in this loss of effect.We tried therapeutic associations, able to stimulate anti-tumor immunity through immune checkpoint blockade (monoclonal antibody against CTLA4, PD1, PDL1, or TIM3) or to block LTreg (cyclophosphamide, anti-GITR antibody) in association with high FKN expression. The goal was to prolong and/or to reinforce its anti-tumoral effect.To date, the used administration protocols weren’t able to induce such an effect. Other protocols need to be tested.This work highlighted an anti-tumoral effect of FKN in this murine model of bone metastasis of lung cancer and identified the underlying mechanisms. It pointed out new therapeutics associations options based on the anti-tumoral implication of LB, and pro-tumoral action of LTreg
Mansuet-Lupo, Audrey. "Influence des caractéristiques morphologiques et mutationnelles des carcinomes pulmonaires sur leur environnement immunitaire et leur pronostic". Electronic Thesis or Diss., Paris 5, 2014. https://wo.app.u-paris.fr/cgi-bin/WebObjects/TheseWeb.woa/wa/show?t=647&f=1599.
Pełny tekst źródłaThe major role of the immune system against tumor development is now clearly established, including lung carcinoma. Nevertheless, interaction between tumoral cells and immune environment is less well-defined. In that study, we have studied morphological and molecular tumoral cells characteristics from lung adenocarcinoma and their role in the composition of immune environment. We reported the prognostic value of morphological parameters, as histological grade of adenocarcinoma, and their association with molecular EGFR and KRAS status. We hypothesized that morphological and molecular diversity of these tumors could be associated with a specific intratumoral immune signature, and could have an impact in prognosis. We showed that mature dendritic cells density, located in tertiary lymphoid structures, differed according to EGFR and KRAS status. Morever, molecular status of tumors modified the pronostic value of mature dendritics cells and CD8+ T cells. We found a prognostic value of immune environment, represented by dendritic cells and T CD8+ cells, in operated stage III-N2 lung carcinomas treated by neoadjuvant chemotherapy. At last, we demonstrated that chemotherapy is not associated with wide modifications in immune infiltrate, whereas it induced modifications in tumoral cells. All together, these data strongly argue for a close link between tumoral cells and immune environment, which seems to depend on tumoral cell characteristics. This interaction between tumoral cells and immune cells contribute to the prognosis of these tumors. These results show the evidence that combine cytotoxic treatment, like conventional chemotherapy, with immunomodulators, favour a protective anti-tumor immune response
Neuzillet, Cindy. "Inter- and intra-tumoral heterogeneity and dynamics of cancer-associated fibroblasts in pancreatic ductal adenocarcinoma". Thesis, Sorbonne Paris Cité, 2018. https://theses.md.univ-paris-diderot.fr/NEUZILLET_Cindy_2_va_20181015.zip.
Pełny tekst źródłaCancer-associated fibroblasts (CAF) are orchestrators of the pancreatic ductal adenocarcinoma (PDAC) microenvironment. Stromal heterogeneity may explain differential pathophysiological roles of the stroma (pro- vs. anti-tumoral) in PDAC. We hypothesised that multiple CAF subtypes exist in PDAC that contribute to stromal heterogeneity through interactions with cancer and immune cells. This project comprised three parts:- In Part 1, by applying extended bioinformatics analysis and a wide range of in vitro assays to human PDAC-derived primary CAF cultures, we demonstrated the biological diversity of human pancreatic CAFs; we identified four CAF subtypes (A-D) with specific molecular and functional features (matrix- and immune-related signatures, vimentin and ?-smooth muscle actin expression, proliferation rate), and we showed that CAF heterogeneity had an impact on the interactions with cancer cells in mini-organotypic models.- In Part 2, we showed that the combination of CAF sub-populations was associated with distinct phenotypic characteristics of the tumours (tumour molecular subtype and grade, stromal abundance and activity, immune infiltrates, angiogenesis) and patient survival, in silico in the ICGC dataset and by immunohistochemistry in an extensively characterised patient cohort.- In Part 3, we showed that several CAF subtypes may emerge in vitro (conditioned media experiments) and in vivo (orthotopic xenografts) from the dynamic interactions of pancreatic stellate cells with cancer cells, through an “imprinting” process, and may be further modulated by other factors and/or cellular partners in the tumour microenvironment; in addition, we confirmed in a murine setting our findings about the association between CAF subtype marker expression and immune phenotype observed in human tumours.This unique classification for pancreatic CAFs (pCAFassigner) demonstrates the inter- and intra-tumoral phenotypic heterogeneity of CAFs in human PDAC. Our results provide a framework for future functional studies and pave the way for the development of therapies targeting specific CAF sub-populations in PDAC
Ogier, Charline. "Nouvelle perspective thérapeutique pour le cancer du pancréas : ciblage des ligands des récepteurs de la famille HER exprimés par la tumeur et son microenvironnement". Thesis, Montpellier, 2017. http://www.theses.fr/2017MONTT040.
