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  • About
  • The Global ETD Search service is a free service for researchers to find electronic theses and dissertations. This service is provided by the Networked Digital Library of Theses and Dissertations.
    Our metadata is collected from universities around the world. If you manage a university/consortium/country archive and want to be added, details can be found on the NDLTD website.
1

Smac Mimetic Compound Treatment Induces Tumour Regression and Skeletal Muscle Wasting

Vineham, Jennifer January 2014 (has links)
Of all of the cancer patients throughout the world, approximately 50% of them are affected to some degree by cachexia. This syndrome involves significant skeletal muscle wasting, loss of adipose tissue and overall decrease in body weight in patients, particularly those with lung, pancreatic and gastric cancers. Cancer-induced cachexia is characterized by the presence of increased cytokines, notably TNF-α, IL-1β and IL-6. Most patients suffering of cancer-induced cachexia experience increased toxicity in response to chemotherapy, leading to fewer rounds of treatment and thus impeding the patients’ chances for recovery. More research into effective treatments for cancer-induced cachexia would therefore be indispensable. The inhibitor of apoptosis proteins (IAPs) have emerged as important cancer targets, primarily because of their roles as caspase inhibitors and regulators of NF-κB signalling. Small molecule IAP antagonists known as Smac mimetic compounds (SMCs) are currently in stage I/II clinical trials. They function by targeting cIAP1 and cIAP2 (and to a lesser extent, XIAP) resulting in a cytokine mediated death response in cancer cells. SMCs induce the production of TNF-α, a cytokine with which SMCs can potently synergize. However, limited efficacy occurs in some cancer cell lines (presumably because TNF-α cannot be induced in an autocrine fashion) and an exogenous source of the cytokine, such as that induced by using an oncolytic virus, is required. Notably, TNF-α (initially known as “cachectin”) is known to play a significant role in the induction of skeletal muscle atrophy. We therefore wanted to examine the effects of TNF-α induction by SMC and oncolytic virus co-treatment on both tumour regression and skeletal muscle in tumour bearing mice. We investigated the effects of SMC treatment on Lewis Lung Carcinoma (LLC) and B16F10 melanoma cell lines, both of which have been shown to be established cachectic cancer cell lines. Our in-vitro analysis of LLC and B16F10 cells revealed that LLC cells are sensitive to SMC and TNF-α co-treatment whereas B16F10 cancer cells remain resistant. SMC treatment, in combination with an oncolytic virus, VSVΔ51, increased tumour regression and survival time in LLC tumour bearing mice. Based on findings from previous studies, we investigated the role of cellular FLICE-like inhibitory protein (c-FLIP) in the resistance of the B16F10 melanoma cell line to SMC treatment. We were able to determine that the down-regulation of c-FLIP sensitizes the B16F10 cells to SMC and TNF-α induced cell death. In extending these findings, we found that SMC treatment alone can cause skeletal muscle wasting in the tibialis anterior muscle of LLC tumour bearing mice. However, the atrophic response was observed to be minimal as documented by a slight but significant decrease (approximately 10%) in muscle fibre cross-sectional area. Moreover, no biochemical evidence of muscle atrophy, as visualized by changes in the expression of myosin heavy chain (MHC) and Muscle RING Finger protein 1 (MuRF1), was found. Regardless, we speculate that the impact of SMC treatment on muscle wasting would be transient and reversible, and propose that the benefits of such a combination immunotherapy would greatly outweigh the risks.
2

Investigation of TRAIL resistance in ovarian cancer cell lines and translational application in primary ovarian cancer cells / Erforschung von TRAIL Resistenz in Ovarialkarzinom Zelllinien sowie dessen Übertragung in primäre Ovarialkarzinomzellen

