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Dissertations / Theses on the topic 'Tumour necrosis; Cancer'
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1
Naylor, Michael Stuart. "Tumour necrosis factor and ovarian cancer." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.332896.
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Sampson, Louise E. "Investigations into the mechanism of action of tumour necrosis factor." Thesis, Open University, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304660.
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Sagoo, Jasbir K. "Towards nuclear magnetic resonance studies of human tumour necrosis factor - alpha." Thesis, University of Nottingham, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335697.
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Leek, Russell D. "The role of tumour associated macrophages in breast cancer angiogenesis." Thesis, Oxford Brookes University, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302449.
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Kahmann, Jan D. "Structural and functional studies on the link module from human TSG-6." Thesis, University of Oxford, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.302067.
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Bossard, Maud. "The role of epithelial cell-derived tumour necrosis Factor Alpha in pancreatic carcinogenesis." Thesis, Queen Mary, University of London, 2012. http://qmro.qmul.ac.uk/xmlui/handle/123456789/8563.
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Activating mutations of the kras proto-oncogene are found in more than 90% of human pancreatic ductal adenocarcinoma (PDAC) and can result in increased activity of the NF-κB pathway, leading to constitutive production of proinflammatory cytokines such as TNF-α. Pancreatic cancer progression occurs through a series of pre-invasive lesions, pancreatic intraepithelial neoplasias (PanIN lesions), which progress into invasive carcinoma. The aim of this thesis is to understand the autocrine role of TNF-α produced by premalignant epithelial cells in pancreatic tumour progression. This cytokine has already been shown to be involved in the progression of cancer. The major hypothesis therefore tested was that TNF-α secreted by pre-malignant epithelial cells promotes the early stages of pancreatic carcinogenesis by sustaining an inflamed microenvironment. In the spontaneous kras+/LSL-G12D; pdx1-cre mouse model of pancreatic cancer, concomitant genetic deletion of the TNF-α/IKK2 pathway substantially delayed pancreatic cancer progression and resulted in downregulation of the classical Notch target genes hes1 and hey1. Cell lines from the different PanIN bearing mice were established and used to dissect the cooperation between TNF-α/IKK2 and Notch signalling during PanIN progression. Optimal expression of Notch target genes was induced upon TNF-α stimulation of the canonical NF-κB signalling pathway, in cooperation with basal Notch signals. Mechanistically, TNF-α stimulation resulted in phosphorylation of histone H3 at the hes1 promoter and this signal was lost upon ikk2 genetic deletion. HES1 suppressed the expression of pparg, which encodes for the anti-inflammatory nuclear receptor PPAR-γ. Thus, crosstalk between TNF-α/IKK2 and Notch sustained an intrinsic inflammatory profile of the transformed cells. The treatment of PanIN bearing mice with rosiglitazone, a PPAR-γ agonist, also delayed PanIN progression. A malignant cell-autonomous, low-grade inflammatory process was shown to operate from the very early stages of kras-driven pancreatic carcinogenesis, which may cooperate with the Notch signalling pathway to promote pancreatic cancer progression.
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Fielding, David Ivor Keith. "Effects of interstitial laser photoagulation and photodynamic therapy on lung parenchyma." Thesis, University College London (University of London), 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.264699.
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Chambers, George. "A study of the production of the selected cytokines interleukin 1, interleukin 6, and tumour necrosis factor by certain tumours and tumour cell lines." Thesis, University of Glasgow, 1996. http://theses.gla.ac.uk/4041/.
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An investigation was carried out to examine the production of the inflammatory cytokines IL1, IL1, IL6, TNF, and TNF in two tumour cell lines, the MCF-7 breast cell line and the T-24 bladder cell line, and in samples of breast, bladder, lung and ovarian tumours. Two methods were used to investigate cytokine production. These were the polymerase chain reaction method (PCR) to examine cytokine mRNA production and immuno-staining of frozen or paraffin-embedded tissue sections to demonstrate the presence of the cytokine polypeptide directly. In the PCR experiments, the most frequently found cytokine was IL6, followed by IL1. Only a few tumours of any type displayed TNF, and even fewer produced TNF. In the immunostaining experiments performed on frozen sections, IL1 and IL6 proteins were detected in sections of tumours which gave positive results with PCR. Cell phenotyping indicated that the IL1 and IL6 were probably being synthesised by the tumour cells themselves although there was lymphocyte infiltration in every section examined. In the immuno-histology study performed on the paraffin-embedded sections, a new collection of tumours was used. These tumours were not subjected to parallel PCR due to size of tumour samples being too small. The results obtained from these experiments conflicted with the results observed in the PCR study. IL1 was detected in all of the breast tumours used for immuno-histology but in none of the breast tumours in the PCR experiments. While the conflict could not definately be resolved, it was thought that the results of the immuno-histology experiments were more accurate as they detected expression of cytokine protein on a cellular scale. The immuno-histology experiments demonstrated that some tumour cells produced IL1 in breast and bladder carcinomas, and some produced IL6 in breast and lung carcinomas.
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Pusztai, Lajos. "Regulation of the growth of human breast cancer by tumour necrosis factor-alpha." Thesis, University of Oxford, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.333180.
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Mohamed, Ahmed A. A. "Cross-talk between kinases and proteases in tumour necrosis factor-#alpha# receptor subtype-induced apoptosis." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274797.
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Firstly, we demonstrated that caspase-dependent cell death was enhanced by the over-expression of the type II TNF receptor (TNFR2). HeLa cells, which naturally express high levels of type I TNF receptor (TNFR1) and low levels of TNFR2, were engineered to stably over-express TNFR2. This combined with the use of genetically-engineered mutated TNFs that preferentially activate TNFR1 or TNFR2, we showed that both receptors can induce cell death, although this process occurred predominantly through TNFR1. TNF-induced cell death was inhibited by the stable expression of cytokine response modifier A (CrmA), a potent inhibitor of receptor proximal caspases. By isolating early apoptotic cells, we were able to identify differential activation profiles of members of the mitogen-activated protein kinase (MAPK) family during TNF-induced apoptosis. In dying HeLa-TNFR2 cells, there was increased activation of c-Jun NH2-terminal kinase (JNK) while the activation levels of p38 MAPK and p42/44 MAPK remained unchanged. The use of peptidergic caspase inhibitors demonstrated that caspase-dependent modulation of JNK but not p38 MAPK or p42/44 MAPK takes place, and as such may provide a mechanism which accounts for the differences observed in MAPK activity during TNF-induced cell death. Through expression of a dominant negative upstream activator of JNK (SEK-1-AL) and a pharmacological inhibitor of JNK activity, we were able to determine the role of JNK activation in TNF receptor-mediated apoptosis. These findings clearly demonstrate that through cross-talk, TNF receptors, are able to further modulate the tightly regulate cellular consequences of TNF treatment and that JNK is a TNF-induced kinase that may play a role in the cytokine’s apoptotic cellular signalling.
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Lynch, Eileen Marie. "The effect of oxygen tension on the cytotoxic action of tumour necrosis factor-alpha." Thesis, University College London (University of London), 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.362843.
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Littlejohn, Alison F. "Investigations into the molecular mechanisms that regulate whether tumour necrosis factor (TNF) induces cell survival or cell death." Thesis, University of Aberdeen, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.274803.
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TNFR2 can activate NR-kB independently of TNFR1 although to a lesser degree. It was also demonstrated that caspases and NF-kB do not interact directly as caspase inhibition could not prevent NF-kB activation. The interaction between caspases and MAP kinases in HeLa-TNFR2 cells was also investigated. It was shown that JNK activation in response to TNF was attenuated following caspase inhibition while p42/44 MAP kinase and p38 MAP kinase activation were unaffected by caspase inhibition (Littlejohn et al, 2002). Further to these studies TNF receptor associated cytoplasmic adaptor proteins, in particular TRAF1, TRAF2 and RIP, were investigated with a view to determining the molecular switch between life and death in HeLa-TNFR2 cells. It was established using immunoprecipitation that TNFR2 could associate with RIP, as could TRAF1 and TRAF2. However, on the whole this technique gave limited information and further experiments are required to determine more conclusively the interactions taking place between the adaptor proteins, TNFR1 and TNFR2. In order to investigate the molecular switch more effectively, TF-1 cells were used. It was already known that TF-1 cells proliferate in response to TNF it cultured in the absence of GMCSF however, if cultured in the presence of GMCSF then TNF stimulation induces apoptotic cell death. This model of TNF induced life versus death demonstrated that caspase mediated RIP cleavage only occurs in the death scenario. RIP degradation is accompanied by reduced NF-kB activation suggesting that NF-kB activation is indeed a protective mechanism. Although many different avenues have been investigated the main conclusions that can be drawn from these studies are that TNF can regulate NF-kB via TNFR1 and TNFR2 and that competent NF-kB activation is required to protect cancer cells from TNF induced death. Perhaps if it was possible to inhibit NF-kB then TNF could be used effectively as a cancer killing agent.