Pełny tekst źródłaPancreatic cancer is an extremely aggressive cancer with a 5-year survival rate of no more than 5%. Late detection, lack of biomarker and effective therapy are the main causes. This cancer is characterized by a very dense microenvironment composed of cancer-associated fibroblasts (CAFs). This stroma is in constant communication with the tumor via the production of growth factors and metabolites, which promotes tumor development. Our project consists in disrupting this crosstalk with monoclonal antibodies targeting Neuregulin 1 (NRG1), ligand of the HER3 receptor. Its overexpression has been shown in pancreatic tumor cells and CAFs. We confirmed the involvement of NRG1 in the pancreatic tumors growth and then we generated a monoclonal antibody (7E3 mAb) specific for this ligand. This antibody has been characterized in terms of its specificity, its affinity and its epitope on NRG1. We then studied its therapeutic effect in different models of pancreatic cells alone or in co-culture with CAFs coming from human samples. The anti NRG1 antibody inhibits HER3 signaling as well as cell growth in 2D and 3D culture. In addition, its efficacy on tumor growth was shown in orthoptic xenograft models of tumor cells mixed with CAFs.In order to study more specifically the antibody effect on tumor microenvironment as well as its toxicity, a second mAb targeting murine and human NRG1 was produced by phage display. Its in vitro and in vivo characterization is ongoing. Combinations of 7E3 with chemotherapy (gemciatbine or Folfirinox) or other targeted therapies are being considered.This thesis proposes a new therapeutic solution for patients with pancreatic cancer. We demonstrated the importance of disrupting the crosstalk between tumor cells and CAF by validating the efficacy of targeting NRG1 by monoclonal antibody
Al-Thawadi, Hamda. "Microparticles Mediated Cross-Talk Between Tumoral And Endothelial Cells". Thesis, Université Paris-Saclay (ComUE), 2015. http://www.theses.fr/2015SACLS105.
Pełny tekst źródłaIn our study, we showed that microparticles participate to a complex dialogue between cancer and ECs. Our main finding showed the ability of MPs mediated cross-talk between cancer and ECs to functionalize an activated angiocrine pro-tumoral endothelial niche. Using endothelial Akt activation as a readout, we were able to differentiate MPs from cells with mesenchymal from cells with epithelial traits. Our data showed that MPs from mesenchymal-like cell lines were able to promote an activation of ECs through Akt phosphorylation, compared to MPs from epithelial-like cell lines. The overexpression of Arf6 in activated ECs is associated with quantitative changes of EC-MPs. Additionally, we were interested in determining the mechanisms that derive the activation of ECs toward supporting tumor growth and expansion. Here we showed that ovarian cancer MPs trigger β-catenin activation in ECs by inducing the upregulation of Wnt/bcatenin target genes and increasing the angiogenic proprieties. Interestingly, the activation of bcatenin in ECs was Wnt/Frizzled independent; but dependent on VE-cadherin localization disruption, bcatenin integrin activation and MMP activity
Cadassou, Octavia. "Cancer and microenvironment : the functional interplay between intra- and extracellular nucleotide metabolisms". Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1189/document.
Pełny tekst źródłaNucleotides play a major role in nucleic acids constitution and are involved in various cell phenomena. Indeed, intracellular ATP, GTP, AMP, GMP and their cyclic forms are components of cell signaling and define the energetic balance. Extracellularly, they also play multiple roles. Thus, when nucleotide pools are deregulated various processes are impacted. For example, a low availability of nucleotides supports genetic instability and aberrant levels of extracellular adenosine can lead to an immunosuppressive microenvironment. Interestingly, the cited parameters are among the Cancer Hallmarks described by Hanahan and Weinberg. These observations confirm the possibility of a key role of these molecules in this pathology. cN-II and CD73 are 5’-nucleotidases, involved in intra- and extracellular nucleotide metabolism respectively and have been identified as possible targets for new anti-cancer therapies. Nevertheless, very little is known about their biological roles on cancer cells and what parameters of cell biology could be impacted by such strategies. Considering the involvement of these purines in cell metabolism, we wondered what changes a decrease in cN-II and/orCD73 expressions or their silencing could trigger in cancer cells as well as in the interplay with their microenvironment.We studied cancer cell aggressiveness and the interplay with innate immune cells under cN-II and CD73 modulations. We observed that cN-II is involved in metabolic adaptability. The association of cN-II and CD73 invalidations results in glucose-metabolism-related gene modifications. CD73 can regulate migration-related genes expression but does not affect the process. cN-II is also involved in cell migration, via the COX-2/PGE2 axis. Again, these characteristics are accentuated when associated with CD73 deficiency. Here, cN-II and CD73 do not seem to be involved in cancer cell proliferation or in their interplay with a subset of innate immune cells
Cascales, Élodie. "L’enzyme CD10 : un acteur clé dans l’identification et la régulation des cellules souches mammaires humaines". Thesis, Lyon 1, 2010. http://www.theses.fr/2010LYO10313/document.