Prieske, Katharina 10 August 2011 (has links)
Das Ovarialkarzinom ist eines der tödlichsten Malignome in der Gynäkologie und birgt eine große therapeutische Herausforderung. Trotz Platin und Taxan haltiger Chemotherapie liegt die Rezidivrate des Ovarialkarzinoms bei 70%. Tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) gilt aufgrund seiner Eigenschaft spezifisch in Krebszellen Apoptose zu induzieren ohne normalen Körperzellen zu schaden in der Krebsforschung als vielversprechendes Therapeutikum. Seit einiger Zeit ist jedoch ersichtlich, dass 50% der Zelllinien und die Mehrheit aller primären humanen Krebszellen resistent für TRAIL induzierte Apoptose sind (Koschny, Walczak et al. 2007) und zunächst sensitiviert werden müssen. In dieser Studie konnte gezeigt werden, dass primäre Ovarialkarzinomzellen die mit Hilfe von EpCAM Dynabeads aus der Aszites von Krebspatientinnen isoliert wurden, sowohl mit Bortezomib (Proteasominhibitor) als auch mit PIK75 (PI3K- Inhibitor)spezifisch für TRAIL induzierte Apoptose sensitiviert werden konnten. Desweiteren konnte gezeigt werden, dass diese Kombinationstherapie normale hämatopoietische Zellen nicht beschädigt. Dies bekräftigt vor allem die Eigenschaft von TRAIL, krebszellspezifisch Apoptose zu induzieren. Wichtig ist vor allem, dass diese Kombinationstherapie sogar Chemotherapie resistente primäre Ovarialkarzinomzellen in Apoptose führen konnte.
3

Tweak and cIAP1 Mediate Alternative NF-κB Signalling to Promote Myogenesis

Adam, Nadine Jessica January 2016 (has links)
The NF-κB family of transcription factors can be activated through canonical (classical) or non-canonical (alternative) signalling pathways, which are regulated by the redundant ubiquitin ligases, cellular inhibitor of apoptosis 1 and 2 (cIAP1 and cIAP2). While the canonical NF-κB pathway is needed for myoblast proliferation, it is inactivated during myoblast differentiation. However, the non-canonical NF-κB pathway is a major factor in promoting myoblast fusion, which is crucial to the processes of myogenesis and muscle repair. Ablation of cIAP1 levels through a chemical antagonist such as a SMAC- mimetic compound (SMC) activates non-canonical signalling to enhance myogenesis. The cytokine TNF-like weak inducer of apoptosis (TWEAK) has also been shown to activate primarily the alternative NF-κB pathway when signalling through its receptor Fn14. Here I show that alternative NF-κB signalling activity, stimulated by the addition of TWEAK or loss of cIAP1, can promote myogenesis. I also demonstrate that TWEAK is an endogenous myokine produced by myoblasts to promote their own differentiation, and suggest that targeting the alternative NF-κB pathway, with SMAC-mimetics or recombinant TWEAK for example, would be of therapeutic value in the repair and regeneration of muscle for various myopathies.
4

Propriétés biologiques du récepteur TLR3 dans les carcinomes des voies aérodigestives supérieures : contribution à l’oncogénèse et intérêt comme cible thérapeutique / Biological properties of the TLR3 receptor in Head and Neck carcinomas : oncogenic role and potential as a therapeutic target