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Sundelin, Kaarina. "Head and Neck Cancer : Factors Affecting Tumour Growth." Doctoral thesis, Linköping : Univ, 2007. http://www.bibl.liu.se/liupubl/disp/disp2007/med1032s.pdf.
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Halford, Emily Elisabeth. "The role of group 3 innate lymphoid cells and tumour necrosis factor receptors in the survival and function of regulatory T cells." Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6679/.
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The ability to therapeutically manipulate regulatory T (Treg) cell survival/function would have far reaching implications; with the potential to limit immune pathology in autoimmune disease, allergy and transplantation; and to reduce regulation of anti-tumour responses in cancer. This study has established a method to study the survival and function of antigen specific Treg cells in vivo, adapting an existing approach in which an endogenous naïve T cell population is expanded and tracked. Multiple immunisation of antigen, and an agonistic anti-DR3 antibody were used to ensure a sufficient number and proportion of Treg cells could be expanded. Further to this, an assay for investigating Treg cell function in vivo was applied to this system. This approach revealed that the tumour necrosis factor receptors OX40 and CD30 may play a role in Treg function, as well as expansion. Unexpectedly, these data also revealed that in the absence of OX40 there is a gross defect in the function of CD4 T cells. A regulatory role of group 3 Innate Lymphoid cells is emerging in the literature, and in accordance with this, this study demonstrates that Treg cell expansion is grossly impaired in mice which lack RORγt, their lineage defining transcription factor.
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Jabbar, Shireen Arjumand Bano. "The response of human lung cancer cell lines to interferons and tumour necrosis factor, alone or in combination with cytotoxic drugs." Thesis, University of Cambridge, 1990. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.335163.
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Pedro, Renato Nardi. "Uso da nanopartícula de ouro ligada a moléculas de fator alfa de necrose tumoral como adjuvante da termoablação por radiofrequência de tumores renais = modelo animal experimental." [s.n.], 2010. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310676.
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Orientadores: Marcelo Lopes de Lima, Nelson Rodrigues Netto JuniorTese (doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O tratamento definitivo das massas renais malignas é primordialmente cirúrgico, sendo a nefrectomia radical eleita por muitos anos a cirurgia padrão para o tratamento do câncer renal localizado. Entretanto, com o envelhecimento populacional, maiores são as preocupações em se manter a capacidade funcional dos órgãos e sistemas do corpo humano. Portanto, a necessidade de se preservar tecido renal sadio durante o tratamento do câncer renal localizado, com auxílio de cirurgias parciais poupadoras de néfrons, se tornou imperativa. O tratamento de lesões renais sólidas pequenas passou a ter diferentes formas de abordagem, que variam desde técnicas de termoablação percutânea ou laparoscópica, nefrectomia parcial laparoscópica e aberta à até tradicional nefrectomia radical aberta. O uso de modalidades de tratamento cirúrgico com mínimo grau de agressão passou a ganhar atenção, devido à rápida recuperação do paciente, ao menor risco de complicações cirúrgicas e aos bons resultados oncológicos. Ablação por radiofreqüência (ARF) tem se mostrado um meio eficiente no tratamento de tumores renais pequenos e exofiticos. Atualmente, sua indicação é restrita a lesões de até 4 cm. O presente estudo foi montado para avaliar o uso conjunto da nanopartícula de ouro e fator alfa de necrose tumoral (TNF alfa) à ARF no tratamento de um modelo experimental de tumor renal. Materiais e Métodos: Trinta e sete coelhos brancos da raça New Zealand tiveram implantados em seus rins, através de uma laparotomia, um fragmento de 1 mm3 de tumor VX-2. Após 14 dias do implante, quando seus rins haviam desenvolvido uma lesão tumoral sólida menor que 1 cm, os animais foram divididos em 3 grupos de 10 e 1 grupo de 7 integrantes (sham) de acordo com o tratamento selecionado para o tumor renal focal: 1) Nanopartícula com TNF alfa; 2) Ablação por radiofreqüência; 3) Nanopartícula com TNF alfa seguido de Ablação por radiofreqüência; 4) Grupo sham. Todos os animais foram submetidos a mesma cronologia de tratamento, composta por 2 laparotomias e eutanásia. Os grupos tratados com as nanopartículas de ouro com fator alfa de necrose tumoral isolada ou complementarmente, as receberam 4 horas antes do procedimento cirúrgico na dose de 200 µm/Kg. A análise de resultados foi realizada com medidas macroscópicas e microscópicas do volume da área de ablação ou tumoral, segundo a fórmula do volume de uma elipsóide. Avaliação estatística foi realizada com Teste T Student, sendo considerado significante p<0.05. Resultados: O grupo que recebeu a nanopartícula com fator alfa de necrose tumoral e depois foi submetido à ARF apresentou maior zona de morte celular completa quando comparado ao grupo tratado somente com ablação por radiofreqüência (0.30 ± 0.07 vs 0.23 ± 0.03 mL, P=.03). A zona de transição foi menor no grupo que recebeu a nanopartícula com fator alfa de necrose tumoral e ablação por radiofreqüência quando comparada ao grupo tratado somente com ablação por radiofreqüência (0.08 ± 0.02 vs 0.13 ± 0.05 mL, P =.01). Conclusão: O presente estudo demonstrou que o uso da nanopartícula de ouro com TNF alfa sensibiliza o insulto térmico sofrido por tumores sólidos decorrentes da ablação por radiofreqüência
Abstract: Radical nephrectomy has long been considered as gold standard treatment for localized renal tumors. However due to an increase in life expectation, organ sparing surgeries have emerged with the purpose of preserving as much healthy tissue as possible. Therefore, nephron sparing surgeries have become another valid option for localized renal tumors. There are different modalities of nephron sparing procedures, including open partial nephrectomy, laparoscopic nephrectomy and termoablative procedures. The later is associated with less morbidity and fast patient recovery. Radiofrequency ablation (RFA) is a well-known termoablative procedure and it has been most effective when the tumors are small, exophytic, and away from vital structures. The present study was designed to analyze the adjuvant use of gold nanoparticle with tumor necrosis factor alpha prior to radiofrequency ablation in a translational model of localized renal tumor. Material and Methods: A total of 37 New Zealand White rabbits had VX-2 tumors implanted into their kidneys; they were allowed to grow for 14 days, when a tumor mass of less than 1 cm could be detected. The animals were then split into 3 treatment groups of 10 rabbits each and a sham group of 7 rabbits as follows: (1) Tumor necrosis factor alpha plus nanoparticle, (2) Radiofrequency ablation, (3) Tumor necrosis factor alpha nanoparticle (200 µm/Kg) followed 4 hours later by radiofrequency ablation. All groups were subjected to the same milestones of the experiment which was comprised of 2 laparotomies and sacrification. Gross and microscopic measurements of the ablation size as well as histological analysis using hematoxylin and eosin staining were performed to determine the effect of TNF alpha nanoparticle on the ablation. Statistical analysis was performed with Student's T test, considering p < 0.05 as significant. Results: The RFA plus TNF alpha nanoparticle group had a larger zone of complete cell death than the RFA-only group (0.30 ± 0.07 vs 0.23 ± 0.03 mL, P=.03). The zone of partially ablated tissue was smaller in the RFA plus TNF alpha nanoparticle group than in the RFA-only group (0.08 ± 0.02 vs 0.13 ± 0.05 mL, P =.01). Conclusions: We have demonstrated the efficacy of TNF alpha nanoparticle in enhancing RFA in a translational kidney tumor model. The potential usage of TNF alpha nanoparticle to improve RFA of renal cell carcinoma merits further study
Doutorado
Fisiopatologia Cirúrgica
Doutor em Ciências
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Svangård, Erika. "Cytotoxic Cyclotides : Structure, Activity, and Mode of Action." Doctoral thesis, Uppsala universitet, Institutionen för läkemedelskemi, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-6028.
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Cyclotides are small cyclic plant proteins, and this thesis addresses their cytotoxic structure-activity properties and their mode of action on human cancer cell lines. Cyclotides were isolated from Viola odorata and Viola tricolor; three novel cyclotide sequences and two known sequences, but of new origin, were identified using mass spectrometry, amino acid analysis, and Edman degradation. The cyclotide structure includes three disulphide bonds in a knotted arrangement, which forces hydrophobic amino acid residues to be exposed on the surface of the molecule; 3-D homology models of cyclotides have revealed an amphipathic surface and charged residues located at similar positions in the molecules. The charged amino acid residues were shown to play a key role in the cytotoxicity of the cyclotide cycloviolacinO2 on a human lymphoma cell line. Methylation of Glu caused a dramatic change in cytotoxicity, lowering the potency 48 times, whereas concealing the charge of Arg with 1,2-cyclohexanedione caused virtually no change in potency. Acetylation of the two Lys caused a 3-fold reduction in potency, and masking all positive charges caused a 7-fold reduction. Additionally, disturbing the amphipathic structure by reducing and alkylating the disulphide bonds abolished the cytotoxicity. The time dependency of cytotoxicity and cell gross morphology after cyclotide exposure were investigated on the lymphoma cell line. Cells exposed to 4 µM of cycloviolacinO2 showed necrotic characteristics, such as membrane disintegration, within 5 min; a membrane disruptive effect of cycloviolacinO2 was also observed in a functional assay based on liposomes at a peptide-to-lipid molar ratio of 6.5. The anti-tumour properties of cycloviolacinO2 were evaluated on three human cancer cell lines using the hollow fibre assay in vitro and in vivo. The cyclotide exhibited potent anti-tumour activity in the micro-molar concentration range on all cell lines in vitro, but no effect on tumour growth could be established in vivo.
