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Grégoire, Murielle. "Polynucléaires neutrophiles, cellules stromales, lymphocytes B : interaction tripartite dans la niche des lymphomes B." Thesis, Rennes 1, 2014. http://www.theses.fr/2014REN1S156/document.
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Les polynucléaires neutrophiles ont longtemps été considérés comme des cellules n’intervenant que dans la réponse immune innée. Cependant, au cours de ces dernières années, de nombreuses publications suggèrent que ces cellules, retrouvées au sein du microenvironnement de nombreux cancers, pourraient également jouer un rôle dans la tumorigénèse et la progression tumorale. Ces études mettent en évidence leur fréquence comme marqueur pronostique dans différents cancers solides, mais peu de travaux se sont intéressés à la caractérisation fonctionnelle de ces cellules dans la progression tumorale. Dans de nombreux cancers dont les lymphomes B issus du centre germinatif, les cellules tumorales, qui sont incapables de proliférer et de survivre seules, sont dépendantes de leur microenvironnement de soutien. Dans cette étude, nous avons évalué la fonctionnalité des polynucléaires neutrophiles dans la croissance des lymphomes B. Ainsi, nous avons démontré pour la première fois que les polynucléaires neutrophiles soutiennent directement la croissance et la survie des cellules tumorales de lymphomes B. De plus, un dialogue bidirectionnel existe entre les polynucléaires neutrophiles et les cellules stromales. D’une part, les cellules stromales soutiennent la survie des polynucléaires neutrophiles, qui en retour induisent les caractéristiques d’un stroma lymphoïde. L’induction de ce phénotype permet aux cellules stromales d’acquérir de meilleures capacités de soutien envers les cellules tumorales. Cette étude confirme donc que les polynucléaires neutrophiles sont une composante importante du microenvironnement tumoral, et pourraient devenir une nouvelle cible thérapeutique pour le traitement des lymphomes B issus du centre germinatifFor long time, neutrophils have only been considered as cells involved in the innate immune response. More recently, in descriptive publications, neutrophils were found in the microenvironment of many solid cancers, hypothesizing that they could also play a role in tumorigenesis and cancer progression. These studies highlighted the prognostic value of their frequency, but few of them focused on the functional characterization of these cells in tumor growth. In many cancers, including germinal centre-derived B-cell lymphomas, tumor cells are dependent on their microenvironment to proliferate and survive. In this study, we focused on the role of neutrophils in the progression of B-cell lymphomas, and for the first time we demonstrated that neutrophils directly support the growth and survival of tumor Bcells. In addition, we highlighted the existence of bidirectional cooperation between neutrophils and stromal cells. In one hand stromal cells support the survival of neutrophils. On the other hand, neutrophils induce a lymphoid stroma phenotype which is well known to enhance their supportive effect on tumor cells. This study demonstrates that neutrophils are a significant component of the tumor microenvironment and may be considered as a potential therapeutic target for the treatment of B-cell lymphomas
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Laviron, Marie. "Etude de la modulation des niches de macrophages au cours du développement tumoral et en réponse à la chimiothérapie." Electronic Thesis or Diss., Sorbonne université, 2021. https://accesdistant.sorbonne-universite.fr/login?url=https://theses-intra.sorbonne-universite.fr/2021SORUS225.pdf.
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Les macrophages représentent la population la plus abondante dans la tumeur et leur accumulation est associée à un mauvais pronostic dans beaucoup de cancers. Ils forment un ensemble de sous-populations pouvant varier en termes d’origine, de localisation et de fonction. Ces caractéristiques, définissant l’interaction entre le macrophage et son environnement, forment la niche du macrophage. Les niches de macrophages ont été largement décrites dans les différents tissus à l’homéostasie mais leur évolution dans la tumeur est mal connue. Mon projet de thèse s’intéresse à caractériser les niches de macrophages et s’articule autour de deux projets ; l’évolution des niches de macrophages lors du développement tumoral ; et l’impact de la chimiothérapie sur les niches de macrophages, en particulier le rôle des Treg dans la polarisation de celles-ci. A travers ces projets, nous mettons en évidence que l’hétérogénéité des macrophages est directement associée à la diversité des niches spatiales définies dans la tumeur. La polarisation des macrophages est dictée par les signaux de ces niches. Nous suggérons également que la chimiothérapie favorise les interactions entre Treg et macrophages dans la tumeur, que la déplétion des Treg post-chimiothérapie conduit à une repolarisation des macrophages vers un phénotype pro-inflammatoire, associée à un contrôle de la croissance tumorale. Ce travail met en évidence l’importance de la relation du macrophage avec la tumeur dans l’induction de ses fonctions et pourrait permettre d’identifier les populations à cibler pour rétablir une réponse immunitaire anti-tumorale efficaceMacrophages represent the most abundant population within the tumor and their accumulation is associated with bad prognosis in most cancers. They form a group of sub-populations that vary in terms of origin, localization and function. Those characteristics, defining the interaction between the macrophage and its environment, constitute the macrophage niche. Macrophage niches have been described in different tissues at homeostasis but their evolution during tumor development remains to be elucidated. My thesis project aims at characterizing macrophage niches and focuses on two parts; the evolution of macrophage niches during tumor development; and the impact of chemotherapy on macrophage niches, and specifically the role of Treg on their polarization in this setting. Through those projects, we highlight that the heterogeneity of macrophages is directly linked to the diversity of tumor spatial niches. Macrophage polarization is dictated by signals derived from the niche. We also suggest that chemotherapy favors Treg and macrophage interactions, and that Treg depletion post-chemotherapy leads to the repolarization of macrophages towards a pro-inflammatory phenotype, associated with better tumor control. This work sheds light on the importance of the relationship between the macrophage and the tumor for the induction of its functions, and could identify specific populations to target to restore an efficient anti-tumor immune response
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Gualtieri, Marco. "In vivo analysis and manipulation of an invasive brain tumour." Electronic Thesis or Diss., Sorbonne université, 2022. http://www.theses.fr/2022SORUS388.
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Les tumeurs cérébrales primaires sont extrêmement agressives, et souvent incurables. Des cellules partageant de nombreuses caractéristiques des cellules souches neurales (CSNs) ont été identifiées dans plusieurs tumeurs cérébrales primaires. Celles-ci sont appelées cellules souches cancéreuses (CSCs) et présentent un potentiel d'autorenouvellement avec une prolifération illimitée. Les tumeurs dépendent fortement de leur microenvironnement cellulaire, qui résulte en parti du remodelage de populations préexistantes, telles que les cellules gliales et les vaisseaux sanguins (la barrière hémato-encéphalique). Dans ce projet, le système nerveux central de la drosophile est utilisé comme modèle in vivo afin de suivre les tumeurs cérébrales tout au long de la vie de l’hôte. Les CSNs de la drosophile représentent un modèle de cellules souches bien caractérisé à partir duquel des tumeurs peuvent être générées au cours du développement de l’hôte, puis survivre et proliférer largement à l’âge adulte. Dans ce système, je peux distinguer différentes populations de cellules dans la niche et explorer leur comportement par rapport aux CSC pendant la croissance tumorale. Je me suis particulièrement intéressé aux mécanismes d'interaction cellulaire qui se produisent dans les cellules gliales à l'interface avec les tumeurs. Mes résultats montrent qu'une sous-population de cellules gliales (les cellules gliales du cortex) subit une apoptose lors de la croissance tumorale, un mécanisme qui semble favoriser la propagation de la tumeur. Lorsque la mort des cellules gliales du cortex est stoppée, la croissance tumorale est réduite, ce qui suggère que la tumeur a, en partie, besoin de la mort des cellules gliales afin de se développer. En retour, une apoptose précoce des cellules gliales du cortex favorise la croissance tumoral, soulignant une interaction à double sens entre ces deux populations. Une analyse transcriptionnelle des cellules gliales du cortex durant la croissance tumorale a révélé des voies de signalisation augmentées ou réduites, et dont la fonction est en train d'être testée. En parallèle, prenant avantage d'une analyse transcriptionnelle de telles tumeur déjà disponible, j'ai sélectionné plusieurs candidats potentiels servant de médiateurs des interactions entre protéines à l'interface entre la tumeur et les cellules gliales. Enfin, j'ai évalué le rôle des protéines Rab dans la croissance tumorale. Ces travaux permettront de mieux comprendre comment les tumeurs des CSN envahissent et progressent dans les tissus sainsPrimary brain tumours are extremely aggressive, and often incurable. Interestingly, cells sharing many of the features of neural stem cells (NSCs) have been identified in several primary brain tumors. These cells are coined cancer stem cells (CSCs), and display self-renewal potential with illimited proliferation. Tumours strongly depend on a cellular microenvironment, which results in part from the remodelling of pre-existing populations, such as glial cells and blood vessels (the blood-brain barrier). The project uses the Drosophila Central Nervous System as an in vivo model to track brain tumors during the entire life of the host. The fly NSCs are a well-characterised stem cell model from which tumous can be generated during development, are CSC-driven and can survive and proliferate extensively during adulthood. In this system I can discriminate between different cell populations within the niche, and explore their behavior with respect to the CSCs during tumor growth. In particular I am interested in the mechanisms of cellular interactions happening in glial cells at the interface with the tumors. My results show that a sub-population of glial cells (cortex glia) undergoes apoptosis upon tumor growth, a mechanism that appears to promote tumor propagation. Interestingly, preventing cortex glia death leads to reduced tumor growth, suggesting that the tumour is at least in part required to eliminate glia to grow. In return, precocious killing of cortex glia favors tumor growth, pinpointing a reciprocal relationship between these two cell populations. Performing a transcriptional analysis of cortex glia during tumor growth has revealed multiple signalling pathways with a changing expression, and whose functional relevance is currently being assessed. In parallel, taking advantage of a published tumor transcriptome, I have selected several potential candidates mediating protein protein interactions at the interface between the tumour and the glia cells. Finally, I have also evaluated the role of known Rab proteins in the context of tumor development. This on-going work will shed light on how CNS tumors progress within and invade the healthy tissue
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Deynoux, Margaux. "Incidence de l'hypoxie sur le métabolisme oxydatif des leucémies aiguës myéloïdes : établissement et caractérisation d'un modèle in vitro de niche leucémique." Thesis, Tours, 2019. http://www.theses.fr/2019TOUR3303.
