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1
Kam, Siu-kei Christy. "The role of TGF-[beta] signaling in the initiation of TNF-[beta] expression in human PBMC derived macrophages." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B38746049.
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Kam, Siu-kei Christy, and 甘笑琪. "The role of TGF-{221} signaling in the initiation of TNF-α expression in human PBMC derived macrophages." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B38746049.
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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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Molgat, André. "The Effect of Macrophage-secreted Factors on Preadipocyte Survival." Thèse, Université d'Ottawa / University of Ottawa, 2013. http://hdl.handle.net/10393/23628.
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Adipose tissue (AT) expansion and remodeling that maintains healthy function relies on stromal preadipocytes capable of differentiating into new adipocytes (adipogenesis). During chronic positive energy balance, a relative deficit in adipogenesis, from either a decrease in preadipocyte number or their capacity to differentiate, leads to excessive adipocyte hypertrophy and AT dysfunction. AT contains macrophages whose number and activation state is dynamically regulated with changes in AT mass. This study aims to investigate the effect of macrophage-secreted factors on preadipocyte survival.
To assess the effect of macrophage-secreted factors on preadipocytes, murine 3T3-L1 preadipocytes or human primary preadipocytes were incubated with macrophage-conditioned medium (MacCM), prepared from either murine (J774A.1, RAW264.7, bone marrow-derived) or human (THP-1, monocyte-derived) macrophage models, respectively. MacCM inhibited preadipocyte apoptosis and activated pro-survival signaling in both preadipocyte models. Inhibition of PDGFR, Akt, or ERK1/2 reduced the pro-survival effect of MacCM in 3T3-L1 preadipocytes. Inhibition of reactive oxygen species (ROS) generation, or enhancement of ROS clearance, reduced MacCM-dependent 3T3-L1 preadipocyte survival. Whereas anti-inflammatory activated macrophages retained the ability to prevent preadipocyte apoptosis, pro-inflammatory activated macrophages did not. TNF-α immunoneutralization restored the survival activity of pro-inflammatory MacCM on 3T3-L1 preadipocytes.
These studies reveal a novel pro-survival effect of MacCM on preadipocytes, and identify signaling molecules (PDGF, Akt, ERK1/2, and ROS) that underlie this action. Macrophage activation was found to regulate the pro-survival activity of MacCM. These in vitro cell culture studies are consistent with a model in which the extent of preadipocyte apoptosis in vivo may determine preadipocyte number and the ability of AT to expand while maintaining healthy function during chronic positive energy balance.
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Elstow, S. F. "The angiogenesis factors of the eye and their relationship to tumour derived angiogenesis factors." Thesis, University of Manchester, 1985. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.355902.
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Delfini, Marcello. "Jun regulates monocyte-derived macrophage accumulation and tumour progression." Thesis, Aix-Marseille, 2019. http://www.theses.fr/2019AIXM0076.
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Les macrophages sont des cellules immunitaires innées présentes dans chaque organe. Ils sont des cibles thérapeutiques dans de nombreuses maladies, dont le cancer. En dépit de travaux récents sur l'origine des macrophages, les mécanismes régulant leur différenciation sont mal définis. L'expression de Jun, membre de la famille AP-1, augmente pendant la différenciation des macrophages, mais son rôle dans ce processus n'est pas connu.Au cours de mon doctorat, nous avons caractérisé le rôle de Jun dans le développement et l'homéostasie des macrophages, dans un modèle de souris avec délétion conditionnelle de Jun dans la lignée myéloïde (JunΔCsf1r). Nous montrons que Jun contrôle la différenciation, induite par CSF1, des monocytes en macrophages. In vivo, Jun régule l'accumulation de macrophages dérivés de monocytes dans les poumons et intestins. Les macrophages associés aux tumeurs (TAMs) jouent un rôle crucial dans la progression des cancers. L’absence de Jun freine la croissance d’un mélanome et la différenciation, induite par CSF1, des TAMs dérivés de monocytes qui participent à l’angiogénèse tumorale. Cependant, lors d'une inflammation aiguë, Jun n’affecte pas le recrutement de macrophages inflammatoires.En conclusion, nos résultats identifient Jun comme un régulateur central de la différenciation des macrophages. Dans un modèle de mélanome, les macrophages Jun-dépendants exercent des fonctions pro-tumorales. Le fait que Jun soit un régulateur sélectif du développement des macrophages dépendants de CSF-1 permettra de définir de nouvelles approches ciblant sélectivement la différenciation des macrophages, sans altérer les réponses immunitaires dépendantes des monocytesMacrophages are immune cells present in every organ. Given their variety of functions, macrophages are therapeutic targets in many diseases including cancer. Despite the research efforts to characterise their origins, the molecular mechanisms regulating macrophage differentiation are still poorly defined. Expression of the AP-1 factor, Jun, increases during differentiation, but its role in macrophage development is not known.During my PhD, we characterised how Jun affects macrophage development and homeostasis. We developed a conditional mouse model in which Jun is deficient in the myeloid lineage (JunΔCsf1r). We showed that Jun controls CSF1-mediated monocyte to macrophage differentiation, proliferation and survival. In vivo, Jun loss limits macrophage accumulation in lungs and intestine. Tumour-associated macrophages (TAMs) play critical roles in cancer progression. We observed that Jun deficiency dampens melanoma growth and the differentiation of CSF1-dependent monocyte-derived TAMs. We further showed that Jun-dependent TAMs mediate vessel normalisation in melanoma. During inflammation, Jun was dispensable for the recruitment of monocyte-derived inflammatory macrophages.Altogether, our results identify Jun as a master regulator of macrophage differentiation, without altering monocyte effector functions. In a melanoma model, we showed that Jun-dependent TAMs play tumour-promoting roles. Therefore, Jun is a selective regulator of CSF-1-dependent macrophage development, which is redundant during inflammation; this observation should help to define novel approaches to selectively target macrophage differentiation, without altering monocyte-dependent immune responses
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Lam, Chi-tat, and 林知達. "Identification of brain-derived neurotrophic factor (BDNF) as a novel angiogenic factor in tumor angiogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2008. http://hub.hku.hk/bib/B41290355.