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Liddil, James Duncan 1960. "Mechanisms of the cytotoxic actions of tumor necrosis factor (TNF) in cultured cancer cells." Thesis, The University of Arizona, 1987. http://hdl.handle.net/10150/276602.
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Tumor necrosis factor's (TNF) cytotoxic mechanism of action was examined using cultured cancer cell lines. TNF demonstrated cytolytic and cytostatic effects on L929 fibrosarcoma and MCF-7 adenocarcinoma cells. TNF failed to show any specific effects on RNA, DNA or protein synthesis or ATP content in tumor cells in vitro. It did not cause DNA single strand breaks. Decreased cellular levels of reduced thiols did not predict sensitivity to the cytotoxic effects of TNF. Depletion of cellular glutathione failed to increase the sensitivity of TNF-sensitive or resistant cells. However, various non-specific and specific lysosomotropic agents lead to an inhibition of TNF's cytotoxic action. Differences in enzyme activity, primarily lysosomal, were noted between TNF-sensitive and resistant cells. These changes involved a general halving of lysosomal proteins and enzymes in the TNF-resistant cells. The antitumor activity of TNF does not involve specific inhibition of macromolecular synthesis but may involve alterations in lysosomes.
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Weigert, Melanie. "Investigating the role of programmed necrosis in oncolytic adenovirus-induced death." Thesis, University of Glasgow, 2017. http://theses.gla.ac.uk/8054/.
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Oncolytic viruses are a group of viruses that preferentially replicate in cancer cells and are a promising cancer treatment. However, how these oncolytic adenoviruses kill cancer cells is not fully understood. It was long thought that DNA viruses utilize apoptosis to induce cell death but there is now evidence that adenovirus and vaccinia cytotoxicity displays features of necrosis-like programmed cell death. In order to investigate the role of necrosis in cell death as a result of oncolytic adenovirus infection, a panel of ovarian cancer cells with varying sensitivities to the oncolytic adenoviral mutant dl922-947 was used. Cells infected with dl922- 947 displayed key features of necrotic death. Using necrosis inhibitors necrostatin-1, necrosulfonamide, GSK2791840B, GSK2399872B and GSK2393843A, as well as RNAi-mediated knockdown of RIPK1, RIPK3 or MLKL, I showed that cells undergo RIPK3-dependent necrosis and that blockage of the downstream effector mixed lineage kinase domain-like (MLKL) attenuated cell death. While Tumour necrosis factor-α (TNF-α)-induced programmed necrosis(Laster, Wood and Gooding 1988) relies on the (RHIM)-dependent interaction of RIPK1 and RIPK3 (Li et al. 2012, Wu et al. 2014), RIPK1 seems to be redundant for adenovirus-induced death. Further, the addition of TNF-α blocking antibody to virus-infected cells showed no effect on either cell death. Using a RIPK3 overexpression model, I showed that the amount adenovirus- induced cell death correlated with the amount of RIPK3 expression and that RIPK3 expression did not affect virus production, infectivity or the expression of viral proteins. Further, in vivo experiments using human xenografts showed that expression of RIPK3 significantly improved anti-tumour activity following intra-tumoural injection of dl922-947.
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Grigorakaki, Christine. "Etude des mécanismes cellulaires et moléculaires de l'inhibition de l'érythropoïèse par la cytokine pro-inflammatoire Tumor necrosis factor (TNF)-alpha." Thesis, Nancy 1, 2011. http://www.theses.fr/2011NAN10106/document.
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Les anémies liées au cancer et aux inflammations chroniques sont suspectées d'être provoquées par la libération de la cytokine pro-inflammatoire, le «tumor necrosis factor» (TNF)-[alpha]. Il a été décrit comme un inhibiteur potentiel de la production de l'érythropoïétine (Epo) au niveau du rein, conduisant à une diminution de l'érythropoïèse. Cependant, des études in vitro ont suggéré que le TNF[alpha] pouvait agir directement sur les cellules érythroblastiques.Des études réalisées au laboratoire LBMCC sur des lignées érythroleucémiques humaines ont montré que le TNF[alpha] limite la surexpression de gènes érythroïde-spécifiques en corrélation à l'inhibition du facteur de transcription GATA-1. Afin d'étudier l'effet inhibiteur du TNF[alpha] sur l'induction de l'érythropoïèse par l'Epo, nous avons utilisé des cellules souches hématopoïétiques CD34+ comme modèle. Dans notre système de culture in vitro, nous avons pu reproduire les différents stades de l'érythropoïèse en présence d'Epo, permettant ainsi d'étudier l'effet du TNF[alpha] sur cette voie. L'étude de la production d'hémoglobine, de la morphologie cellulaire et l'analyse des marqueurs membranaires spécifiques, a montré que le TNF[alpha] réduit la capacité de l'Epo à engager les cellules vers une différenciation érythroïde terminale. Au niveau moléculaire, nous avons corrélé cet effet à la réduction de l'expression de gènes érythroïdes. De plus, il réduit l'activité trans-activatrice du facteur de transcription GATA-1 et induit son interaction avec le facteur PU.1 via l'activation de la protéine p38MAPK. Enfin, l'expression du facteur GATA-2 est induite et la balance GATA-1/GATA-2 est en partie perturbée par l'inhibition des miR 144/451 par le TNF[alpha]Cancer-related anemia is thought to be mediated by the release of tumor necrosis factor (TNF[alpha]). TNF[alpha] is one of the major mediators of inflammation and has been linked to the inhibition of the erythropoietin (Epo) production from kidney, leading thus to anemia. However, the inhibitory effect of TNF[alpha] on erythroblast differentiation has been suggested by several in vitro studies. Previous results from the LBMCC lab on human leukemia cell lines showed that TNF[alpha] prevents over-expression of erythroid-specific genes in human erythroleukemia cell lines. In all cases, the inhibitory effect of TNF[alpha] was in correlation with the inhibition of the erythroid key transcription factor, GATA-1. In order to study the inhibitory effect of TNF[alpha] on the Epo-mediated erythropoiesis, we used CD34+ hematopoietic stem cells (HSC) as a model. In our in vitro model, we reproduced different stages of erythropoiesis, allowing us to use this model for the study of TNF[alpha] and the erythroid lineage. The study of hemoglobin production, the cell morphology and the analysis of specific erythroid membrane markers, have shown the limited capacity of Epo to stimulate HSC erythroid differentiation under TNF[alpha] treatment. At the molecular level, we have correlated this effect to the reduced expression of erythroid-specific genes. Moreover, TNF[alpha] reduces the transcriptional activity of GATA-1 and induces its interaction with PU.1 via p38MAPK activation. Furthermore, GATA-2 expression is increased and the GATA-1/GATA-2 balance, which is critical for erythropoiesis, is partially disturbed by 144/451 miRs inhibition from TNF[alpha]
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Prasanna, Prateek. "NOVEL RADIOMICS FOR SPATIALLY INTERROGATING TUMOR HABITAT: APPLICATIONS IN PREDICTING TREATMENT RESPONSE AND SURVIVAL IN BRAIN TUMORS." Case Western Reserve University School of Graduate Studies / OhioLINK, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=case149624929700524.
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Kessler, Romain. "Activation du macrophage pulmonaire en vue de son utilisation therapeutique dans le cancer du poumon." Strasbourg 1, 1997. http://www.theses.fr/1997STR15062.
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Hantak, Alison Marie. "Ginsenosides enhance the cytotoxicity of tumor necrosis factor-α in human MDA-MB 231 and MCF-7 breast cancer cells in a caspase-dependent manner." OpenSIUC, 2009. https://opensiuc.lib.siu.edu/theses/123.