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Dans les leucémies aiguës myéloïdes (LAM), un taux élevé d’espèces réactives de l’oxygène (ROS) est connu pour favoriser la prolifération de blastes, alors qu’un niveau faible promeut la quiescence des cellules souches leucémiques. La faible oxygénation, ou hypoxie, de la niche médullaire pourrait contribuer à la chimiorésistance des LAM en diminuant le stress oxydatif. Les facteurs induits par l’hypoxie (HIF) sont impliqués dans le contrôle du métabolisme et des enzymes antioxydantes. Leur inhibition conduit à un stress et à la mort des cellules de LAM. Mon objectif était d’étudier un lien entre l’hypoxie, le métabolisme oxydatif et la chimiorésistance dans un modèle in vitro de culture de cellules de LAM. L’acquisition d’un profil hypoxique par les cellules souches hématopoïétiques (CSH), cultivées avec des cellules stromales mésenchymateuses (CSM) médullaires, a été montré. Nous avons postulé que les cellules leucémiques pouvaient également l’acquérir en coculture avec des CSM humaines. Pour le démontrer, nous avons cultivé des cellules de LAM primaires ou de la lignée MV4-11 sur des CSM humaines primaires ou de la lignée HS-27a. A l’instar des CSH, nous avons identifié trois populations leucémiques en fonction de leur capacité d’adhésion sur les CSM : en suspension, adhérentes aux CSM et nichées dans les CSM. Les cellules nichées, les plus adhérentes, ont une plus forte expression du CXCR4 que les autres. Elles sont aussi plus résistantes de 2 à 7 fois à la cytarabine. Cependant, aucune modification du phénotype souche et des capacités clonogéniques, de repopulation ou de xénogreffe, n’a pu être associée aux cellules nichées comparées aux deux autres populations. En revanche, les cellules nichées présentent un profil hypoxique, une plus faible prolifération avec une augmentation de la phase G0, et de plus faibles niveaux de ROS en lien avec une masse mitochondriale diminuée. Ceci suggère donc un lien entre la chimiorésistance et l’hypoxie ou le métabolisme, plutôt qu’avec une capacité souche. Nous avons aussi montré que l’acriflavine, un inhibiteur non spécifique des HIF, pouvait avoir un effet synergique avec la cytarabine sur les cellules nichées chimiorésistantes. Nos résultats montrent que le surnageant ou le simple contact avec les CSM ne suffisent pas à induire le changement métabolique et la résistance à la cytarabine. Nous pensons que l’hypoxie dans la niche peut moduler le métabolisme oxydatif et donc la chimiorésistance par des mécanismes directs et/ou indirects via l’expression de CXCR4, montré récemment comme impliqué dans la régulation du stress oxydatif des CSHIn acute myeloid leukemia, a high level of ROS is known to favor blasts proliferation, whereas a low level promotes stem cells quiescence. The low oxygenation, or hypoxia, of the bone marrow niche could contribute to chemoresistance of AML cells by reducing the oxidative stress. Hypoxia-inducible factors (HIF) are involved in the control of the cell metabolism and antioxidant enzymes. HIFs inhibition leads to AML cells stress and death. The purpose of this work was to study a link between hypoxia, oxidative metabolism and chemoresistance in an in vitro model of leukemic cell culture. The acquisition of a hypoxic profile by hematopoietic stem cells (HSC) cultured with medullary mesenchymal stromal cells (MSC), has been shown. We hypothesized that AML cells may also acquire such profile in a coculture with human MSCs. To demonstrate that, we cultivated primary AML cells or the MV4-11 cell line on primary human MSCs or the HS-27a cell line. Like HSCs, we identified three leukemic populations according to their adhesion capacity to MSCs: in suspension, adherent to MSCs and embedded in MSCs. Embedded cells, the most adherent, have stronger CXCR4 expression compared to the others. They are also 2- to 7-fold more resistance to cytarabine. However, no change in the stem cell phenotype profile and in the clonogenic, repopulation or xenograft capacities, could be associated with the embedded cells compared to other populations. In contrast, embedded cells present a hypoxic profile, a weak proliferation with increased G0 phase, and lower ROS level that may rely on lower mitochondrial mass. This suggests that chemoresistance mainly relies on hypoxia or cell metabolism rather than a higher stem cell capacity. Furthermore, we have shown that acriflavine, a non-specific HIF inhibitor, could synergize with the cytarabine to eliminate embedded chemoresistant cells. Our results show that the MSC supernatant or a simple contact are not sufficient to induce metabolic change and resistance to cytarabine. We assume that hypoxia in the niche may modulate the oxidative metabolism and the chemoresistance by direct mechanisms and/or indirect ones through CXCR4 expression, a chemokine receptor shown to be involved in the regulation of the oxidative stress in HSC
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Lim, Chetana. "Microenvironnement et angiogénèse : implications dans la stratégie onco-chirurgicale des métastases hépatiques synchrones des cancers colorectaux." Thesis, Sorbonne Paris Cité, 2017. http://www.theses.fr/2017USPCC018/document.
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Lors du diagnostic de cancer colorectal, près d’un quart des patients ont des métastases hépatiques dites synchrones. Lorsque la tumeur primitive est asymptomatique, la stratégie chirurgicale (chirurgie première de la tumeur primitive versus chirurgie première des métastases hépatiques) reste débattue. Les recommandations actuelles ne reposent que sur des accords d’experts qui elles-mêmes sont basées sur des études cliniques rétrospectives. L’étude du microenvironnement tumoral a pris ces dernières années une place majeure dans la recherche sur le cancer. Elle a permis de changer de paradigme avec une nouvelle conception du processus métastatique : une tumeur primitive peut agir sur le microenvironnement du futur site métastatique pour créer une "niche pré-métastatique". Cette niche pré-métastatique permettrait secondairement la croissance des cellules tumorales via une angiogénèse tumorale et la formation de métastases. Par une triple approche à la fois fondamentale, translationnelle et clinique, nous avons obtenu des données qui suggèrent qu’une chirurgie première de la tumeur colique ou rectale permet de moduler l’angiogénèse au sein du microenvironnement hépatique. Cette stratégie chirurgicale permettrait également d’améliorer le pronostic oncologique des malades et l’efficacité des anti-angiogéniquesAt the time of the diagnosis of colorectal cancer, nearly 25% of patients have synchronous liver metastases. When this tumor is asymptomatic, the question of surgical strategy (primary tumor first versus liver-first strategy) remains debated. Current recommendations are based on agreements of experts which are by themselves based on retrospective clinical studies. The study of the tumor microenvironment has taken in recent years a major place in the field of cancer research. It leads to new paradigm with a new conception of the metastatic process. It may be possible that the microenvironment of the metastatic sites can be modulated by the primary tumor to promote the formation of the pre-“metastatic niche”. This leads to promote the growth of cancer cells and increase the metastatic potential of primary tumor. By a multidisciplinary research including fundamental, translational and clinical approaches, we have shown that primary tumor first strategy could modulate tumor angiogenesis and liver metastatic process. It is associated with improved survival of patients and efficacy of the anti-angiogenic therapy
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Dagdelen, Olcay. "Nicht-invasive Dignitätsbestimmung von HNO-Tumoren mittels Positronenemissionstomographie." Diss., lmu, 2004. http://nbn-resolving.de/urn:nbn:de:bvb:19-27595.
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Vahedi, Nadine. "Früh- und Langzeitergebnisse nach Resektion von Lebermetastasen nicht-kolorektaler Tumoren." Diss., lmu, 2009. http://nbn-resolving.de/urn:nbn:de:bvb:19-100951.
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Koczuła, Katarzyna Malgorzata. "Real-time metabolic flux in chronic lymphocytic leukaemia cells adapting to the hypoxic niche." Thesis, University of Birmingham, 2015. http://etheses.bham.ac.uk//id/eprint/6067/.
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Although knowledge of metabolic adaptations in cancer has increased dramatically, little is known about the spontaneous adoptive adaptations of cancer cells to changing conditions in the body. This is particularly important for chronic lymphocytic leukaemia (CLL) cells which continually circulate between different microenvironments in the blood, bone marrow and lymph nodes. To study such metabolic adaptations, a nuclear magnetic resonance (NMR) based approach; capable of monitoring real-time metabolism in primary CLL cells was developed. Using this setup, this thesis demonstrates fast, reversible metabolic plasticity in CLL cells during transition from normoxic to hypoxic conditions, associated with elevated HIF-1α dependent glycolysis. This work also demonstrates differential utilisation of pyruvate in oxygenated and hypoxic conditions where in the latter, pyruvate was actively transported into CLL cells to protect against oxidative stress. Moreover, real-time NMR experiments provided initial evidence that CLL metabolism in hypoxia correlates with stage of disease, adding significant relevance of our method for patient stratification. Additionally, to further investigate alterations between normoxic and hypoxic metabolism, Metabolic Flux Analysis (MFA) was carried out using primary CLL cell extracts, revealing modifications in pyruvate carboxylase (PC) activity and the pentose phosphate pathway (PPP). Despite the recent advent of promising new agents, CLL currently remains incurable and new therapeutic approaches are required. Understanding CLL cell adaptation to changing oxygen availability will permit the development of therapies that interfere with disease aetiology. This study makes several significant contributions towards this goal. Moreover, the findings may be relevant to all migratory cancer cells, and may have importance for the development of strategies to prevent cancer metastasis.
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Fahy, Lucine. "Etude des conséquences d’un environnement hypoxique sur le développement et la chimiorésistance des leucémies aiguës lymphoblastiques T (LAL-T)." Thesis, Sorbonne Paris Cité, 2019. https://theses.md.univ-paris-diderot.fr/FAHY_Lucine_2_complete_20190627.pdf.
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La leucémie aiguë lymphoblastique T (LAL-T) est une hémopathie maligne caractérisée par une prolifération exacerbée de précurseurs lymphocytaires T incapables d’achever leur maturation. Le traitement des LAL-T est efficace dans 90% des cas chez l’enfant. Cependant, les enfants présentant une rechute ont un pronostic très défavorable. La résistance à la chimiothérapie constitue donc un défi thérapeutique majeur dans le traitement des LAL-T ; résistance qui peut être au moins en partie liée aux interactions entre les cellules leucémiques et le microenvironnement qui favorisent la survie des cellules leucémiques. La moelle osseuse, site crucial de maintien et de propagation de la leucémie, est hypoxique avec des taux d’oxygène variant de 0.1% à 5%. Sachant que les cancers solides hypoxiques sont plus résistants à la chimiothérapie et à la radiothérapie, le but de mon projet a été de déterminer les effets d’un environnement hypoxique sur le développement et la chimiorésistance des LAL-T et de comprendre les mécanismes à l’origine des effets observés.Méthodes : Des LAL-T murines et de patients ont été cultivées en hypoxie (3.5% et 1% d’O2) et en normoxie (21% d’O2). Croissance, apoptose, cycle cellulaire, métabolisme et chimiorésistance ont été mesurés ainsi que développement leucémique in vivo en souris immunodéficientes afin de déterminer l’impact de faibles taux d’oxygène sur les LAL-T.Résultats : Les résultats ont montré que l’hypoxie inhibe la croissance des LAL-T en inhibant la progression dans le cycle cellulaire et le métabolisme, les rendant moins sensibles aux traitements chimiothérapeutiques et préservant leur capacité à induire la leucémie in vivo. La perte d’expression de HIF1α par knockdown (KD) a modifié les effets de l’hypoxie observés sur les LAL-T et a restauré leur chimiosensibilité. De manière intéressante, l’activation de la voie mTOR est diminuée dans les LAL-T en hypoxie et le KD de HIF1α en hypoxie a restauré son activation. De plus, l’inhibition de mTOR dans les cellules HIF1α KD a amélioré leur chimiorésistance, montrant une relation fonctionnelle entre ces deux voies.Conclusion : Ce travail a montré que des niches hypoxiques peuvent jouer un rôle protecteur pendant le traitement chimiothérapeutique des LAL-T à travers HIF1α et mTOR. L’inhibition de HIF1α et/ou l’activation de mTOR pourraient améliorer la chimiosensibilité des LAL-T en hypoxieBackground: T cell acute lymphoblastic leukemia (T-ALL) is a malignant hematological disorder characterized by an increased proliferation of T lymphocyte precursors that are unable to complete their maturation. Treatments are effective in 90% of children T-ALL cases. However, children with relapse have a very poor prognosis. Resistance to chemotherapy is thus a major therapeutic challenge in the treatment of T-ALL that can be driven by interactions between leukemic cells and the microenvironment. Bone marrow microenvironment, a crucial site of propagation and maintenance of leukemia, is hypoxic with oxygen levels varying from 0.1 to 5%. As hypoxic solid tumors are more resistant to radiotherapy and chemotherapy, the aims of the study were to investigate to which extent oxygen levels impact on leukemia development and chemoresistance and to characterize the implicated molecular mechanisms. Methods: Mouse models and patients derived samples of T-ALL were cultured in low (1% and 3.5%) and high (21%) oxygen levels. Growth, apoptosis, cell cycle, metabolism and chemoresistance were measured as well as in vivo leukemia propagation using immune deficient mice as ways to define the impact of oxygen levels on T-ALL.Results: Results show that hypoxia inhibits the growth of T-ALL by slowing down cell cycle progression and decreasing metabolism, making them less sensitive to anti-leukemic drugs and preserving their ability to initiate leukemia in vivo after treatment. Knocking down (KD) HIF1α counteracted the effects observed in hypoxic T-ALL and restored their chemosensitivity. Interestingly activation of mTOR was diminished in hypoxic leukemic cells and HIF-1α KD restored mTOR activation in these low O2 conditions. Moreover, inhibiting mTOR in HIF1aKD T-ALL enhanced their chemoresistance, indicating a functional relationship between these two pathways.Conclusion: This work shows that hypoxic niches can play a protective role during the treatment of T-ALL through a HIF1α/mTOR molecular loop. Inhibition of HIF1α and/or activation of the mTOR pathway may help suppress the chemoresistance of T-ALL in hypoxic niches
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Kobelt, Dennis. "Klinische Studie und experimentelle Untersuchungen zur nicht-viralen Gentherapie solider Tumoren." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://dx.doi.org/10.18452/16598.