Pełny tekst źródłaIn breast, the existence of cancer stem cells has been demonstrated and that explain a number of observations as tumour heterogeneity. Other studies have demonstrated the resistance of radio and chemotherapy by different innate or acquired stem cell specific mechanisms that could explain relapse few years after the traitment. For all these reasons, that is very important to understand these mechanisms and to know physiological actors both implicated in the regulation of normal or cancer stem cells. CD10 is a zinc-dependant metallo-endopeptidase that inactivates a number of signalling peptides that could be implicated in mammary growth and differentiation. We have showed that CD10+ cell sorted population is enriched in Stem Cells/Early Common Progenitors/MyoEPithelial cells. We demonstrate that the protease activity of CD10 and the adhesion function of beta1-integrin are required to prevent differentiation of mammary stem cells/early progenitors. Taken together, our data suggest that integrin-mediated contact with the basement membrane and cleavage of signalling factors by CD10 are key elements in the microenvironment that maintains the progenitor and stem cell pools in the mammary gland. Adipose tissue is also a major component of the mammary microenvironment implicated in its homeostasis by the secretion of soluble factors. Our results suggested that the adipose tissue could be considered as a potential source of stem cells that differentiated into the luminal epithelial lineage involved in some breast cancers
Mansuet-Lupo, Audrey. "Influence des caractéristiques morphologiques et mutationnelles des carcinomes pulmonaires sur leur environnement immunitaire et leur pronostic". Thesis, Paris 5, 2014. http://www.theses.fr/2014PA05T017/document.
Pełny tekst źródłaThe major role of the immune system against tumor development is now clearly established, including lung carcinoma. Nevertheless, interaction between tumoral cells and immune environment is less well-defined. In that study, we have studied morphological and molecular tumoral cells characteristics from lung adenocarcinoma and their role in the composition of immune environment. We reported the prognostic value of morphological parameters, as histological grade of adenocarcinoma, and their association with molecular EGFR and KRAS status. We hypothesized that morphological and molecular diversity of these tumors could be associated with a specific intratumoral immune signature, and could have an impact in prognosis. We showed that mature dendritic cells density, located in tertiary lymphoid structures, differed according to EGFR and KRAS status. Morever, molecular status of tumors modified the pronostic value of mature dendritics cells and CD8+ T cells. We found a prognostic value of immune environment, represented by dendritic cells and T CD8+ cells, in operated stage III-N2 lung carcinomas treated by neoadjuvant chemotherapy. At last, we demonstrated that chemotherapy is not associated with wide modifications in immune infiltrate, whereas it induced modifications in tumoral cells. All together, these data strongly argue for a close link between tumoral cells and immune environment, which seems to depend on tumoral cell characteristics. This interaction between tumoral cells and immune cells contribute to the prognosis of these tumors. These results show the evidence that combine cytotoxic treatment, like conventional chemotherapy, with immunomodulators, favour a protective anti-tumor immune response
Grandal, Rejo Beatriz. "Beyond Breast Cancer : The Interplay of Immunity, Comedications, and Comorbidities in Treatment Response and Outcomes". Electronic Thesis or Diss., université Paris-Saclay, 2023. http://www.theses.fr/2023UPASL063.
Pełny tekst źródłaCancer caused almost 10 million deaths in 2020 and is predicted to affect nearly 24.5 million people by 2035 due to lifestyle changes, aging, and environmental factors. Breast cancer (BC) is the most frequent cancer diagnosis and the first cause of oncology mortality among females. The incidence of BC escalates with increasing âge, paralleling the rising prevalence of co-existing conditions (comorbidities) and chronic médication prescriptions (comedications), reported in roughly half of ail cancer patients. Administering chemotherapy prior to surgery (NAC) allows clinicians to evaluate in vivo tumor chemosensitivity. The objective of this thesis is to perform a comprehensive analysis to investigate the intricate relationships among tumor-infiltrating lymphocytes (TILs), checkpoints, genetic déterminants, breast cancer subtypes, comedications, comorbidities, treatment response, and oncological outcomes in patients with breast cancer. This objective will be achieved via an intégrative examination of datasets from real-world evidence (RWE) and a post-hoc analysis of randomized controlled trials (RCTs). The opening section of this thesis provides a comprehensive review of the neoadjuvant treatment paradigm in breast cancer, focusing on the interconnectedness of tumor biology, TILs,chemosensitivity, and survival. This research offers valuable insights into the intricate network that governs treatment outcomes. The subséquent segment seeks to study the rôle of comedications in cancer treatment by examining the associations between comedication use, comorbidities, immune infiltration, and treatment response. This chapter aims to identify unsuspected interactions that may improve patient outcomes by discovering novel therapeutic applications for existing drugs (drug repurposing). Moreover, we undertake an in-depth examination of the effects of regularly prescribed concomitant médications on BC survival using data from the French National Health Data System (SNDS). We endeavor to delineate a detailed map of potential interactions between concomitant médications and survival in the context of the entire French population. In conclusion, BC epitomizes a complex network of tumor and microenvironment interactions, with numerous influencing factors yet to be fully elucidated. Neoadjuvant settings and vast database intégration can identify novel therapeutic targets and drug-drug interactions, which are vital for advancing cost-effective, safe précision medicine
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.
Pełny tekst źródłaColorectal 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