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Ginsenosides (GF) are a major bioactive constituent of ginseng and have been shown to elicit a multitude of actions ranging from the improvement of synaptic plasticity to the improved uptake of glucose into a cell. Furthermore, ginsenosides and their metabolites have been shown to be potent anti-cancer agents in multiple experimental cancer models. The aim of this study was to investigate the potential influence of GF derived from American ginseng root (Panax quinquefolius), and a ginsenoside metabolite Rh2, on tumor necrosis factor-α (TNF-α) cytotoxicity in MDA-MB 231 and MCF-7 human breast cancer cells. In combination, these agents significantly increased cell death in both cell lines. Together, ginsenosides and TNF-α induced a robust increase of the pre-G0/G1 and accompanying decrease in S phase cell populations in breast cancer cells. This cell death was the result of the induction of apoptosis, as determined by annexin-V/7-AAD and Hoechst staining. Furthermore, the mechanism of ginsenoside and TNF-α induced apoptosis is caspase-dependent, as determined by the pan-caspase inhibitor Z-VAD-FMK, with caspase-8, but not caspase-9, serving as initiator caspase in both cell lines. Additionally, ginsenoside treatment significantly XIAP expression in both MDA-MB 231 and MCF-7 cells, in the absence of TNF-α. In addition to enhancing apoptosis, it was also hypothesized that ginsenosides would abrogate pro-survival pathways induced by TNF-α. However, ginsenosides failed to block TNF-α effects on NFκB expression in either cell line. JNK which, when activated by TNF-α in MDA-MB 231 cells has a pro-survival function, was reduced by ginsenosides. However, JNK inhibition had no effect on cell death, suggesting that it does not play an integral role in the mechanism of action. In MCF-7 cells, JNK has been shown to have a pro-apoptotic function. Treatment with ginsenosides had no effect on TNF-α activation of JNK, but inhibition of JNK significantly reduced cell death in combined ginsenoside and TNF-α treated cells. To conclude, combined treatment with ginsenosides and TNF-α can enhance cell death in the sensitive MCF-7 cell line, and induce cell death in the insensitive MDA-MB 231 cell line in a caspase-dependent manner that is aided by the reduction of XIAP by ginsenosides.
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Hossain, Akter. "Studies on Redox-proteins and Cytokines in inflammation and Cancer." Doctoral thesis, Linköping : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:liu:diva-8798.
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Charles, Thierry. "Mise en évidence et caractérisation d'une activité tumor necrosis factor-a inhibitrice (tnf a-1) chez des patients atteints d'un cancer bronchique." Nancy 1, 1993. http://www.theses.fr/1993NAN19420.
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Rousseau, Adrien. "Tumor necrosis factor Receptor-Associated Factor 4 (TRAF4) est une nouvelle protéine interagissant avec les phosphoinositides, impliquée dans la polarité et la migration cellulaire." Thesis, Strasbourg, 2013. http://www.theses.fr/2013STRAJ108/document.
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TRAF4 est un gène fréquemment surexprimé dans les carcinomes suggérant qu’il y joue un rôle. Tandis que la protéine TRAF4 est majoritairement localisée dans les jonctions serrées (JS) des cellules épithéliales mammaires (CEM) normales, elle s’accumule dans le cytoplasme des CEM malignes. Dans cette étude, nous montrons que TRAF4 possède un nouveau domaine liant les phosphoinositides (PIP) et que ce dernier est requis pour son recrutement aux JS. Des analyses moléculaires et structurales ont montré que le domaine TRAF de TRAF4 forme un trimère pouvant lier jusqu’à trois molécules de lipides grâce à des résidus basiques présents à la surface. Des études cellulaires indiquent que TRAF4 régule négativement les JS et augmente la migration cellulaire. Ces deux fonctions sont dépendantes de sa capacité à lier les PIPs. Notre travail suggère que la surexpression de TRAF4 pourrait contribuer à la progression des cancers du sein en déstabilisant les JS et en favorisant la migration cellulaireTRAF4 (tumor necrosis factor (TNF) receptor-associated factor 4) is frequently overexpressed in carcinomas suggesting a specific role in cancer. While TRAF4 protein is predominantly found at tight junctions (TJ) in normal mammary epithelial cells (MEC), it accumulates in the cytoplasm of malignant MEC. How TRAF4 is recruited and functions at TJ is unclear. Here we show that TRAF4 possesses a novel phosphoinositide (PIP)- binding domain crucial for its recruitment to TJ. Molecular and structural analyses revealed that the TRAF domain of TRAF4 exists as a trimer which binds up to 3 lipids using basic residues exposed at its surface. Cellular studies indicated that TRAF4 acts a negative regulator of TJ and increases cell migration. These functions are dependent from its ability to interact with PIPs. Our results suggest that TRAF4 overexpression might contribute to breast cancer progression by destabilizing TJ and favoring cell migration
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Atanasov, Georgi [Verfasser]. "The clinical significance of the host immunologic competence and related angiogenesis and necrosis in the tumor microenvironment of hepatobiliary cancer / Georgi Atanasov." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2020. http://d-nb.info/1214641261/34.
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Farias, Rogério Estevam. "Avaliação da Apoptose e Produção de TNF-a no Câncer de mama: correlação com fatores prognósticos." Universidade Federal Fluminense, 2004. http://www.bdtd.ndc.uff.br/tde_busca/arquivo.php?codArquivo=335.
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A apoptose é um importante fator no crescimento do câncer de mama, tendo sido relacionada a progressão tumoral. Por outro lado, o fator de necrose tumoral alfa (TNF-α) que é uma citocina mediadora da apoptose é reconhecida por ter
citotoxicidade contra células malignas destes tumores. Neste estudo, a presença de células apoptóticas em tumores graus I, II e III foi investigada e comparada com outros fatores prognósticos estabelecidos do câncer de mama. A detecção in situ da apoptose em células tumorais foi investigada pelo método TUNEL e a produção
de TNF-α, proliferação celular, receptores hormonais, expressão dos genes c-erbB-2 e p53 foram analisados utilizando-se procedimento imunoistoquímico. Nossos dados demonstraram que alto índice apoptótico esta relacionado a maiores níveis de proliferação, a expressão de p53, a tumores pouco diferenciados e a negatividade
para receptores hormonais. Entretanto, quando analisados somente em tumores grau III, pacientes com história clínica de recidiva e metástase apresentaram menores níveis de apoptose, maiores índices prolifertivos e menor expressão de TNF-α no infiltrado associado ao tumor. Estes achados indicam que em tumores grau III o número de células em apoptose está diretamente relacionado a um comportamento tumoral agressivo. Adicionalmente, foi observado maior expressão
de TNF-α no infiltrado inflamatório associado ao tumor e maior índice apoptótico pode estar relacionado a ausência de expansão ganglionar e recidiva do câncer de mama.Tumor necrosis factor alpha (TNF-α) is a cytokine recognized as an important mediator of apoptosis process and also showed citotoxicity against breast malignant tumor cells. In the present study, the presence of tumor apoptotic cells was investigated in grade I, II and III invasive breast cancer and compared with another prognostic factors. In situ detection of tumor apoptotic cells was investigated by direct immuno-peroxidase of digoxigenin-labeled genomic DNA. The production of TNFα, tumor cell proliferation, hormonal receptor, c-erbB-2 and p53 was investigated using immuhistochemical procedure. Our data demonstrated that patients with high apoptotic rate correlates with higher levels of cell proliferation, positive p53 expression, negative hormonal expression and high grade breast cancer. Otherwise patients with a clinical history of cancer recurrence and metastasis presented a lower number of cancer apoptotic cells, higher tumor proliferation rate and lower expression of TNF-α by inflammatory cells than that observed among patients diagnosed with the same histopathological type of breast cancer but with absence of tumor recurrence and metastasis. Taken together the results suggested that the rate of apoptosis reflect degrees of histological breast cancer and correlates with another prognostic factors. In addition, it is also possible that TNF-α produced by tumorassociated inflammatory cells play an important role in the control of apoptosis of breast cancer cells and clinical behavior.
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Flores, Marcelo Benedito da Silva 1969. "O aumento do fator de necrose tumoral-a induzido pela obesidade leva ao desenvolvimento do câncer de cólon em camundongos = Obesity-induced increase in tumor necrosis factor-a leads to development of colon cancer in mice." [s.n.], 2012. http://repositorio.unicamp.br/jspui/handle/REPOSIP/312401.