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Krebs gehört zu den häufigsten Todesursachen weltweit. Ein großer Hoffnungsträger für die Behandlung maligner Tumore ist die Gentherapie. Die nicht-virale Gentherapie gilt als sicherere Alternative zur viralen Gentherapie. Für den nicht viralen Gentransfer sind sowohl Vektor als auch Gentransfertechnologie von entscheidender Bedeutung. Im Rahmen dieser Arbeit wurde die Gentransfereffizienz und Sicherheit der Jet-Injektion in einer klinischen Phase I Gentransferstudie mit Hilfe des Swiss-Injektors untersucht. Es konnte gezeigt werden, dass diese Technologie sicher klinisch angewendet werden kann, dass jedoch die Sicherheit der Vektoren und vor allem die Gentransfereffizienz weiter optimiert werden müssen. Ausgehend von diesen Ergebnissen wurden optimierte nicht-virale Vektoren (Minicircle, MIDGE) miteinander und mit ihren parentalen Plasmiden verglichen. Mit Hilfe des MIDGE Vektors konnte die höchste Transgenexpression aufgrund einer erhöhten Transkription erzielt werden. In Vorbereitung der klinischen Anwendung des MIDGE-Vektors wurde die Kombination von hTNF-alpha Gentransfer und Vindesin Chemotherapie untersucht. Auch hier zeigte der MIDGE-Vektor eine erhöhte in vitro Genexpression, die in vitro zu einer erhöhten Zytotoxizität von Vindesin aufgrund einer verstärkten Aktivierung der Apoptose führte. Auch in vivo konnte die verbesserte hTNF-alpha-Genexpression des MIDGE-Vektors nach Jet-Injektion gezeigt werden. Dies führte in Kombination mit Vindesin zu einem signifikant reduzierten Tumorwachstum. Durch Analyse der systemischen Vektorverteilung im Blut und in den Organen sowie in einer präklinischen toxikologischen Untersuchung konnte die sichere Anwendung des MIDGE-Vektors bestätigt werden. Abschließend wurden weitere Anwendungsmöglichkeiten des MIDGE-Vektors für die stabile Genexpression und für die Verwendung in kombinierten Gentransferprotokollen untersucht.Cancer is one leading causes of death worldwide. Gene therapy belongs to the promising options for treatment of malignant tumors. The non-viral gene therapy is known as safer alternative to the viral gene therapy. For non-viral gene transfer the vector and the transfer technology are of crucial importance. As part of this work a clinical trial was performed to assess efficiency and safety of the non-viral jet-injection. It was shown, that this technology can be used safely in a clinical setting. As a result of this clinical trial we concluded, that vector safety and especially efficiency need further improvements. Based on this optimized non-viral vectors (minicircle, MIDGE) were compared with each other and their respective parental plasmids. The MIDGE vector showed the highest transgene expression due to increased transcription. In preparation of a clinical trial the combined treatment of hTNF-alpha gene transfer and Vindesine chemotherapy was analyzed. Again, the MIDGE vector showed the highest transgene expression. This expression led to an increased cytotoxicity of Vindesine in vitro due to an elevated apoptosis signaling. Furthermore, these results could be assigned to an in vivo model. The increased hTNF-alpha expression after MIDGE vector jet-injection in combination with Vindesine led to a significant decrease in tumor growth. Detailed analysis of systemic vector distribution in the blood and organs as well as the preclinical toxicity evaluation showed the safety of the non-viral MIDGE vector. Initial experiments were performed to show further options for stable gene expression and combined gene transfer protocols using the MIDGE vector.
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Correnti, M. "THE ROLE OF STEM CELL NICHE AND TUMOR-ASSOCIATED MACROPHAGES IN HUMAN CHOLANGIOCARCINOMA." Doctoral thesis, Università degli Studi di Milano, 2017. http://hdl.handle.net/2434/484683.
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Background and Aims: Cholangiocarcinoma (CCA) is a highly malignant and extremely heterogeneous adenocarcinoma arising from epithelial cells of bile ducts. CCA is currently associated with poor clinical outcome and, together with hepatocellular carcinoma (HCC), is the major primitive liver cancer in adults. Severity of CCA, lack of good diagnostic markers and frustrating benefit of current therapeutic strategies has rendered this disease a major challenge. Therapeutically challenging subset, termed cancer stem cells (CSCs) has been proposed as a driving force of tumor initiation, dissemination and drug-resistance, including in liver cancer. CSCs could be responsible for CCA wide multi-layered heterogeneity and clinical severity. Although it has already been shown that HCC progression is driven by CSCs, little is known about the presence of CSCs in human CCA. Similar to normal stem cells, CSCs are believed to reside in a specialized microenvironment (“CSC-niche”) within tumor-context that supports self-renewal and drug-resistance. Among various immune-subgroups within CSC-niche, tumor-associated macrophages (TAMs) represent a poor defined but very intriguing immune-subset, whose presence has prognostic significance in CCA and other malignancies. Thus, we hypothesized that CSCs may actively shape their tumor-supportive immune niche, specifically CCA-associated macrophages.
Methods: CCA cells were cultured in 3D-condition to generate spheres (SPH). CCA-SPH analysis of in vivo tumorigenic-engraftment in immune-deficient mice and molecular characterization was performed as well as evaluation of drug responsiveness. In vitro and in vivo effect of CCA-SPH on macrophage-precursors was tested after culturing healthy donor CD14+ with CCA-SPH conditioned medium (CM). Evaluation of monocyte recruitment as well as macrophage markers’ expression and presence of macrophage functional properties. CCA cells grown in adherence conditions as monolayer (MON) and matched CM used as control. Validation in human specimens.
Results: CCA-SPHs engrafted 100% of transplanted mice, revealed a significant 20.3-fold increase in tumor-initiating fraction (p=0.0011) and a sustained tumorigenic potential through diverse xenograft-generations. Moreover, CCA-SPHs were highly enriched for CSC, liver cancer and embryonic stem cell markers both at gene and protein levels. CCA-SPH showed also a higher resistance to common chemotherapeutic drugs compared to MON. Analysis of CD14+ chemotaxis revealed that SPH-CM acted as a strong monocyte attractor. Next, fluorescence-activated cell sorting (FACS)-analysis showed that in presence of CCA-SPH-CM, CD14+ expressed key macrophage (MØ) markers (CD68, CD115, HLA-DR, CD206) indicating that CCA-SPH-CM was a strong MØ-activator. Gene expression profile of CCA-SPH activated MØ (SPH MØ) revealed unique molecular TAM-like features confirmed by high invasion capacity. Also, freshly isolated MØs from CCA-resections recapitulated similar molecular phenotype of in vitro educated-MØs. Consistently with invasive features, largest CD163+ set was found in tumor-front of human CCA specimens (n=23) and correlated with high level of serum CA19.9 (n=17). Among mediators released by CCA-SPHs, only IL13, IL34 and Osteoactivin (OA) were detected and further confirmed in CCA patient sera (n=12). Surprisingly, significant association of IL13, IL34 and OA with SPH stem-like genes was provided by CCA database (n=104). In vitro combination of IL13, IL34, OA was responsible for MØ-differentiation and invasion as well as for in vivo tumor-promoting effect.
Conclusion: CCA-CSCs molded a specific subset of stem-like associated-MØs, thus providing a rationale for a synergistic therapeutic strategy for CCA-disease.
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Wagner, Manuela. "Maligne Tumoren als Zufallsbefunde bei klinischen Obduktionen - Eine retrospektive Untersuchung am Obduktionsgut des Institutes für Pathologie des Universitätsklinikums Leipzig." Doctoral thesis, Universitätsbibliothek Leipzig, 2013. http://nbn-resolving.de/urn:nbn:de:bsz:15-qucosa-124575.
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Auf der Basis der Obduktionsprotokolle der Jahre 2000-2009 des Institutes für Pathologie des Universitätsklinikums Leipzig wurden die Häufigkeiten und Verteilungen maligner Tumoren sowie der zu Lebzeiten nicht bekannten malignen Tumoren untersucht.
Bei insgesamt 4592 durchgeführten Sektionen wurden in 263 Fällen zu Lebzeiten nicht bekannte maligne Tumoren diagnostiziert. Dies entsprach 5,7% des gesamten Sektionsgutes bzw. 20,2% aller nachgewiesenen Malignome.
Nach Analyse der pTNM-Klassifikation wurden 70,9% der Malignome in den Tumorkategorien pT1 und pT2 erfasst. In 24,7% der Fälle traten Lymphknotenmetastasen, in 19,4% Fernmetastasen auf.
23,2% der postmortal entdeckten Malignome waren todesursächlich. Über die Hälfte der Obduzierten mit klinisch nicht bekannten Tumoren waren 70 Jahre oder älter.
Die häufigsten klinisch nicht bekannten malignen Tumoren waren die Prostatakarzinome (23,9%), die kolorektalen Karzinome (16,3%), die Nierentumoren (13,0%), die Lungenkarzinome (12,7%) sowie die Leberkarzinome (6,5%).