Verillaud, Benjamin 06 February 2015 (has links)
Contexte. Les carcinomes des voies aérodigestives supérieures (VADS) arrivent en 6ème position parmi les cancers les plus fréquents au niveau mondial. La fonction du récepteur TLR3 dans les cellules de carcinomes des VADS est encore très mal comprise. Objectifs et méthodes. 1) Déterminer le niveau d’expression du récepteur TLR3 dans les lignées et les biopsies de carcinomes des VADS par western blot et par immunohistochimie. 2) Etudier le rôle de TLR3 dans la croissance tumorale de ces tumeurs, en utilisant notamment des lignées invalidées de façon conditionnelle pour TLR3. 3) Evaluer in vitro les effets cytotoxiques de ligands artificiels de TLR3 soit seuls, soit utilisés en combinaisons avec un inhibiteur d’IAP (inhibitor of apoptosis protein).Résultats. La protéine TLR3 est détectée à un niveau élevé en western blot dans les lignées de carcinomes des VADS étudiées, comparativement à un panel d’autres tumeurs épithéliales humaines. TLR3 est également constamment détecté en immunohistochimie dans les biopsies. TLR3 semble jouer un rôle dans la croissance tumorale des carcinomes des VADS : dans certaines conditions de culture (culture en hypoxie ou en milieu pauvre en SVF et en nutriments), la stimulation de TLR3 par un ligand exogène, le poly(A:U), favorise la croissance des cellules tumorales. Nous avons étudié l’effet de la stimulation de TLR3 sur le métabolisme glucidique dans ces mêmes cellules en utilisant un appareil de type Seahorse® qui mesure la consommation d’oxygène et la production de protons à partir de cellules cultivées en microplaques. Ces expériences montrent que la stimulation de TLR3 fait augmenter l’activité des voies du métabolisme cellulaire anaérobie (glycolyse extra-mitochondriale). Une étude métabolomique a mis en évidence des différences significatives dans le profil métabolique des cellules tumorales stimulées par le poly(A:U) comparativement aux cellules non traitées. Par ailleurs, nous avons montré que la stimulation de TLR3 permettait de détecter le facteur de transcription HIF1 en Western blot, même en conditions normoxiques. Sachant que des ARN libérés par des cellules en état de nécrose peuvent stimuler TLR3, il est tentant de penser que ce récepteur pourrait favoriser la survie des cellules malignes en zone hypoxique au voisinage de cellules nécrotiques. Néanmoins, l’expression de TLR3 représente aussi un facteur de vulnérabilité pour les cellules de carcinome des VADS : en effet les ligands artificiels de TLR3 utilisés en combinaison avec un inhibiteur d’IAP (Inhibitor of Apoptosis Protein) produisent des effets cytotoxiques sur les lignées de carcinomes des VADS étudiées. / Background. Head and Neck (HN) carcinomas are the 6th most frequent type of cancer worldwide. The role of the TLR3 receptor in HN carcinomas remains poorly understood.Objectives and Methods. 1) To assess the expression level of TLR3 in HN carcinoma cell lines and biopsies by Western blot and immunohistochemistry, respectively. 2) To study the role of TLR3 in tumour growth using specific cell lines with conditional knock-down of TLR3. 3). To assess in vitro the cytotoxic effects of artificial ligands of TLR3 used either alone or in combination with an IAP (inhibitor of apoptosis protein) inhibitor.Results. TLR3 protein was detected at a high level by Western blot analysis in HN carcinoma cell lines, by comparison with a panel of other human epithelial cancer cell lines. TLR3 was also consistently detected by immunohistochemistry in tumour biopsies. TLR3 seem to play a role in HN carcinoma cell growth: under certain culture conditions (hypoxic or low fetal calf serum/low nutrient culture conditions), TLR3 stimulation by a synthetic ligand, the poly(A:U), favours tumour cell growth. We investigated the effects of TLR3 stimulation on glucose metabolism using a Seahorse® analyzer, which measures the oxygen consumption and the proton production in living cells. Our results indicate that TLR3 stimulation induces an increase in anaerobic metabolism (extra-mitochondrial glycolysis). A metabolomic study revealed significant changes in the metabolic profile of cancer cells treated by poly(A:U) by comparison with untreated cells. We also showed that under TLR3 stimulation, HIF1 became detectable by Western blot analysis, even in normoxia. Given the fact that RNA fragments released by dying cells are able to trigger TLR3, one can assume that TLR3 might favour cancer cell survival in hypoxic areas located near the necrotic core of the tumour. However, TLR3 expression is also a factor of vulnerability for HN carcinoma cells: indeed, the combination of TLR3 artificial ligands with an IAP inhibitor has a strong cytotoxic effect on HN carcinoma cells in vitro.

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