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Orientador: Jose Barreto Campello CarvalheiraTese (Doutorado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
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Resumo: O câncer colorretal é um dos maiores problemas de saúde em todo o mundo acometendo 1 milhão de pessoas por ano. O índice de morte associado a essa doença é de aproximadamente 33% no mundo desenvolvido. A associação entre a obesidade e o risco para o desenvolvimento desse câncer é observada tanto em homens quanto em mulheres. A inflamação e a hiperinsulinemia, condições verificadas na obesidade podem contribuir, a princípio, para o risco de desenvolvimento do câncer colorretal. O fator de necrose tumoral alfa (TNF-alfa) é um dos mais importantes mediadores da resposta inflamatória e sua alta expressão pelo tecido adiposo é verificada nas condições de obesidade tanto em modelos animais quanto em humanos. O TNF-alfa contribui para a desregulação da via da sinalização insulínica através da fosforilação em serina dos substratos do receptor desse hormônio (IRS) mediada pela ativação de quinases como c-jun N terminal quinase (JNK) e da quinase inibidora do fator nuclear NF-kB (IKK). A ativação dessas quinases induz a fosforilação inibitória do substrato 1 do receptor de insulina (IRS-1) através da serina 307 (Ser307). Esse mecanismo reduz a ativação da via da fosfatidilinositol 3-quinase (PI3K)/Akt e da proteína alvo da rapamicina em mamíferos (mTOR) mediada pela insulina. TNF-alfa foi, a princípio, identificado como um agente antitumoral. Atualmente essa citoquina é reconhecida como uma promotora da tumorigênese e que associa a inflamação ao câncer. A importância do TNF-alfa e de seus mediadores intracelulares, JNK e IKK, como promotores do câncer de cólon é corroborada por estudos farmacológicos que utilizaram o azoximetano (AOM) ou AOM associado ao dextran sulfato de sódio (DSS) como indutores do câncer colorretal. Ademais, o aumento das concentrações do TNF-alfa associado à obesidade é um mecanismo comprovado de aumento do câncer de fígado em modelos animais. Embora as evidências de que a inflamação e a hiperinsulinemia tenham um envolvimento em potencial na gênese tumoral mediada pela obesidade, à avaliação sistemática da contribuição independente desses fatores para o desenvolvimento do câncer colorretal ainda é inconsistente. Neste trabalho, foi avaliado se a obesidade modulou a sinalização insulínica e a inflamação em tecido colônico e nos tumores colorretais. Foi mostrado que a resposta inflamatória anormal induzida pela obesidade promoveu de forma contundente o câncer colorretal
Abstract: Colorectal cancer (CRC) remains a major health burden with more than 1 million cases worldwide and a disease-specific mortality of approximately 33% in the developed world. The association between obesity and the risk for CRC development is observed in both men and women. In addition to its association with obesity, inflammation and hyperinsulinemia also primarily may contribute to the risk for development of CRC. Among the major mediators of the inflammatory response is tumor necrosis factor (TNF-alfa), whose overexpression in adipose tissue is a common feature in human and animal models of obesity. TNF-alfa contributes to the deregulation of the insulin-signaling pathway, including serine phosphorylation of insulin-receptor substrate (IRS) proteins by kinases such as c-jun N terminal kinase (JNK) and inhibitor of nuclear factor-kB kinase (IKK). JNK and IKK activation induce inhibitory serine 307(Ser307) phosphorylation of IRS-1, which decreases insulin-mediated phosphatidylinositol 3-kinase (PI3K)/Akt/mammalian target of rapamycin (mTOR) pathway activation. TNF-alfa, first identified as an antitumor agent, now also is recognized as a tumor-promoting cytokine that links inflammation and cancer. The importance of TNF-alfa and its intracellular mediators, such as JNK and IKK, as colonic tumorigenic promoters is strengthened by knockout and pharmacologic studies, using azoxymethane (AOM) or AOM combined with dextran sulfate sodium (DSS) as inducers of colorectal carcinogenesis. Furthermore, the increased TNF-alfa levels associated with obesity are a potent liver tumor promoter in mice. Although the evidence for the potential involvement of inflammation and hyperinsulinemia in the development of obesity-mediated cancer is quite extensive, a systematic evaluation of the independent contribution of these factors to CRC development is lacking. Here, we examined whether obesity modulates insulin signaling and inflammation in the colon and CRC. We show that the obesity induced abnormal inflammatory response strongly promotes CRC
Doutorado
Clinica Medica
Doutor em Clínica Médica
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Shek, Lydia L. M. "Prognosis of breast cancer : a survival analysis of 1184 patients with 4-10 years follow-up, illustrating the relative importance of estrogen receptors, axillary nodes, clinical stage and tumor necrosis." Thesis, University of British Columbia, 1988. http://hdl.handle.net/2429/29388.
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Prognostic indicators, measured at diagnosis, are important in breast cancer. They help clinicians select optimal treatment, provide rational bases for stratification of treatment trials and assist analysis of response to treatment. Univariate statistical survival curves have identified many such indicators. However, they do not explain why some patients, classified as favoured by one or other factor(s), experience early treatment failure, nor why a substantial number with unfavourable signs remain recurrence-free many years later. This study was undertaken to identify independent prognostic factors with the use of multivariate regression.
A Cox proportional hazards model of disease-specific survival was based on 1184 primary breast cancer patients referred to the Cancer Control Agency of B.C. between 1975 and 1981 (median follow-up 60 months). Significant univariate associations with overall survival were found for estrogen receptor concentration ([ER]), axillary nodal status (NO, Nl-3, N4+), clinical stage (TNM I, II, III, IV), histologic differentiation and confluent tumor necrosis (minimal, marked). These factors were assessed at primary diagnosis. A subset of 859 patients with complete data on these variables and also histologic type, menopausal status, age, tumor size and treatment was used to fit the multivariate model. Nodal status was the most important independent factor but three others, TNM stage, [ER] and tumor necrosis, were needed to make adequate predictions. A derived Hazard Index defined risk groups with 8-fold variation in survival. Five-year predicted survival ranged from 36% (N4+, loge[ER]=0, marked necrosis) to 96% (NO, loge[ER]=6, no necrosis) with TNM I and 0% to 70% for the same categories in TNM IV. This wide variation occurred across all stages. Study of post-recurrence survival (369 patients) yielded a model with only three independent predictors: [ER], nodal status and tumor necrosis.
Survival - overall, recurrence-free and post-recurrent - is predictable by modelling a few factors measureable at diagnosis. Use of ER concentration, rather than the more common ER status (+ or -), greatly strengthens the model. Presence of ER was also shown to be increasingly important as 'protective', attenuating the effect of other factors, as risk of mortality increases.Medicine, Faculty of
Pathology and Laboratory Medicine, Department of
Graduate
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Hantak, Alison Marie. "Ginsenosides enhance the cytotoxicity of tumor necrosis factor-[alpha] in human MDA-MB 231 and MCF-7 breast cancer cells in a caspase-dependent manner /." Available to subscribers only, 2009. http://proquest.umi.com/pqdweb?did=1967998531&sid=1&Fmt=2&clientId=1509&RQT=309&VName=PQD.
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Garcia, Juliana Albarracin [UNESP]. "Propriedades oncolíticas do vírus da cinomose canina: expressão da proteína 8 (TNFAIP8) em células de carcinoma mamário: Juliana Albarracin Garcia. -." Universidade Estadual Paulista (UNESP), 2015. http://hdl.handle.net/11449/138431.
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Oncolytic virotherapy is a novel strategy for treatment of cancer in humans and companion animals as well. Canine distemper virus (CDV), a paramyxovirus, has proven to be oncolytic through induction of apoptosis in canine-derived tumour cells, yet the mechanism behind this inhibitory action is poorly understood. In this study, three human mammary tumour cell lines and one canine-derived adenofibrossarcoma cell line were tested regarding to their susceptibility to CDV infection, apoptosis, mitochondrial membrane potential (MMP) and expression of tumour necrosis factor-alpha-induced protein 8 (TNFAIP8). CDV replication induced cytopathic effect and > 45% of infected cells were considered death and/or under late apoptosis/necrosis. TNFAIP8 and CDV M gene expression were positively correlated in all cell lines. In addition, MMP was highly associated with increase in virus titres (p<0.005). Thus, these results strongly suggest that both human and canine mammary tumour cells are potential candidates for studies concerning CDV-induced cancer therapy
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Garcia, Juliana Albarracin. "Propriedades oncolíticas do vírus da cinomose canina: expressão da proteína 8 (TNFAIP8) em células de carcinoma mamário / Juliana Albarracin Garcia. -." Araçatuba, 2015. http://hdl.handle.net/11449/138431.
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Resumo:A Viroterapia oncolítica é uma nova estratégia para o tratamento de câncer em seres humanos e também em animais de companhia. O vírus da cinomose canina (CDV), um paramixovírus, tem se mostrado ser oncolítico através da indução de apoptose em células tumorais derivadas de cães, ainda que o mecanismo subjacente a esta acção inibidora seja pouco compreendida. Neste estudo, três linhagens de células tumorais mamarias humanas e uma linhagem celular derivada de adenofibrossarcoma canino foram testados quanto à sua suscetibilidade à infecção por CDV, a apoptose, o potencial de membrana mitocondrial (MMP) e a expressão de necrose tumoral-alfa induzida pela proteína de fator 8 (TNFAIP8 ). A replicação CDV induziu o efeito citopático e > 45% das células infectadas foram consideradas no âmbito de morte e/ou apoptose tardia sob necrose. TNFAIP8 e expressão gênica CDV foram positivamente correlacionadas em todas as linhagens celulares. Além disso, a MMP foi altamente associada com o aumento nos títulos de vírus (p <0,005). Assim, estes resultados sugerem fortemente que ambas as células tumorais mamárias humanas e caninas são potenciais candidatos para estudos sobre a terapia do câncer induzido por CDVAbstract:Oncolytic virotherapy is a novel strategy for treatment of cancer in humans and companion animals as well. Canine distemper virus (CDV), a paramyxovirus, has proven to be oncolytic through induction of apoptosis in canine-derived tumour cells, yet the mechanism behind this inhibitory action is poorly understood. In this study, three human mammary tumour cell lines and one canine-derived adenofibrossarcoma cell line were tested regarding to their susceptibility to CDV infection, apoptosis, mitochondrial membrane potential (MMP) and expression of tumour necrosis factor-alpha-induced protein 8 (TNFAIP8). CDV replication induced cytopathic effect and > 45% of infected cells were considered death and/or under late apoptosis/necrosis. TNFAIP8 and CDV M gene expression were positively correlated in all cell lines. In addition, MMP was highly associated with increase in virus titres (p<0.005). Thus, these results strongly suggest that both human and canine mammary tumour cells are potential candidates for studies concerning CDV-induced cancer therapy
Orientador:Tereza Cristina Cardoso da Silva
Banca:Andréa Fontes Garcia
Banca:Roberto Gameiro de Carvalho
Mestre
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Väyrynen, S. (Sara). "Histological and molecular features of serrated colorectal adenocarcinoma and its precursor lesions." Doctoral thesis, Oulun yliopisto, 2016. http://urn.fi/urn:isbn:9789526212883.