Patienten mit synchronen Doppel- beziehungsweise Dreifachtumoren traten bei 1,8% des Sektionsgutes auf. Der Anteil nicht erkannter maligner Tumoren an den Mehrfachmalignomen betrug 41,7%.
Diese Sektionsanalyse bestätigte, dass auch im 21. Jahrhundert trotz der rasanten Entwicklungen in Medizin und Technik weiterhin maligne Tumoren erst bei der Autopsie festgestellt werden.
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Olivera-Salguero, Rubén 1991. "New roles for Snail1 -expressing CAF during primary tumor progression and secondary niche colonization." Doctoral thesis, Universitat Pompeu Fabra, 2019. http://hdl.handle.net/10803/667308.
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Snail1 is the master regulator of the Epithelial-to-Mesenchymal Transition (EMT) and is also crucial for fibroblast activation upon TGFβ signaling. In cancer, Snail1 expression in primary tumors correlates with the appearance of metastasis. We have previously shown that Snail1-expressing cancer-associated fibroblasts (CAF) enhance metastasis. Here we demonstrate that Snail1-expressing CAF attenuate the anti-tumor effector immune response. We observed that Snail1-expressing CAF determine macrophages to present a pro-tumor phenotype in vitro and in the in vivo model of breast cancer MMTV-PyMT what enhanced tumor progression. Moreover, in the context of metastasis, we show that Snail1-dependent TGFβ-induced activation of liver fibroblasts is determinant for colorectal cancer colonization of the organ. Snail1-expressing CAF determine cancer cell evasion of the adaptive anti-tumor effector immunity. In consequence, the absence of Snail1 prevents CAF activation in newly formed metastases and allows immune rejection. These new roles for Snail1-expressing CAF during primary tumor progression and secondary niche colonization increase the relevance of Snail1 protein in oncology.Snail1 és el principal regulador de la Transició Epiteli-Mesènquima (EMT, per les sigles en anglès) i també resulta crucial per a l’activació dels fibroblasts en presència de TGFβ. En càncer, l’expressió de Snail1 en tumors primerencs correlaciona amb l’aparició de metàstasis. Prèviament, el nostre grup va demostrar que els fibroblasts actius associats a tumors (CAF) que expressen Snail1 desencadenen metàstasis. Aquí demostrem que els CAF que expressen Snail1 atenuen la resposta immunitària efectora anti-tumoral. Hem observant que els CAF que expressen Snail1 determinen un fenotip pro-tumoral en macròfags in vitro i també in vivo fent servir el model de càncer de mama MMTV-PyMT on la progressió tumoral es veia accentuada. En el context metastàtic, mostrem que l’activació dels fibroblasts del fetge induïda per TGFβ és determinant per a la colonització d’aquest òrgan per part del càncer colorectal. Els CAF que expressen Snail1 determinen que les cèl·lules del càncer evadeixin la resposta immunitària anti-tumoral. En conseqüència i malgrat la senyalització per TGFβ, l’absència de Snail1 anul·là la presència de CAF actius en les noves metàstasis i foren rebutjades. Aquestes noves funcions dels CAF que expressen Snail1 durant la progressió del tumor primari i la colonització d’un nínxol secundari incrementen la rellevància de la proteïna Snail1 en oncologia.
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Cartier, Régis. "Verwendung von synthetischen NLS-Sequenzen für den nicht-viralen Gentransfer in humane Tumoren." [S.l.] : [s.n.], 2004. http://www.diss.fu-berlin.de/2004/174/index.html.
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Nor, Carolina. "Modulação da sobrevivência e proliferação de células de câncer : mecanismos relacionados ao estado da cromatina e ao nicho tumoral." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2013. http://hdl.handle.net/10183/104742.
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Câncer é a principal causa de morte nos países desenvolvidos e a segunda causa de morte nos países em desenvolvimento. O trabalho de diversos grupos de pesquisa tem sugerido que os tumores estão organizados em uma hierarquia de células, na qual uma pequena fração apresenta propriedades de células-tronco. Essas células tem se mostrado resistentes à quimioterapia convencional, dependentes da sinalização do microambiente tumoral e responsivas à terapia diferenciativa. Aqui nós mostramos que butirato sódico (NaB), um inibidor de desacetilase de histonas, diminui a proliferação celular e a formação de colônias em linhagens celulares de meduoblastoma humano. Estes efeitos foram acompanhados de um aumento da expressão de RNAm Gria2, um marcador de diferenciação neuronal, em duas das três linhagens celulares testadas. A formação de neuroesferas também foi impedida com a exposição de uma linhagem crescida em meio de cultura apropriado para células-tronco e NaB. NaB se mostrou capaz de potencializar os efeitos do quimioterápico etoposídeo e do fator neurotrófico derivado de cérebro (BDNF) na inibição da viabilidade celular de meduloblastoma. Além disso, nós observamos que o tratamento com cisplatina aumenta a proporção de células-tronco tumorais (CTT), identificadas por ALDH+CD44+, em células de carcinoma de cabeça e pescoço, quando tratadas também com interleucina 6 (IL-6), uma citocina liberada pelo nicho perivascular. O mesmo tratamento promoveu a proliferação, sobrevivência e auto-renovação de CTTs in vitro ao aumentar o número de esferas em placas de baixa aderência e a expressão de Bmi-1 em western blots. A fosforilação do transdutor de sinal e ativador de transcrição 3 (STAT3), um indicativo de propriedades de CTTs, induzida por IL-6 não foi afetada pelo tratamento com cisplatina em células de HNSCC, enquanto que a indução de fosforilação de quinases reguladas por sinais extracelulares (ERK), indicativo de processo de diferenciação, por IL-6 foi parcialmente inibido por cisplatina. Células resistentes a baixas doses de cisplatina também expressaram mais Bmi-1 do que células nunca expostas ao quimioterápico. Experimentos in vivo corroboram os achados in vitro, uma vez que tumores humanos induzidos em camundongos imunocomprometidos apresentaram aumentada proporção de células ALDH+CD44+ após tratamento dos animais com cisplatina. O anticorpo contra o receptor de IL-6 foi capaz de reverter a indução de expressão de Bmi-1 por cisplatina e IL-6. Em conjunto, esses resultados sugerem que a modulação de mecanismos epigenéticos das células tumorais e de sinais provenientes do nicho tumoral são novos alvos promissores para o desenvolvimento de terapias adjuvantes contra o câncer.Cancer is the leading cause of death in economically developed countries and the second cause of death in developing countries. Work from a number of laboratories strongly suggests that tumors are organized as a hierarchy based on a subset of cancer cells that have stem-cell properties. These cells have been shown to be resistant to conventional therapy, dependent on contextual signals within the tumor microenvironment and, to be responsive to differentiation therapy. Here we show that sodium butyrate (NaB), a histone deacetylase inhibitor, decreases cell proliferation and colony formation in human medulloblastoma cell lines. These effects were accompanied by an increased mRNA expression of Gria2, a neuronal differentiation marker, in two out of three cell lines tested. In addition, neurosphere formation was impaired by NaB exposure in a cell line submitted to stem cells proper media. NaB also may potentiate the effect of etoposide chemotherapy and BDNF (Brain-derived neurotrophic factor) on the inhibition of medulloblastoma cells viability. Moreover, we observed that cisplatin treatment increased the proportion of cancer stem cells (CSC), identified by ALDHhighCD44high cells, in head and neck squamous cell carcinoma (HNSCC), when treated together with recombinant human IL-6 (rhIL-6). The same regimen promoted proliferation, self-renewal and survival of CSC in vitro as seen by the increase in orosphere number formed in ultra-low attachment plates, and Bmi-1 expression induction in western blots. IL-6–induced signal transducer and activator of transcription 3 (STAT3) phosphorylation (indicative of stemness) was unaffected by treatment with cisplatin in HNSCC cells, whereas IL-6–induced extracellular signal-transducer kinases (ERK) phosphorylation (indicative of differentiation processes) was partially inhibited by cisplatin. Cells resistant to lower doses of cisplatin also expressed more Bmi-1. In vivo experiments corroborated in vitro findings by showing increased proportion of ALDH highCD44high cells in xenograft tumors of mice treated with cisplatin. An antibody against the receptor of IL-6 was able to revert the induction of Bmi-1 expression seen in cells treated with cisplatin plus IL-6. Taken together, these results suggest that the modulation of the epigenetic states of the cancer cell and modulation of signals provided by the niche are promising new molecular targets for the development of adjuvant therapy for cancer.
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Burgett, Monica E. "Direct contact with perivascular tumor cells enhances integrin αvβ3 signaling and migration of endothelial cells." Kent State University / OhioLINK, 2016. http://rave.ohiolink.edu/etdc/view?acc_num=kent1466174564.
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BERTOCCHI, ALICE. "ROLE OF THE GUT VASCULAR BARRIER IN METASTATIC COLON CANCER." Doctoral thesis, Università degli Studi di Milano, 2019. http://hdl.handle.net/2434/608839.
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Spreading of neoplastic cells from colon cancer to regional lymph nodes (LN) is often associated with distant recurrence. However, a number of clinical trials have shown that lymphadenectomy is not increasing Colon Cancer (CC) patient’s survival. This phenomenon is probably due to a metastatic dissemination that occurs via the systemic blood circulation, rather than the lymphatic vessels. How such dissemination is achieved is unknown. We hypothesized that the disruption of the vasculature in colon tumors can be linked to cancer cells dissemination. We identified a new marker of deranged vasculature which is expressed in primary tumors of CC patients that have developed metachronous distant metastases, independently from the presence of metastases in regional LN. Moreover, we studied vasculature disruption in a mouse model that develops spontaneous tumors mainly in the colon. These mice showed dismantled vasculature at tumor level and they concomitantly exhibited the formation of a pre-metastatic niche at distant sites which favored the recruitment of metastatic cells. Vascular impairment can shed light on the process of colon metastases and this new marker can be used as a prognostic marker for distant recurrence.
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Kontoyannis, Angeliki. "Development of the NICE clinical guideline on the diagnosis and management of colorectal cancer." Thesis, Cardiff University, 2014. http://orca.cf.ac.uk/71966/.
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This thesis examines the evidence base on which the NICE guideline for colorectal cancer was developed. The information supporting guidelines varies. Six separate studies researching the availability and quality of different types of such information were carried out. Methodology, epidemiology, clinical practice, diagnostic accuracy, therapeutic, and internationally sourced data was examined. The information was sourced by online data mining, national database queries, systematic reviewing of literature databases, and the observation of the NICE guideline development process through both membership of the guideline development group established to produce the recommendations, and the technical development team supporting its production. Results show that : • NICE methodology data is available publicly, is easily accessible online, and has been developed following an internationally accepted guideline quality assessment and development tool. • Epidemiology data on colorectal cancer is easily accessible and of good quality. • Data regarding current clinical practice on colorectal cancer collected by national databases has methodological challenges and is not easily accessible. • Diagnostic accuracy studies are less robustly developed comapared to therapeutic studies. Their design is heterogeneous making the results subject to bias and reporting is inconsistent. Quality assessment when evaluating diagnostic evidence for a guideline ensures clarity with regard to the strength of the recommendations. • Systematic reviews of therapeutic studies can be inappropriately considered high quality evidence using traditional quality appraisal and evidence classification methods. All outcomes of a study should be considered when assesing study quality and recommendations based on a more holistic grading of the evidence are a more accurate reflection of the evidence. • Evidence considered for guideline development is international in its nature and the national setting of a study does influence guideline recommendations. Overall, NICE methodology is of high quality. The research helps identify challenges that the evidence can present as a platform for future improvements.