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Abstract In the Western world, colorectal cancer (CRC) is one of the most common cancers and causes of cancer deaths. It is estimated that up to a third of CRCs represent a recently defined subtype, serrated adenocarcinoma (SAC), which develops via the serrated pathway and differs from conventional cancer by molecular, histological, and clinicopathological characteristics. The oncogenic mutation of BRAF V600E is characteristic to the serrated pathway lesions, and VE1 is a novel antibody that has been reported to recognize this mutated BRAF protein. In these studies, two independent cohorts of CRCs and a cohort of 922 colorectal polyps (545 patients) consecutively removed in Oulu University Hospital were utilized to study potential immunohistochemical markers (annexin A10 and VE1) as markers for the serrated pathway lesions, to investigate the presence of ectopic crypt foci (ECF) in different colorectal polyps and CRCs, and to study the network of determinants and the clinical impact of tumor necrosis with special regard to SAC. VE1 immunohistochemistry was found a sensitive and accurate method in the detection of BRAF V600E mutation with potential applications in the recognition of the BRAF V600E-mutated SACs. Annexin A10 immunohistochemistry was indicated to be a marker with high specificity for the serrated pathway lesions. ECF were found to be frequently encountered in addition to traditional serrated adenomas also in the tubular, tubulovillous and villous adenomas. Tumor necrosis in CRC was associated with high tumor stage and inversely associated with the serrated histology. High tumor necrosis percentage correlated with poor survival in CRC independently of other clinicopathological factors. In conclusion, these studies add to the knowledge of the molecular and histological features of SAC and its precursors. The results suggest that VE1 and ANXA10 immunohistochemistry may help in the recognition of the serrated pathway lesions. ECF can be found in other colorectal polyps in addition to traditional serrated adenomas. Tumor necrosis represents a relevant histomorphological prognostic indicator in CRCTiivistelmä Paksu-peräsuolisyöpä on yksi yleisimmistä syövistä länsimaissa. Arviolta kolmasosaa kaikista paksu-peräsuolisyövistä edustava sahalaitainen adenokarsinooma eroaa tavallisesta adenokarsinoomasta molekulaaristen muutostensa sekä histologisten ja kliinispatologisten piirteidensä perusteella. BRAF-onkogeenin V600E-mutaatiota tavataan vain paksu-peräsuolisyövän sahalaitaisen kehittymisreitin muutoksissa ja VE1-immunohistokemian on todettu tunnistavan tämän mutatoituneen BRAF-proteiinin. Tutkimuksessa käytettiin kahta itsenäistä paksu-peräsuolisyöpäaineistoa sekä polyyppiaineistoa, joka käsitti 922 Oulun yliopistollisessa sairaalassa peräkkäisissä kolonoskopioissa poistettua paksu-peräsuolen polyyppia (545 potilasta). Tutkimuksen tarkoituksena oli selvittää kahden immunohistokemiallisen merkkiaineen (VE1 ja annexin A10) spesifisyyttä sahalaitaiselle adenokarsinoomalle ja sen esiastemuutoksille, ektooppisten kryptafokusten esiintymistä paksu-peräsuolen polyypeissa sekä kasvaimen nekroosiin yhteydessä olevia tekijöitä ja nekroosin ennustevaikutusta. VE1-immunohistokemia oli sekä sensitiivinen että spesifinen BRAF V600E-mutaation toteamisessa, minkä vuoksi sitä voidaan käyttää BRAF V600E-mutatoituneiden sahalaitaisten adenokarsinoomien tunnistamisessa. Annexin A10-immunohistokemia osoittautui spesifiseksi sahalaitaisen kehittymisreitin muutosten toteamissa. Ektooppisia kryptafokuksia havaittiin traditionaalisen sahalaita-adenooman lisäksi myös tubulaarisissa, tubulovillooseissa ja villooseissa adenoomissa. Kasvaimen nekroosi oli vähäisempää sahalaitaisessa adenokarsinoomassa sekä matalan levinneisyysasteen kasvaimissa. Runsas nekroosin määrä oli kasvaimen levinneisyydestä riippumatta yhteydessä huonompaan ennusteeseen. Tutkimus lisää tietoa sahalaitaisesta adenokarsinoomasta ja sen esiastemuutoksista. Tulokset osoittavat, että VE1 ja annexin A10 -immuno¬histokemia auttaa sahalaitaisen kehittymisreitin muutosten tunnistamisessa; ektooppisia kryptafokuksia voidaan nähdä traditionaalisten sahalaita-adenoomien lisäksi myös muissa paksu-peräsuolen polyypeissa; lisäksi todettiin, että kasvaimen nekroosin määrällä on vaikutusta paksu-peräsuolisyövän ennusteen arvioinnissa
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Ghimirey, Nirmala. "Combination of Th1 cytokines plus small molecule kinase inhibitors Palbociclib or Sunitinib potentiate apoptosis in breast cancer cell lines." Kent State University / OhioLINK, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=kent1530017347709489.
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Baloche, Valentin. "Contributions négatives et positives de la galectine-9 au développement tumoral : étude dans des modèles tumoraux murins syngéniques In the MB49 Murine Model, Genetic Ablation of Galectin-9 Enhances Anti-Tumor Immune Response: Possible Role of a Greater CXCL9/Il-6 Production Tumor Exosomal Micrornas Thwarting Anti-Tumor Immune Responses in Nasopharyngeal Carcinomas Interferon β and Anti-PD1/PD-L1 Checkpoint Blockade Cooperate in NK Cell-Mediated Killing of Nasopharyngeal Carcinoma Cells Interferon Beta Increases NK Cell Cytotoxicity against Tumor Cells in Patients with Nasopharyngeal Carcinoma via Tumor Necrosis Factor Apoptosis-Inducing Ligand Emerging Therapeutic Targets for Nasopharyngeal Carcinoma: Opportunities and Challenges Galectin-9 Promotes a Suppressive Microenvironment in Human Cancer by Enhancing STING Degradation." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASS117.
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Comme les autres galectines, la galectine-9(gal-9) est une lectine animale qui interagit avec un sous-groupe défini de polysaccharides portés par des glycoprotéines ou des glycolipides. La gal-9 associée aux cellules exerce de multiples fonctions dans le cytoplasme, dans le noyau et à la surface de la membrane plasmique. Quelques publications suggèrent que la gal-9 intra-cellulaire inhibe la mobilité des cellules malignes et exerce un effet antimétastatique. En outre la gal-9 peut être sécrétée dans le milieu extra-cellulaire où elle se comporte comme une cytokine avec des effets principalement immunosuppresseurs. Ces effets ont été mis en évidence dans un contexte tumoral chez l’homme et dans des modèles murins. Cependant, on ne disposait pas jusqu’à présent d’un modèle tumoral murin permettant d’évaluer les effets pro-tumoraux ou antitumoraux de la gal-9 indépendamment de la gal-9 des cellules infiltrantes. Pour résoudre ce problème, nous avons dérivé, en employant la technologie CRISPR/Cas9, des clones isogéniques invalidés ou non pour la gal-9 à partir de 2 lignées tumorales murines : CT26 (fond génétique BALB/c) et MB49 (fond génétique C57BL/6). Dans le cas de la lignée MB49, nous avons pu mettre en évidence un phénotype remarquable in vivo. Lors de transplantations itératives, on assiste pour les tumeurs dérivées des clones invalidées à une réduction drastique de la croissance tumorale au bout de 3 ou 4 passages sur les souris syngéniques mais pas sur les souris immunodéficientes. L’émergence de la réponse immunitaire responsable de cet arrêt de la croissance tumorale a été étudiée par immunohistochimie, dosage de cytokines en multiplex dans les extraits tumoraux et analyse du transtriptome par RNAseq. L’augmentation de la production intra-tumorale d’interféron-γ, de CXCL9 et d’Il-6 semble jouer un rôle important dans le renforcement de la réponse immunitaire contre les tumeurs KO-gal-9Like other galectins, galectin-9 (gal-9) is an animal lectin which interacts with a defined subgroup of glycans carried by glycoproteins or glycolipids. Gal-9 associated with cells performs multiple functions in the cytoplasm, in the nucleus and at the surface of the plasma membrane. Some publications suggest that intracellular gal-9 inhibits the mobility of malignant cells and exerts an anti-metastatic effect. In addition, gal-9 can be secreted into the extracellular medium where it behaves like a cytokine with mainly immunosuppressive effects. These effects have been demonstrated in the context of human tumors and in mouse tumor models. However, so far there was no murine tumor model available to assess the pro-tumor or anti-tumor effet of gal-9 independently of gal-9 produced by infiltrating cells. To address this issue, we derived isogenic clones invalidated or not for gal-9 from 2 murine tumoral lines : CT26 (BABL/c genetic background) and MB49 (C57BL/6 genetic background), using CRISPR/Cas9 technology. In the case of the MB49 line, we were able to demonstrate a remarkable phenotype in vivo. During serial transplantations, we saw, for tumors derived from invalidated clones, a dramatic reduction in tumor growth after 3 or 4 passages in syngenic mice but not in immunodeficient mice. The emergence of the immune response responsible for this arrest of tumor growth was investigated by immunohistochemistry, multiplex cytokine assay in tumor extracts and transcriptome analysis by RNAseq. Increased intra-tumor production of interferon-γ, CXCL9 and Il-6 appears to play an important role in enhancing the immune response against KO-gal-9 tumors
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Ta, Ngoc Ly. "Rôle des signaux pro-survie du récepteur Fas/CD95 dans le cancer colorectal : importance du dialogue moléculaire entre Fas et l’EGFR (Epidermal Growth Factor Receptor)." Thesis, Université Côte d'Azur (ComUE), 2018. http://www.theses.fr/2018AZUR4078.