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Garcia, Gerique Laura. "Study of disseminated high-risk neuroblastoma in the bone marrow niche; from microenvironmental modelling to therapeutic targeting." Doctoral thesis, Universitat de Barcelona, 2020. http://hdl.handle.net/10803/672256.
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Neuroblastoma (NB) is the most common extracraneal solid tumor diagnosed in the first 5 years of childhood and accounts for approximately 15% of all pediatric cancer-related deaths. At the time of diagnosis, about half of NB patients present disseminated disease, being the bone marrow (BM) the most common site of dissemination. The persistence of infiltrated BM during treatment or relapse is predictive of patient poor outcome. The BM microenvironment has unique biologic properties that favor progression of disseminated NB tumor cells. In this environment, the receptor CXCR4 has a pivotal role for BM homeostasis and is involved in metastatic dissemination in several cancers. In NB, CXCR4 is expressed in tumor cells; however, its oncogenic role in relation with its ligand CXCL12 has shown contradictory results. Using an in vitro model that recapitulates low oxygen levels and chemokine signaling present in the BM environment, we explored whether CXCR4 together with MIF, a second ligand, is critical for NB survival and proliferation in the niche. We also evaluated MIF inhibition as a therapeutic option for NB.
To develop a BM-based in vitro model, NB cells were cultured in different conditioned media (CMs) derived from supernatants of patient-derived BM primary cells (CM-BM) and NB cell lines (CM-NB) cultured alone, or in combination (CM-BM/NB). To mimic BM oxygen levels, NB cells were cultured under hypoxia (1% O2), as compared to cell culture normoxia (21% O2). Expanded BM cultures used to generate CMs contained a heterogenic population with a predominant cellularity positive for mesenchymal stromal markers measured by flow cytometry. Cytokine arrays and ELISA assays of CMs revealed MIF as the highest NB released cytokine, whereas CXCL12 was not detected. The expression of MIF and CXCL12 signaling pathways was analyzed with different public NB databases. Among the analyzed genes, the high expression of CXCR4 and MIF was associated with patient poor outcome and high-risk disseminated staging. To further explore the role of CXCR4/MIF axis in high- risk disseminated NB, in vitro and in vivo functional studies were performed with or without the covalent MIF inhibitor 4-IPP and the CXCR4 antagonist AMD3100.
When exposed to BM-derived CMs and hypoxia, BM-derived NB cell lines showed increased surface expression of CXCR4 by flow cytometry. The same culture condition increased
phosphorylated levels of AKT/PI3K and ERK/MAPK measured by western blot. Cell viability assays showed that hypoxic conditions and BM-derived CMs enhanced NB cell proliferation at different time points. Similarly, in vivo, the co-injection of BM cells favored NB tumor progression by reducing engraftment times in contrast to NB injection alone. Using wound healing assays and Matrigel-coated Transwells, CM-BM/NB chemoattracted and enhanced migration and invasion of LAN-1 cells cultured under hypoxic conditions. These aggressive phenotypes promoted by the BM-based model were reverted by adding sub-lethal concentrations of the MIF inhibitor 4-IPP. We also explored whether MIF present in our CMs affected response to chemotherapy. After treatment with doxorubicin and etoposide at IC50 values LAN-1 cell viability increased in CM-BM/NB compared to control media. In both cases, chemo-sensitivity was restored when 4-IPP was added to CM-BM/NB. Finally, the administration of 4-IPP delayed the tumor progression and increased mice survival in a LAN- 1 subcutaneous xenograft model.
In conclusion, our findings provide new understanding of the contribution of BM microenvironment to NB progression. Based on our BM-model, the relationship between the BM microenvironment and NB cells appears mediate, in part, by the autocrine CXCR4/MIF signaling axis. Furthermore, our results suggested that MIF could represent a therapeutic target for the treatment of patients with high-risk NB.
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Bures, Vanessa [Verfasser], and P. H. [Akademischer Betreuer] Kann. "Endosonographische Morphologiekriterien nicht-funktioneller pankreatischer neuroendokriner Tumoren (pNET) : Evaluation des endosonographischen Nachweises neuroendokriner Tumoren des Pankreas im Vergleich zu anderen bildgebenden Verfahren / Vanessa Bures. Betreuer: P. H. Kann." Marburg : Philipps-Universität Marburg, 2011. http://d-nb.info/1014851866/34.
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Mihailovic, Dean [Verfasser], Jorge [Akademischer Betreuer] Frank, and Michèle [Gutachter] Hoffmann-Massier. "Untersuchungen zur Entwicklung von Tumoren bei den nicht-akuten Porphyrien / Dean Mihailovic ; Gutachter: Michèle Hoffmann-Massier ; Betreuer: Jorge Frank." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2021. http://d-nb.info/1229191615/34.
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Zhao, Jiangang [Verfasser], and Karl-Walter [Akademischer Betreuer] Jauch. "Tumor-derived exosomes inhibit natural killer cell function in the pre-metastatic niche of pancreatic cancer / Jiangang Zhao ; Betreuer: Karl-Walter Jauch." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2019. http://d-nb.info/1198112409/34.
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Kobelt, Dennis [Verfasser], W. [Akademischer Betreuer] Uckert, W. [Akademischer Betreuer] Walther, and H. [Akademischer Betreuer] Lage. "Klinische Studie und experimentelle Untersuchungen zur nicht-viralen Gentherapie solider Tumoren / Dennis Kobelt. Gutachter: W. Uckert ; W. Walther ; H. Lage." Berlin : Humboldt Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2012. http://d-nb.info/102733959X/34.
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Schnurbus, Lea Elaine [Verfasser], Florian [Akademischer Betreuer] Ringel, Florian [Gutachter] Ringel, and Bernhard [Gutachter] Meyer. "Chirurgische Therapie von primär als nicht-operabel eingestuften hirneigenen Tumoren / Lea Elaine Schnurbus ; Gutachter: Florian Ringel, Bernhard Meyer ; Betreuer: Florian Ringel." München : Universitätsbibliothek der TU München, 2018. http://d-nb.info/1172880093/34.
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Müller-Hümmrich, Christine [Verfasser], and C. [Akademischer Betreuer] Alexiou. "Retrospektive Erhebung zum Krankheitsverlauf von Patienten mit nicht-plattenepithelialen Tumoren der Nasenhöhle und der Nasennebenhöhlen / Christine Müller-Hümmrich. Betreuer: C. Alexiou." Erlangen : Universitätsbibliothek der Universität Erlangen-Nürnberg, 2012. http://d-nb.info/101880143X/34.
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Strömvall, Kerstin. "Extratumoral effects of highly aggressive prostate cancer." Doctoral thesis, Umeå universitet, Patologi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-140154.
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Prostate cancer (PC) is the most common cancer in Sweden. Most patients have slow growing tumors that will not cause them any harm within their lifetime, but some have aggressive tumors and will die from their disease. The ability of current clinical practice to predict tumor behavior and disease outcome is limited leading to both over- and undertreatment of PC patients. The men who die from their disease are those that develop metastases. It is therefore of great value to find better and more sensitive prognostic techniques, so that metastatic spread can be detected (or predicted) at an early time point, and so that appropriate treatment can be offered to each subgroup of patients. The aim of this thesis was to investigate if, and by what means, highly aggressive prostate tumors influence extratumoral tissues such as the non-malignant parts of the prostate and regional lymph nodes (LN), and also if any of our findings could be of prognostic importance. Gene- and protein expression analysis were the main methods used to address these questions. Our research group has previously introduced the expression Tumor Instructed (Indicating) Normal Tissue (TINT), and we use the term TINT-changes when referring to alterations in non-malignant tissue due to the growth of a tumor nearby or elsewhere in the body. In the Dunning rat PC-model we found that MatLyLu (MLL)-tumors, having a high metastatic ability, caused pre-metastatic TINT-changes that differ from those caused by AT1-tumors who have low metastatic ability. Prostate-TINT surrounding MLL-tumors had elevated immune cell infiltration, and gene ontology enrichment analysis suggested that biological functions promoting tumor growth and metastasis were activated in MLL- while inhibited in AT1-prostate-TINT. In the regional LNs we found signs of impaired antigen presentation, and decreased quantity of T cells in the MLL-model. One of the downregulated genes in the MLL-LNs was Siglec1 (also known as Cd169), expressed by LN resident macrophages that are important for antigen presentation. When examining metastasis-free LN tissue from PC patients we found CD169 expression to be a prognostic factor for PC-specific survival, and reduced expression was linked to an increased risk of PC-specific death. Some of our findings in prostate- and LN-TINT could be seen already when the tumors were very small suggesting that differences in TINT-changes between tumors with different metastatic capability can be detected early in tumor progression. However, before coming of use in the clinic more research is needed to better define a suitable panel of prognostic TINT-factors as well as the right time window of when to use them.Populärvetenskaplig sammanfattning Prostatacancer är den i särklass vanligaste cancerformen hos män i Sverige. De flesta patienter har en mycket långsamt växande tumör som inte orsakar dem några större besvär under deras livstid, men enbart i Sverige dör ca 2500 patienter/år av sjukdomen. Det är först vid uppkomst av metastaser som sjukdomen blir dödlig. Befintliga diagnos- och prognosmetoder är otillräckliga när det gäller att uppskatta och förutse tumörens aggressivitet och risk för att bilda metastaser. Detta gör att vissa patienter inte får tillräcklig behandling eller behandlas försent medan andra behandlas i onödan. Behovet av förbättrad diagnostik är därför stort. Om vi kan hitta markörer för potentiellt metastaserande sjukdom, och i bästa fall också behandla innan metastaser uppstår, skulle det förbättra chansen för överlevnad markant. För att kunna växa och spridas behöver en tumör inte bara förbereda närliggande vävnader utan förmodligen hela kroppen. Vår hypotes är att potentiell dödliga tumörer sannolikt är bättre på detta än mer ofarliga. Man vet från studier av andra cancerformer att farliga tumörer orsakar förändringar i det organ dit cancern senare sprids. Dessa förändringar sker för att de tumörceller som senare anländer ska kunna överleva, och processen har fått namnet pre-metastatisk nisch. Bl.a. har man sett att immunsystemet hämmas och nybildning av kärl ökar. Det är vanligt att metastaser uppstår i närliggande lymfkörtlar innan uppkomst av metastaser i andra organ. Dock är väldigt lite känt om pre-metastatiska förändringar i lymfkörtlar eftersom den forskning som hittills är gjord främst har tittat på andra organ. Inom prostatacancer finns det förvånande få studier av premetastatiska nischer överhuvudtaget, och man vet därför inte om de alls förekommer eller vilka förändringar som i så fall sker. Vår grupp har tidigare myntat uttrycket TINT som står för Tumor Instructed (Indicating) Normal Tissue (TINT är ett engelskt verb som betyder färga) och syftar på förändringar i normal vävnad som inducerats av tumören, dvs. att tumörer färgar av sig på omgivningen. Det kan vara förändringar i normal vävnad nära tumören, som i det här fallet resten av prostatan, eller i vävnad långt ifrån tumören som till exempel regionala lymfkörtlar, lungor och benmärg. Syftet med det här avhandlingsarbetet var att undersöka TINT-förändringar inducerade av aggressiv cancer och se om dessa skiljer sig från TINT-förändringar inducerade av mindre farliga tumörer, samt att utvärdera om någon TINT-förändring skulle kunna användas för att prognostisera vilka patienter som har hög risk att få metastaser. Vi har använt oss av en prostatacancer-modell i råtta där vi analyserat genoch proteinuttryck i pre-metastatiska regionala lymfkörtlar, tumörer och prostata-TINT (dvs. prostatavävnad utanför tumören). TINT-förändringar inducerade av MatLyLu (MLL), en tumör med hög metastaserande förmåga, jämfördes mot TINT-förändringar inducerade av AT1, en snabbväxande tumör men med låg förmåga att bilda metastaser. Vi kunde vi se flera skillnader mellan modellerna. Genuttrycket i MLL-prostata-TINT indikerade en aktivering av cellulära funktioner som visat sig stimulera tumörväxt och spridning såsom celldelning, viabilitet, migration, invasion, och angiogenes (nybildning av kärl). I AT1-prostata-TINT var genuttrycket kopplat till samma funktioner men verkade istället inhibera dessa. Genom att titta på vävnaderna i mikroskop kunde vi se att MLL-tumörer rekryterade färre T-celler (som har en viktig funktion i immunsvaret mot tumören), men istället fler makrofager och granulocyter till både tumören och prostata-TINT (dessa typer av immunceller har visats kunna hjälpa tumörer att växa och sprida sig). MLL-tumörer hade också fler blodkärl och lymfkärl strax utanför tumören. I de regionala lymfkörtlarna från djur med MLL-tumörer visade genuttrycket tecken på försämrad antigenpresentation, samt immunhämning och/eller induktion av immuntolerans. Immuntolerans innebär att immuncellen inte längre reagerar mot det specifika antigen den blivit tolerant emot. Detta är vanligt förekommande hos individer med cancer och är ett sätt för tumören att undkomma immunförsvaret. I vävnadsprover av lymfkörtlarna kunde vi se färre antigenpresenterande celler, och liksom i tumörerna fanns det färre T-celler i MLL-modellen, något vi kunde se redan när tumörerna var väldigt små. CD169 är ett protein som bl.a. uttrycks av sinus-makrofager i lymfkörtlar. Dessa makrofager har en central funktion i att aktivera ett tumör-specifikt immunsvar. I råttmodellen kunde vi se att regionala lymfkörtlar från djur med MLL-tumörer hade lägre nivåer av CD169 än regionala lymfkörtlar från djur med AT1-tumörer, och då antalet sinus-makrofager visat sig ha prognostiskt värde i t.ex. tjocktarmscancer, ville vi se om det kunde vara så även i prostatacancer. Därför kvantifierade vi uttrycket av CD169 i metastasfria regionala lymfkörtlar från prostatacancerpatienter och såg att låga nivåer av CD169 medförde en ökad risk för att dö i prostatacancer. Sammantaget tyder resultaten på att MLL-tumören jämfört med AT1- tumören bättre lyckas förbereda omgivande vävnad för att gynna tumörväxt och spridning, både lokalt i prostatan men också längre bort från tumören i de regionala lymfkörtlarna. Våra fynd stämmer väl överens med aktuell tumörbiologisk forskning om hur tumörer påverkar sin omgivning. Något som inte visats tidigare är att miljön utanför tumören verkar skilja sig drastiskt beroende på tumörens metastaserande förmåga, samt att dessa skillnader går att se relativt tidigt under sjukdomsförloppet och förmodligen även långt bort från tumören. Vi har också visat att särskilt aggressiv prostatacancer verkar inducera en pre-metastatisk nisch i tumördränerande lymfkörtlar likt det som beskrivits i andra modellsystem och i andra cancertyper, men hittills inte i prostatacancer. Fler studier behövs för att bättre karaktärisera de förändringar som en potentiellt dödlig prostatacancer orsakar i andra vävnader, och för att ta reda på hur denna kunskap kan användas för att förbättra diagnostik och behandling.
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Krüger, Konstantin [Verfasser], and Clemens [Akademischer Betreuer] Cyran. "Nicht-invasive Bestimmung des Differenzierungsgrades hepatisch metastasierter neuroendokriner Tumoren anhand der Radiomics basierten Bildanalyse von 68Ga-DOTATATE PET/CT-Daten / Konstantin Krüger ; Betreuer: Clemens Cyran." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2021. http://d-nb.info/1233200690/34.
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Droop, Johanna [Verfasser], Wolfgang A. [Gutachter] Schulz, and Henrike [Gutachter] Heise. "Funktionelle Bedeutung langer nicht-codierender RNAs in der Regulation squamöser Differenzierung in Urothelkarzinomen und Kopf-Hals-Tumoren / Johanna Droop ; Gutachter: Wolfgang A. Schulz, Henrike Heise." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1209736926/34.
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MOSCHETTI, Marta. "Tumor-derived exosomes as factors that promote metastatic niche formation: evaluation of the effects induced by colon cancer derived exosomes on functional activities and structural features of Hepatocytes." Doctoral thesis, Università degli Studi di Palermo, 2023. https://hdl.handle.net/10447/580510.
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Balenci, Laurent. "Etude de la protéine IQGAP1 dans un contexte physiologique de la neurogenèse adulte et dans un contexte pathologique de tumeurs cérébrales." Phd thesis, Grenoble 1, 2006. http://tel.archives-ouvertes.fr/tel-00129290.
Full textAbstract:
Les cellules souches/progénitrices sont douées d'une forte plasticité cellulaire qui leur permet de développer, de maintenir et de régénérer organes ou tissus dans lesquels elles résident. Ces processus requièrent l'intégration de signaux moléculaires et environnementaux qui influencent leur comportement et leur devenir. La perturbation de l'un de ces mécanismes régulateurs aboutit à une perte de contrôle des cellules souches/progénitrices pouvant entraîner le développement de pathologies cancéreuses. De ce fait, la connaissance des éléments cellulaires et moléculaires régulant la biologie des cellules souches/progénitrices est nécessaire pour l'emploi éventuel de ces cellules en médecine régénérative et pour une avancée dans les traitements anti-cancéreux.La protéine IQGAP1, que nous avons étudiée dans le cerveau dans un contexte physiologique et pathologique, s'est révélée être un nouveau marqueur de cellules souches/progénitrices normales et tumorales. A travers une étude comparative de souris sauvages et iqgap1-/-, nous avons analysé les propriétés et le comportement in vivo comme in vitro des cellules souches/progénitrices neurales. Nous avons démontré qu'IQGAP1 joue un rôle dans la neurogenèse adulte en régulant la migration des cellules progénitrices neurales en réponse au VEGF, facteur pléïotropique intervenant notamment dans la neurogenèse et l'angiogenèse tumorale. D'autre part, dans un contexte tumoral de gliomes humains et chimio-induits chez le rat, la caractérisation de cette protéine dans des cellules souches/progénitrices tumorales au sein de tumeurs malignes a permis d'attribuer un rôle putatif à la protéine IQGAP1 dans l'expansion tumorale par la dissémination de ces cellules cancéreuses. L'identification et la caractérisation de tous les mécanismes environnementaux régulant la motilité et la migration des précurseurs neuraux normaux pourraient s'avérer utile pour la compréhension des mécanismes d'invasion tumorale et pour le développement de thérapies anti-cancéreuses plus efficaces.
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Romain, Benoît. "Etude des mécanismes moléculaires et cellulaires impliqués dans la formation des niches métastatiques dans le cancer colorectal : intérêt d’une inhibition ciblée des axes mTOR/HIF-1 alpha et CXCL12/CXCR4/CXCR7." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ081.
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Le cancer colorectal métastatique est l’une des premières causes de décès par cancer dans les pays occidentaux, malgré le développement récent de nouveaux traitements ciblés. L’amélioration de la survie des patients passe par une meilleure compréhension des mécanismes moléculaires impliqués dans la progression tumorale et la formation des métastases. Compte tenu de l’importance du rôle des axes mTOR/HIF1α et CXCL12/CXCR4/CXCR7 dans le processus métastatique, nos objectifs ont été : i) d’analyser de façon extensive le statut de CXCL12 dans une collection de polypes et de tumeurs coliques de tous stades et phénotypes en comparaison avec la muqueuse saine, puis de comprendre les mécanismes régulant l’expression de la chimiokine dans les cellules tumorales ; ii) d’étudier in vitro le rôle de l’hypoxie dans la régulation de la signalisation induite par CXCL12 via CXCR4 et CXCR7 et l’intérêt d’une inhibition des axes mTOR/HIF-1α et CXCL12/CXCR4/CXCR7 en particulier sur les capacités migratoires des cellules tumorales.Nous avons montré que l’extinction du gène CXCL12 est un évènement précoce et systématique au cours de la cancérogenèse colique et que cette perte d’expression pourrait être régulée par un mécanisme d’acétylation au niveau des histones. Une expression différentielle de CXCR4 et CXCR7 au sein des tumeurs du colon a été mise en évidence. L’augmentation d’expression de CXCR7 dans les métastases par rapport aux stades précoces montre l’importance de cet axe dans le processus métastatique. Le maintien de l’expression à la surface cellulaire de CXCR4 en normoxie pendant au moins 24h après un bref passage en hypoxie n’avait pas encore été décrit. Ceci pourrait expliquer le « homing » des cellules tumorales circulantes dans les niches métastatiques selon un gradient de CXCL12. L’utilisation combinée d’irinotécan et de chalcone permettant d’inhiber la migration des cellules tumorales est une approche originale in vitro. Enfin, nous avons initié le développement de modèles métastatiques de cancer du colon par greffe orthotopique sur le caecum de souris NUDE dans l’objectif de tester de nouvelles approches thérapeutiques ciblées in vivoDespite the recent development of new targeted chemotherapies, metastatic colorectal cancer is still one of the leading causes of cancer related deaths in western countries. A better understanding of metastatic process would improve survival. Since the role of mTOR/HIF1α and CXCL12/CXCR4/CXCR7 axes in metastasis formation, our objectives were: i) to analyze extensively CXCL12 status in a collection of polyps and colon tumors whatever stages and phenotypes; ii) to study the role of hypoxia in CXCL12/CXCR4/CXCR7 signaling pathway in vitro and on tumor cells migration. We have shown that the CXCL12 extinction is a systematic early event during colorectal carcinogenesis. CXCL12 loss expression may be regulated by histone acetylation mechanism. There is a differential CXCR4 and CXCR7 expression in colon tumors. Increased CXCR7 expression in metastasis compared to early stages underlines the importance of this axis in metastatic process. We have shown for the first time that CXCR4 expression remained stabilized at the cell membrane 24 hours after a transient passage in hypoxia. It could explain circulating cells are attracted in metastatic niches under CXCL12 gradient. Drug combinations with chalcone and irinotecan are an original approach for inhibiting cell migration in vitro. Finally, we have initiated the development of a metastatic model of colon cancer with orthotopic colon human tumors xenograft in NUDE mice to test new therapeutic approaches in vivo
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Rosentraeger, Markus Johannes [Verfasser], Christoph [Akademischer Betreuer] Röcken, and Heiner [Gutachter] Mönig. "Funktionell aktive versus funktionell nicht aktive, sporadische, Gastrin produzierende, neuroendokrine Tumoren des Duodenum : Vergleich von histopathologischen Merkmalen, Lokalisation, funktioneller Aktivität, biologischem Verhalten und Follwo-Up / Markus Johannes Rosentraeger ; Gutachter: Heiner Mönig ; Betreuer: Christoph Röcken." Kiel : Universitätsbibliothek Kiel, 2017. http://d-nb.info/1215101333/34.