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Le cancer colorectal (CCR) est la troisième maladie maligne la plus fréquente et la deuxième cause de décès par cancer. La famille des récepteurs tyrosine kinases transmembranaires ErbB a été identifiée comme l'un des principaux moteurs du développement et de la progression du CCR et l'un de ses membres les plus connus, le récepteur du facteur de croissance épidermique (EGFR / ERBB1 / Her1), considéré comme l'une des cibles les plus importantes en traitement CRC. Deux autres membres de la famille ErbB, les récepteurs Her2 et Her3, apparaissent également comme de nouvelles cibles importantes pour le CRC en raison de la mutation somatique, de l’amplification génique ou de la résistance aux traitements anti-EGFR. La protéine transmembranaire, Fas (TNFRSF6 / CD95), est un membre de la superfamille des récepteurs du facteur de nécrose tumorale (TNFRSF). Il peut transmettre des signaux multiples qui mènent à des destins de cellules complètement différents. Selon les contextes cellulaires, Fas initie la mort cellulaire par apoptose, essentielle pour arrêter les réponses immunitaires chroniques et prévenir l'auto-immunité et le cancer, ou pour stimuler la survie, la prolifération et la motilité des cellules, ce qui favorise l'auto-immunité, la croissance cancéreuse et les métastases. Avec des preuves de plus en plus nombreuses de la signalisation pro-survie médiée par Fas, les activités de promotion du cancer chez les patients atteints de cancer sont maintenant reconnues comme étant significatives et cliniquement pertinentes. Bien que cette polyvalence de signalisation ait été particulièrement bien démontrée dans le cancer du côlon, les mécanismes moléculaires qui sous-tendent les voies de survie sont encore largement inconnus. Dans ce contexte, l'objectif principal de mon doctorat Le projet visait à étudier l’importance du crosstalks entre les membres de la famille Fas et ErbB et, plus particulièrement, à déterminer si la signalisation Fas pouvait influencer la signalisation de l’EGFR favorisant le cancer.Plus précisément, je décris comment l’état de phosphorylation de la tyrosine Fas influence fortement la signalisation de la voie EGFR dans les cellules colorectales. Mes données démontrent que Fas dans son état prosurvival, phosphorylé à Y291 (pY291-Fas), interagit en effet avec EGFR et que cette interaction intensifie significativement la signalisation de l'EGFR dans les cellules cancéreuses colorectales anti-EGFR via la voie Yes-1 / STAT3. Le pY291-Fas s'accumule dans le noyau lors du traitement par EGF et favorise la localisation nucléaire du phospho-EGFR et du phospho-STAT3, l'expression de la cycline D1, l'activation des voies Akt et MAPK médiées par STAT3 et enfin la prolifération et la migration cellulaires. De plus, je découvre également le rôle potentiel que Her3 pourrait jouer avec Fas dans la libération des cellules cancéreuses colorectales de l'inhibition anti-EGFR.Tous ensemble mon doctorat des études permet de mieux comprendre le rôle des voies de survie de Fas dans la signalisation ErBb dans le CRC. Fait important, en démontrant un lien entre l'émergence d'une résistance aux traitements anti-ErbB et le signal de Fas pro-survie, mon travail justifie le développement d'une thérapie ciblée Fas / phospho-Fas comme nouvelle option thérapeutique pour surmonter les anti-EGFR, chez les patients présentant une résistance anti-EGFR secondaireColorectal cancer (CRC) is the third most common malignant disease and the second most frequent cause of cancer-related death. The ErbB family of transmembrane receptor tyrosine kinases has been identified as a major driver of the development and progression of CRC and one its best-known member, the epidermal growth factor receptor (EGFR /ERBB1/Her1), considered one of the most important targets in CRC treatment. Two others members of the ErbB family, the receptors Her2 and Her3, also emerge as important new targets for CRC due to the somatic mutation, gene amplification or resistance to the anti-EGFR therapies. The transmembrane protein, Fas (TNFRSF6/CD95), is a member of the tumor necrosis factor receptor superfamily (TNFRSF). It can transmit multiple signals that lead to completely different cell fates. Depending on cellular contexts, Fas either initiates cell death by apoptosis, which is essential for shutting down chronic immune responses and preventing autoimmunity and cancer, or stimulates cell survival, proliferation, and motility, which can promote autoimmunity, cancer growth, and metastasis. With increasing evidence of Fas-mediated pro-survival signaling, the cancer-promoting activities of Fas are now recognized as significant and clinically relevant. While this signaling versatility has been particularly well demonstrated in colon cancer, the molecular mechanisms underlying the survivals pathways are still largely unknown. In this context, the main aim of my Ph.D. project was to study the importance of the crosstalks between Fas and the ErbB family members and more specifically to determine whether the Fas signaling could influence the cancer-promoting signaling of EGFR.More precisely, I describe how the Fas tyrosine phosphorylation status strongly influences the signaling of the EGFR pathway in colorectal cells. My data demonstrate that Fas in its prosurvival state, phosphorylated at Y291 (pY291-Fas), indeed interacts with EGFR and that this interaction significantly intensifies EGFR signaling in anti-EGFR-resistant colorectal cancer cells via the Yes-1/STAT3-mediated pathway. The pY291-Fas accumulates in the nucleus upon EGF treatment and promotes the nuclear localization of phospho-EGFR and phospho-STAT3, the expression of cyclin D1, the activation of STAT3-mediated Akt and MAPK pathways, and finally the cell proliferation and migration. Additionally, I also uncover the potential role that Her3, may play along with Fas, in the colorectal cancer cell escape from anti-EGFR inhibition. All together my Ph.D. studies provide a better understanding of the role of the Fas survival pathways in the ErBb signaling in CRC. Importantly, by demonstrating a connection between the emergence of resistance to anti-ErbB therapies and the Fas pro-survival signal, my work provides a rationale for the development of Fas/phospho-Fas targeted therapy as a new therapeutic option for overcoming anti-EGFR, in patients with secondary anti-EGFR resistance
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Wu, Terry Hung-Ta. "Development of antigenic tumors in tumor progression and endogenous IFN[Greek letter gamma] pathway in suppression of tumor growth by TNF /." 2001. http://wwwlib.umi.com/dissertations/fullcit/3029550.
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Huang, Tsai-Yun, and 黃彩雲. "The association of tumor necrosis factor beta-NcoI polymorphism with colorectal cancer." Thesis, 2013. http://ndltd.ncl.edu.tw/handle/90514448673110496480.
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碩士中山醫學大學
生化暨生物科技研究所
101
Colorectal cancer represents the third most common cancer worldwide, and also the second highest prevalence, and its ranks third in cancer mortality in Taiwan region. It has been proposed that risk factors for colorectal cancer include increased age, gender (men are more predisposed to the development of colorectal cancer), the presence of inflammatory bowel disease, certain hereditary conditions and a family history of colorectal cancer. There are many studies indicated that single nucleotide polymorphism (SNPs) are associated with some cancers and diseases. Tumor necrosis factor (TNF) is a kind of cytokine which cause tumor cell death directly. It can initiate signals for cell proliferation and apoptosis (programmed cell death) to prevent inflammation, autoimmune diseases or cancer pathogenesis. TNF-β belongs to the TNF superfamily. When lymphocytes are stimulated to produce secretory LTα (TNF-β), it can interact with TNFR1 or TNFR2, resulting in apoptosis or NF-κB–dependent activation of inflammatory genes or events leading to lymphoid neogenesis. Many current studies have been confirmed that TNF-β gene polymorphism is associated various malignant diseases. In this study, we investigated the possible association of TNF-β gene polymorphism with colorectal cancer in Taiwan region. Using polymerase chain reaction and restriction fragment length polymorphism (PCR-RFLP), the allele frequency of the TNF-β polymorphism was investigated in 55 patients with colorectal cancer and 134 healthy control ( group IIA, without disease risks, n = 58; group IIB, personnel don’t have any conventional cardiovascular disease risk factors, n = 76). Experimental results show that TNF-β G/G genotype homozygous vs AG + AA genotype in both the experimental group CRC and control group IIA have significant difference (P-value = 0.035). Our study presents preliminary but intriguing data suggesting that TNF-β NcoI may be associated with CRC formation in Taiwan region.
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Stillie, RoseMarie. "INSIGHTS INTO THE ROLE OF INFLAMMATION IN COLITIS-ASSOCIATED CANCER: TARGETING TUMOR NECROSIS FACTOR RECEPTORS." 2011. http://hdl.handle.net/10222/14393.
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Inflammatory bowel diseases (IBD) are associated with an elevated risk of colorectal cancer that increases with disease duration and severity. Tumor necrosis factor (TNF) is a major therapeutic target in IBD, but long-term anti-TNF therapy is associated with increased risks of infection and lymphoma, therefore we asked whether TNF signaling through its receptors TNFR1 and TNFR2 could impact colitis and colitis-associated cancer (CAC). In acute dextran sulphate sodium (DSS)-colitis, no major inflammatory differences were found between wildtype (WT), TNFR1- and TNFR2-deficient mice, with the exception of reduced macrophage infiltration into inflamed tissue in TNFR1-/- mice. Chronic colitis and tumor development was assessed in these mice using the carcinogen azoxymethane and 4 cycles of DSS. TNFR1-/- mice were protected against colorectal tumor development compared to WT and TNFR2-/- mice, while inflammation was similar between strains. Hematopoietic TNFR1 deficiency resulted in reduced inflammation and tumor incidence, while stromal/epithelial TNFR1 deficiency reduced indices of cancer without affecting inflammation. 8-OHDG was significantly lower in TNFR1-/- mice compared to other strains, suggesting that TNF could contribute to oxidative stress within the colon. Mice lacking leukocyte NADPH oxidase were protected against clinical illness and CAC despite similar histological inflammation, indicating that inflammation-associated oxidative stress can play a role in CAC. In conclusion, TNF signaling through TNFR1 contributes significantly to the development of colorectal cancer in a model of CAC in a manner that involves both stromal/epithelial and hematopoietic TNFR1. This is significant because anti-TNF therapies may be effective at reducing CAC in the absence of a clinical reduction of IBD symptoms.
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孟加樂. "Graphene Oxide Enhances Autophagy, Nuclear Transport of Cisplatin, Cancer Cell Necrosis and Exerts Anti-tumor Effects." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/zxe624.
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碩士國立清華大學
化學工程學系
102
Graphene oxide (GO) is a derivative of graphene and we recently uncovered that GO itself is sufficient to provoke both autophagy and toll-like receptor (TLR) responses in CT26 colon cancer cells and confer antitumor effects in immunocompetent mice bearing CT26 colon tumor. Cisplatin (CDDP) is an anticancer drug for the treatment of solid tumors by inducing cell death, but colon cancer cells have evolved chemoresistance to CDDP, hence compromising the therapeutic efficacy. Here we examined whether GO can act as a chemosensitizer to potentiate the efficacy of chemotherapy drugs. We found that combination of GO with irinotecan, doxorubicin and oxaliplatin failed to potentiate the killing of CT26 cells, but GO in combination with CDDP (GO/CDDP) significantly potentiated the CT26 cell killing mainly via necrosis and elicited CT26 autophagy. In addition to regular autophagic flux, GO/CDDP co-treatment also strikingly induced nuclear transport of autophagy marker LC3 and CDDP (but not GO), which was concomitant with the enhanced necrosis. Prior treatment of cells with nuclear import inhibitor (ivermectin) or cell necrosis inhibitor (necrostatin-1) hindered the import of LC3 puncta and CDDP into the nucleus and impaired the cell necrosis. Intratumoral injection of GO/CDDP into colon cancer in mice augmented the antitumor effects, enhanced the intratumoral autophagy, necrosis and immune cell infiltration. These data collectively demonstrated that combination of GO and CDDP synergistically triggers autophagy, necrosis and suppresses tumor growth, thus implicating the potentials of GO as a chemosensitizer of CDDP in colon cancer chemotherapy.
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McMahon, Kelly M., Milène Volpato, H. Y. Chi, P. Musiwaro, Krzysztof Poterlowicz, Yonghong Peng, Andy J. Scally, Laurence H. Patterson, Roger M. Phillips, and Chris W. Sutton. "Characterization of Changes in the Proteome in Different Regions of 3D Multicell Tumor Spheroids." 2012. http://hdl.handle.net/10454/6365.
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Three dimensional multicell tumor spheroids (MCTS) provide an experimental model where the influence of microenvironmental conditions on protein expression can be determined. Sequential trypsin digestion of HT29 colon carcinoma MCTS enabled segregation into four populations comprising proliferating cells from the surface (SL), an intermediate region (IR), nonproliferating hypoxic cells from the perinecrotic region (PN), and a necrotic core (NC). Total protein was extracted from each population and subjected to iTRAQ-based quantitative proteomics analysis. From a total of 887 proteins identified, 209 were observed to be up-regulated and 114 were down-regulated in the PN and NC regions relative to the SL. Among the up-regulated proteins, components of glycolysis, TCA cycle, lipid metabolism, and steroid biosynthesis increased progressively toward the PN and NC regions. Western blotting, immunohistochemistry, and enzyme assays confirmed that significant changes in the expression of proteins involved in cellular metabolism occur in the nonproliferating fraction of cells within the viable rim. The presence of full length, functional proteins within the NC was unexpected, and further analysis demonstrated that this region contains cells that are undergoing autophagy. This study has identified possible targets that may be suitable for therapeutic intervention, and further studies to validate these are required.
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"4-MU synergistically kills cancer cells with TRAIL and suppresses reversal of cells from TRAIL-induced apoptosis." 2015. http://repository.lib.cuhk.edu.hk/en/item/cuhk-1290683.
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TRAIL has been widely investigated as an anti-cancer agent due to its high efficacy in vitro and its safety to normal cells. However, TRAIL-based agents only showed modest effect in clinical studies because of TRAIL resistance. In addition to apoptosis, TRAIL has also been reported to promote pro-survival signalings, cell migration and metastasis. One of the current strategies in the development of TRAIL-based therapeutics focuses on the search of sensitizing agents that help overcome TRAIL resistance without increasing harm to normal cells.This study reports a novel combination of TRAIL and 4-methylumbelliferone (4-MU) which can kill HeLa cells and HepG2 cells synergistically without cytotoxicity to Hs68 non-tumorigenic cells. This combination also effectively inhibited cancer cell proliferation and potentiated apoptosis by accumulation of tBid, down-regulation of anti-apoptotic proteins and inhibition of Akt. More importantly, 4-MU could suppress the recovery of HeLa cells from TRAIL-induced apoptosis, a process previously implicated to be associated with cancer relapse and tumor heterogeneity. This study has provided solid evidences substantiating further research on TRAIL-4-MU combination.
腫瘤壞死因子相關凋亡誘導配體 (TRAIL) 在體外實驗中有良好抗癌作用，且不會傷害正常細胞，使之得到廣泛研究，成為近年熱門的新抗癌分子。然而TRAIL 在臨床實驗中並沒有顯著抗癌功效，一般認為人體腫瘤細胞對TRAIL 具有耐藥性。研究文獻亦指出，除了細胞凋亡外，TRAIL亦會誘發細胞存活機制、促進細胞移行及癌細胞轉移。目前，對於TRAIL相關藥品抗癌作用的研究有幾個大方向，其中之一就是尋找良好的增敏分子。良好的增敏分子應能夠增力癌細胞對TRAIL的敏感性，對抗癌細胞對TRAIL的耐藥性，同時不能殺傷正常細胞。
本研究揭示了一個全新的抗癌藥物聯合。當TRAIL聯合4-甲基伞形酮(4-MU)能產生協同作用，殺傷HeLa癌細胞和HepG2癌細胞而不會傷害Hs68正常細胞。此組合能有效抑制癌細胞生長，並透過增加tBid蛋白表達、減少抗凋亡蛋白表達及抑制Akt來促進細胞凋亡。更為重要的是，4-MU能抑制HeLa癌細胞自TRAIL誘導凋亡的恢復和逆轉。而癌細胞凋亡逆轉一般被視為與癌症復發及腫瘤多樣性有關。本研究提供了實質證據，支持對TRAIL-4-MU組合的後續研究。
Wu, Hoi Yan.
Thesis (Ph.D.)--Chinese University of Hong Kong, 2015.
Includes bibliographical references (leaves 90-107).
Abstracts also in Chinese.
Title from PDF title page (viewed on 05, October, 2016).
Detailed summary in vernacular field only.
Detailed summary in vernacular field only.
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Bonkoungou, Carole A. "Rôle de CD271 dans l'immunomodulation des cellules T." Thèse, 2018. http://hdl.handle.net/1866/20790.
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