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Tholen, Anika Christiane Katharina [Verfasser], Hans C. W. E. [Akademischer Betreuer] Geinitz, and Michael [Akademischer Betreuer] Molls. "Verträglichkeit und Effektivität von Radiochemotherapie bei älteren Patienten mit malignen Tumoren im Kopf- und Halsbereich, Ösophaguskarzinom und nicht-kleinzelligem Bronchialkarzinom / Anika Christiane Katharina Tholen. Gutachter: Hans C.-W. E. Geinitz ; Michael Molls. Betreuer: Hans C.-W. E. Geinitz." München : Universitätsbibliothek der TU München, 2011. http://d-nb.info/1012187039/34.
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"Investigating the Role of the Perivascular Niche on Glioma Stem Cell Invasion in a Three-Dimensional Microfluidic Tumor Microenvironment Model." Master's thesis, 2020. http://hdl.handle.net/2286/R.I.57302.
Full textAbstract:
abstract: Glioblastoma Multiforme (GBM) is a grade IV astrocytoma and the most aggressive form of cancer that begins within the brain. The two-year average survival rate of GBM in the United States of America is 25%, and it has a higher incidence in individuals within the ages of 45 - 60 years. GBM Tumor formation can either begin as normal brain cells or develop from an existing low-grade astrocytoma and are housed by the perivascular niche in the brain microenvironment. This niche allows for the persistence of a population of cells known as glioma stem cells (GSC) by supplying optimum growth conditions that build chemoresistance and cause recurrence of the tumor within two to five years of treatment. It has therefore become imperative to understand the role of the perivascular niche on GSCs through in vitro modelling in order to improve the efficiency of therapeutic treatment and increase the survival rate of patients with GBM.
In this study, a unique three dimensional (3D) microfluidic platform that permitted the study of intercellular interactions between three different cell types in the perivascular niche of the brain was developed and utilized for the first time. Specifically, human endothelial cells were embedded in a fibrin matrix and introduced into the vascular layer of the microfluidic platform.
After spontaneous formation of a vascular layer, Normal Human Astrocytes and Patient derived GSC were embedded in a Matrigel® matrix and incorporated in the stroma and tumor regions of the microfluidic device respectively.
Using the established platform, migration, proliferation and stemness of GSCs studies were conducted. The findings obtained indicate that astrocytes in the perivascular niche significantly increase the migratory and proliferative properties of GSCs in the tumor microenvironment, consistent with previous in vivo findings.
The novel GBM tumor microenvironment developed herein, could be utilized for further
in-depth cellular and molecular level studies to dissect the influence of individual factors within the tumor niche on GSCs biology, and could serve as a model for developing targeted therapies.Dissertation/Thesis
Masters Thesis Biomedical Engineering 2020
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Facklam, Heide. "Angiogenese in polypoiden neoplastischen und nicht-neoplastischen Tumoren des Kolon und Rektum." 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=014189153&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Dagdelen, Olcay [Verfasser]. "Nicht-invasive Dignitätsbestimmung von HNO-Tumoren mittels Positronenemissionstomographie / vorgelegt von Olcay Dagdelen." 2004. http://d-nb.info/972835377/34.
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Vahedi, Nadine [Verfasser]. "Früh- und Langzeitergebnisse nach Resektion von Lebermetastasen nicht-kolorektaler Tumoren / vorgelegt von Nadine Vahedi." 2009. http://d-nb.info/994507976/34.
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Cartier, Régis [Verfasser]. "Verwendung von synthetischen NLS-Sequenzen für den nicht-viralen Gentransfer in humane Tumoren / Régis Cartier." 2004. http://d-nb.info/971794316/34.
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Groll, Mathias Jakob. "MALDI-TOF Untersuchungen an Zystenflüssigkeiten aus zerebralen Tumoren im Vergleich zu Liquorproben nicht tumorerkrankter Patienten." 2017. https://ul.qucosa.de/id/qucosa%3A31599.
Full textAbstract:
Das Glioblastom ist eine hochmaligne Tumorerkrankung des zentralen Nervensystems und geht trotz intensiver Forschungsbemühungen mit einer eingeschränkten Prognose und einer Überlebenszeit im Rahmen von einigen Monaten nach Diagnosestellung einher. Cerebrale Metastasen maligner Tumoren treten in Abhängigkeit vom Primärtumor auf, und beschränken nach Erreichen des ZNS die Überlebenszeit ebenfalls auf wenige Monate. Etwa 10% der Glioblastome weisen zystische Veränderungen auf, cerebrale Metastasen maligner Tumoren präsentieren sich ebenfalls nicht selten mit einer zystischen Konfiguration.
Streng histologisch gesehen handelt es sich hierbei um Pseudozysten, in denen sich eine zellarme Flüssigkeit befindet, die tumorzellassoziierte Proteine in einer geringen Konzentration enthält. Aufgrund der engen Beziehung der Zysten zu den Tumorzellen gibt die Proteinanalyse der Zystenflüssigkeit über Tumorgenese und Metabolismus Aufschluss.
Bereits in einer vorangegangenen Promotionsarbeit der neuroonkologischen Arbeitsgruppe war es gelungen, Proben zystischer Glioblastome und Metastasen im Vergleich zu Liquorproben tumorfreier Patienten mittels SELDI (surface enhanced laser desorption / ionisation) TOF (time of flight) MS (Massenspektrometrie) zu vermessen. Hierbei wurden Alleinstellungsmerkmale im Sinne von isoliert auftretenden Protein-Massenpeaks sowohl in den neoplastischen Proben, als auch in den Liquorproben detektiert. Der theoretische Teil der vorliegenden Arbeit widmet sich der Charakterisierung möglicher Tumorsuppressorproteine, mittels einer Evidenzanalyse / Literaturrecherche unter Verwendung der SELDI-TOF-MS Daten.
Da mittlerweile mehrere Bestandteile der SELDI-TOF Hardware kommerziell nicht mehr verfügbar sind, bestand die Notwendigkeit, ein Alternativverfahren zur Proteinbestimmung von Zystenflüssigkeiten zu etablieren. Hierzu wurde in dieser Dissertation die Methode der MALDI (matrix assisted laser desorption / ionisation) TOF-MS zur Messung eines Sets neuer Proben angewendet. Die MALDI-TOF-MS war bereits in mehreren Publikationen zur Massenspektroskopie von Liquorproben beschrieben worden, wohingegen zur Untersuchung cerebraler Zystenflüssigkeiten bisher keine Berichte zu finden sind. Dementsprechend wurde im praktischen Teil ein Aufbereitungs- und Untersuchungsprotokoll eigenständig etabliert.
Hiermit konnten Massenspektren der Proben abgeleitet werden, welche in den drei Diagnosegruppen (GBM, Metastasen, Liquorproben) untereinander verglichen wurden.
Ergebnisse:
Anhand von 20 Massenpeaks aus der SELDI-TOF Untersuchung wurden mittels Datenbanksuche in Expasy Tagident (UniProt) initial 792 Kandidatenproteine ermittelt, welche in Vergleichsliquorproben gesunder Probanden nachweisbar, in Glioblastomzysten aber absent waren, und somit eine tumorsuppressive Aktivität besitzen können. Mittels Evidenzanalyse und erweiterter Literaturrecherche wurde ein Bewertungsalgorithmus erstellt, und es konnte die Anzahl auf 54 Kandidaten reduziert werden. Unter diesen befinden sich bereits bekannte Tumorsuppressoren wie Tumor-Nekrose-Faktoren und Kinase-Inhibitoren, aber auch beispielsweise Ciliary neurotrophic factor und Inhibitor of growth protein als mögliche Tumorsuppressoren, deren Bezug zu Glioblastomen in aktuellen Veröffentlichungen diskutiert wird.
Im experimentellen Teil wurde festgestellt, dass die massenspektrometrische MALDI-TOF Messung von nativer Hirntumorzystenflüssigkeit oder nativem Liquor keine verlässlichen Spektren liefert, sodass ein standardisiertes Aufarbeitungsprotokoll notwendig wurde. Nach Einsatz verschiedener Aufreinigungsverfahren, Verdünnungsreihen und Matrices erwiesen sich die Aufreinigung per magnetic beads mit schwachem Kationen-Austausch (WCX) und die Verwendung von 4mg/ml HCCA-Matrix als reliabel. Zusätzlich erfolgte eine 1:5 Vorverdünnung der neoplastischen Proben mit TRIS Puffer pH 6,8, während Liquorproben unverdünnt blieben.
Insgesamt wurden 62 Proben untersucht, 25 aus Glioblastomzysten, 15 aus zystischen Hirnmetastasen und 22 Liquorproben als Kontrollgruppe. Im Schnitt konnten 20 Peaks pro Probe abgebildet werden; die jeweils 10 intensitätsstärksten hiervon wurden zur statistischen Aufarbeitung innerhalb der jeweiligen Diagnosegruppe herangezogen.
Hierbei zeigten sich signifikante Unterschiede des Auftretens bestimmter Proteinbanden im Vergleich von Tumorproben zu Liquor, zum Teil auch zwischen Metastasen und Glioblastomen. Besonders hervorzuheben sind:
- Der in Glioblastomproben signifikant häufig auftretende Peak bei 6433 Dalton entspricht dem Protein LuzP6 oder einer Splice-Variante des Apo-C1.
o Für LuzP6 werden in der Literatur Assoziationen mit Neoplasien wie myeloproliferative Erkrankungen und Prostatakarzinom beschrieben. Das Gen für LuzP6 befindet sich auf Chromosom 7q33 und sein Translationsprodukt ist als Self-Tumor-Antigen beschrieben worden.
o Apo-C1 wird als Mediator des Lipidstoffwechsels in der Leber synthetisiert und kann immunhistochemisch in Liquor und Gehirngewebe nachgewiesen werden. Eine weitere Splicevariante besitzt eine Größe von 6632 Dalton, dieser Peak liegt ebenfalls signifikant häufiger in Glioblastomen als in Liquor vor.
- Der Peak 4303 Dalton wird in Metastasen signifikant häufig nachgewiesen. Als Kandidat findet sich unter anderen der angiogenetische Faktor Adrenomedullin 2, dessen protoonkogene Funktion in mehreren Publikationen beschrieben wird.
- In über 95% der Vergleichsliquorproben und in unter 10% der neoplastischen Diagnosegruppen findet sich die Bande 3513 Dalton. In der UniProt Datenbank gibt es hierfür jedoch keine Entsprechung. Auch für ein möglicherweise doppelt geladenes Protein mit 7026 Dalton sind bis dato keine bekannt tumorsuppressiv wirkenden Kandidaten hinterlegt. Die Aufgabe zukünftiger Arbeiten besteht somit in der Identifizierung des zugrundeliegenden Proteins.
- Als ubiquitäre Bande in allen drei Diagnosegruppen lässt sich 11725 Dalton beispielsweise dem beta-2-Mikroglobulin zuordnen, das auf allen Körperzellen vorhanden ist und die Antigenpräsentation an das Immunsystem vermittelt. Aufgrund einer Vielzahl weiterer möglicher Kandidatenproteine dieser Größe steht auch hier die eindeutige Identifizierung aus.
Antworten auf die Problemstellung
1. Sowohl MALDI, als auch SELDI TOF MS sind geeignet um Flüssigkeiten aus Glioblastomzysten massenspektrometrisch zu analysieren. Um eine verlässliche Messung per MALDI-TOF zu erreichen, müssen die Proben zuvor eine Aufreinigung erfahren. Die Ergebnisse innerhalb der Diagnosegruppen sind reproduzierbar; die MALDI-TOF MS bildet insbesondere niedrige m/z (1.500Da - 20.000Da) ab, und verschiebt somit im Vergleich zur SELDI-TOF MS (4.000Da - 145.000Da) den Messbereich in Richtung kleinerer Molekulargewichte.
2. Unter Anwendung des Aufreinigungsprotokolls gelingt die Abbildung aussagekräftiger Spektren auch bei Proben zystischer Hirnmetastasen.
3. Für lediglich in den Liquor-Vergleichsproben nachweisbare Massenpeaks lassen sich in den verfügbaren Datenbanken sowohl Proteine finden, welche nachgewiesenermaßen tumorsuppressive Aktivität besitzen, als auch solche, bei denen diese noch diskutiert wird. Eine eindeutige Zuordnung eines Peaks zu einem Protein ist mittels MALDI-TOF MS nicht möglich. Hierzu müssen weitere proteomische Methoden wie Proteinsequenzierung, Immunhistochemie oder mRNA-Analysen eingesetzt werden.
4. Aufgrund der Heterogenität der Messergebnisse und der geringen Fallzahl untersuchter Proben lässt sich eine Massenpeak-Tumorsignatur nicht erstellen. Dies betrifft die Glioblastomsubtypisierung und die Primärtumorbestimmung bei Metastasen, aber auch die Unterscheidung von Tumor- und Liquorprobe.
Aus heutiger Sicht steht die eindeutige Identifizierung der zu den Peaks korrespondierenden Proteine mittels supplementärer proteomischer, histologischer und molekularbiologischer Verfahren an. Somit kann, ausgehend von dem hier vorgestellten „discovery oriented approach“ als langfristiges Ziel die Beschreibung von Tumormetabolismus und Proteinregulation verbunden mit der Etablierung von Biomarkern angestrebt werden, um neue therapeutische Ansätze zu ermöglichen.:Inhaltsverzeichnis 2
Tabellenverzeichnis 4
Abbildungsverzeichnis 5
Abkürzungsverzeichnis 6
1. Einleitung 8
1.1 Hirneigene Tumore 8
1.1.1 Diagnostik 10
1.1.2 Operatives Vorgehen 11
1.1.3 Postoperative Weiterbehandlung – Adjuvante Therapie 12
1.2 Metastasen 14
1.3 Zystische Tumore 16
1.4 Proteomik 20
1.4.1 Proteomanalyse 21
1.4.2 Protein-Analyseverfahren 21
1.4.3 MALDI TOF 23
1.4.4 SELDI TOF 25
2. Problemstellung 26
3. Material und Methoden 27
3.1 Materialliste 27
3.2 Internetbasierte Recherche möglicher Tumorsuppressorgene 27
3.2.1 Evidenzlevel (gemäß der Internet Datenbank UniProt) 30
3.2.2 Proteincharakteristika 30
3.2.3 Schlagwortbezogene Literatursuche 31
3.3 Massenspektrometrische Untersuchungen 31
3.3.1 Probengewinnung und Aufbewahrung 31
3.3.2 Verwendung und Aufreinigung der Proben 32
3.3.3 Messverfahren 36
4. Ergebnisse 41
4.1 Recherche möglicher Tumorsuppressoren 41
4.2 Probenaufbereitung 48
4.2.1 Ergebnisse der verschiedenen Adaptationsversuche Probe / Matrix ohne weitere Aufreinigung 48
4.2.2 Kit-basierte Aufreinigung 50
4.3 Messergebnisse 52
4.3.1 Häufigkeit der intensitätsstärksten Peaks bei Glioblastomen 54
4.3.2 Häufigkeit der intensitätsstärksten Peaks bei Metastasen 55
4.3.3 Häufigkeit der intensitätsstärksten Peaks der Liquorproben 56
4.3.4 Automatisierte Kontrolle 56
4.3.5 Entitätenvergleich 57
4.4 statistische Aufarbeitung 60
4.4.1 Glioblastom 60
4.4.2 Metastasen 60
4.4.3 Liquor 60
4.5 Nachbetrachtung ausgewählter Peaks (Top 3 jeder Entität) 61
4.5.1 Glioblastom 61
4.5.2 Metastasen 61
4.5.3 Vergleichsproben 62
4.5.4 Exemplarische Vorstellung möglicher Proteinkandidaten 62
5. Diskussion 66
5.1 Diskussion möglicher Tumorsuppressoren 66
5.2 Diskussion der Probenaufbereitung und des Messverfahrens 68
5.3 Diskussion der Messergebnisse 72
5.4 Antworten auf die Problemstellung 76
6. Zusammenfassung 79
Literaturverzeichnis 84
Anlagen 94
Erklärung über die eigenständige Abfassung der Arbeit 101
Lebenslauf 102
Danksagung 104
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Lee, Ko-Chuan, and 李可圈. "Bone Marrow-derived Mesenchymal Stem Cells Contribute to The Heterogeneous Cancer Stem Cell Niche and Promote Tumor Metastasis." Thesis, 2018. http://ndltd.ncl.edu.tw/handle/tu59sc.
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碩士國立清華大學
分子與細胞生物研究所
107
Cancer stem cells (CSCs) are a small subpopulation of cancer cells known to initiate tumor growth, lead to drug resistance and drive tumor metastasis. Studies have shown that bone marrow-derived mesenchymal stem cells (BM-MSCs) contribute to cancer stem cell niche and can regulate cancer metastasis. Our research indicated that two heterogenous subgroups of cancer cells in tumor responsed differently upon MSC-conditional medium (MSC-CM) treatment. MSC-CM elevated STAT3-Y705 phosphorylation in epithelial-type LM cells, and pY705-STAT3 took part in MSC-induced EMT and CSC property induction. STAT3-S727 phosphorylation was enhanced in mesenchymal-type HM20 cells, and contributed to MSC-induced proliferation, MET, and CSC property maintenance. To sum up, we demonstrated that MSCs can induce two-step metastasis cycle on two heterogenous subgroups derived from the same cancer cell line through STAT3-elicited promotion of CSC phenotype.
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Prentl, Simon Q. [Verfasser]. "Handelt es sich bei einem lokal begrenzten Prostatakarzinom mit positivem Resektionsrand um einen organbegrenzten oder um einen nicht-organbegrenzten Tumor? / Simon Q. Prentl." 2009. http://d-nb.info/998594490/34.
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Franco, Lídia Mafalda Lopes. "Potencialidade das células estaminais no tratamento do cancro." Master's thesis, 2013. http://hdl.handle.net/10451/46194.
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Trabalho Final de Mestrado Integrado, Ciências Farmacêuticas, Universidade de Lisboa, Faculdade de Farmácia, 2013Atualmente, o cancro tornou-se uma doença frequente e uma das principais causas de mortalidade em todo o mundo. Existem várias evidências que o cancro é uma doença de células estaminais. Compreender as propriedades e características das células estaminais tumorais (CETs) é crucial para a investigação na área da oncologia, nomeadamente no isolamento e identificação das CETs, no diagnóstico e na terapêutica do cancro. Os tratamentos anti-cancerígenos convencionais têm muitas vezes efeitos incompletos e temporários, diminuindo apenas o tamanho do tumor e este tende a recidivar devido, maioritariamente, aos múltiplos mecanismos de resistência existentes nas CETs. As CETs também necessitam de um microambiente particular para controlar o seu estado de auto-renovação e indiferenciação. Deste modo, as hipóteses terapêuticas que se focam em atingir as CETs e o seu nicho oferecem uma estratégia promissora no tratamento do cancro. O presente trabalho introduz a informação básica existente sobre as CETs, nomeadamente, a sua definição, origem e as principais características, incluindo a importância do nicho; descreve vários orgãos onde foi demonstrada a existência destas células; compara as diferentes técnicas utilizadas para isolar e identificar as CETs entre a população tumoral total; analisa os múltiplos mecanismos de resistência inerentes às CETs e enumera os principais alvos moleculares e de sinalização com potencial para ser utilizados no desenvolvimento futuro de terapêuticas anti-CETs. Desta forma, é dada uma visão geral do conhecimento atual acerca destas células e os potenciais agentes terapêuticos que estão atualmente em investigação.
Nowadays, cancer has been a frequent disease and the first or second most common cause of death worldwide. Mounting evidence has implicated that cancer is a disease of stem cells. Understanding the properties and characteristics of cancer stem cells (CSC) are key to future study on cancer research, such as the isolation and identification of CSCs, the cancer diagnosis, and the cancer therapy. The standard oncology treatments have incomplete and temporary effects that only shrink the tumor, and the tumor tends to relapse mainly due to the multiple resistant mechanisms existing in CSCs. CSCs also require a special microenvironment to control their self-renewal and undifferentiated state. Thus, therapeutic hypothesis that focuses on targeting CSCs and their microenvironmental niche offer a promising strategy in the treatment of cancer. The present work introduces the basic information about CSCs, namely, the definition, origin, and the main characteristics, including the importance of the de CSC niche; describes different organs where it was demonstrated the existence of these cells; compare different techniques used to isolate and identify CSCs among the bulk tumors; analyze the multiple resistant mechanisms inherent in CSCs and lists the main molecular and signaling targets that have the potential to be utilized for future development of anti-CSC therapeutics. Thus, it is given an overview about the current knowledge regarding CSC and the potential therapeutic agents that are currently under investigation.
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Bellgardt, Tina [Verfasser]. "Nicht-bronchioloalveoläre Adenokarzinome und großzellige Karzinome adenoider Herkunft der Lunge : prognostische Faktoren für das 5-Jahres-Überleben unter Berücksichtigung der SP-A-Expression der Tumoren / vorgelegt von Tina Bellgardt." 2008. http://d-nb.info/992044774/34.
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