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Lam, Chi-tat. "Identification of brain-derived neurotrophic factor (BDNF) as a novel angiogenic factor in tumor angiogenesis." Click to view the E-thesis via HKUTO, 2008. http://sunzi.lib.hku.hk/hkuto/record/B41290355.
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Sanders, Paul Michael. "Mechanism of action of a tumour derived lipid mobilising factor." Thesis, Aston University, 2003. http://publications.aston.ac.uk/11005/.
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Cancer cachexia comprises unintentional and debilitating weight loss associated with certain tumour types. Fat loss in cachexia is mediated by a 43kDa Lipid Mobilising Factor (LMF) sharing homology with endogenous Zinc-a2-Glycoprotein (ZAG). LMF and ZAG induced significant lipolysis in isolated epidydimal adipose tissue. This is attenuated by co-incubation with 10mM of antagonist SR59230A and partially attenuated by 25mM PD098059 (indicating b3-AR and MAPK involvement respectively). LMF/ZAG induced in vitro lipid depletion in differentiated 3T3-L1 adipocytes that seen to comprise a significant increase in lipolysis (p<0.01), with only a modest decrease in lipid synthesis (p=0.09). ZAG significantly increased in vitro protein synthesis (p<0.01) in C2C12 myotubes (without an effect on protein degradation). This increase was activated at transcription and attenuated by co-incubation with 10mM SR59230A. Proteolytic digestion of ZAG and LMF followed by sephadex G50 chromatography yielded active fragments of 6-15kDa, indication the entire molecule was not required for bioactivity. Cachexigenic MAC16 cells demonstrated significant in vitro ZAG expression over non-cachexigenic MAC13 (p<0.001). WAT and BAT excised from MAC16 mice of varying weight loss demonstrated increased ZAG expression compared to controls. Dosing of NMRI mice with s/c ZAG failed to reproduce this up-regulation, thus another cachectic factor is responsible. 0.58nM LMF conferred significant protection against hydrogen peroxide, paraquat and bleomycin-induced oxidative stress in the non-cachexigenic MAC13 cell line. This protection was attenuated by 10mM SR59230A indicating a b3-AR mediated effect. In addition, 0.58nM LMF significantly up regulated UCP2 expression (p<0.001), (a mitochondrial protein implicated in the detoxification of ROS) implying this to be the mechanism by which survival was achieved. In vitro, LMF caused significant up-regulation of UCP1 in BAT and UCP2 and 3 in C2C12 myotubes. This increase in uncoupling protein expression further potentiates the negative energy balance and wasting observed in cachexia.
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Halin, Sofia. "Targeting the prostate tumor microenvironment and vasculature : the role of castration, tumor-associated macrophages and pigment epithelium-derived factor." Doctoral thesis, Umeå universitet, Patologi, 2009. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-30300.
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BACKGROUND: Prostate cancer is the most common cancer among Swedish men. For patients with metastatic prostate cancer the standard therapy is castration, a treatment that initially provides symptomatic relief but unfortunately is not curative. New therapeutic targets for advanced prostate cancer are therefore needed. Prostate cancers are composed of tumor epithelial cells as well as many non-epithelial cells such as cancer associated fibroblasts, blood vessels and inflammatory cells. Many components of the tumor microenvironment such as tumor associated macrophages and angiogenesis have been shown to stimulate tumor progression. This thesis aims to explore mechanisms by which the local environment influences prostate tumor growth and how such mechanisms could be targeted for treatment. MATERIALS AND METHODS: We have used animal models of prostate cancer, in vitro cell culture systems and clinical materials from untreated prostate cancer patients with long follow up. Experiments were evaluated with stereological techniques, immunohistochemistry, western blotting, quantitative real-time PCR, PCR arrays and laser micro dissection. RESULTS: We found that the presence of a tumor induces adaptive changes in the surrounding non-malignant prostate tissue, and that androgen receptor negative prostate tumor cells respond to castration treatment with temporarily reduced growth when surrounded by normal castration-responsive prostate tissue. Further, we show that macrophages are important for prostate tumor growth and angiogenesis in the tumor and in the surrounding non-malignant tissue. In addition, the angiogenesis inhibitor Pigment epithelium-derived factor (PEDF) was found to be down-regulated in metastatic rat and human prostate tumors. Over-expression of PEDF inhibited experimental prostate tumor growth, angiogenesis and metastatic growth and stimulated macrophage tumor infiltration and lymphangiogenesis. PEDF was found to be down-regulated by the prostate microenvironment and tumor necrosis factor (TNF) α. CONCLUSIONS: Our studies indicate that not only the nearby tumor microenvironment but also the surrounding non-malignant prostate tissue are important for prostate tumor growth. Both the tumor and the surrounding non-malignant prostate were characterized by increased angiogenesis and inflammatory cell infiltration. Targeting the surrounding prostate tissue with castration, targeting tumor associated macrophages, or targeting the vasculature directly using inhibitors like PEDF were all shown to repress prostate tumor growth and could prove beneficial for patients with advanced prostate cancer.
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Zandjani, Amir H. Nejad Moghaddam. "Platelet-derived endothelial cell growth factor/thymidine phosphorylase and tumour angiogenesis." Thesis, University of Oxford, 1994. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.386659.
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Wong, Hing-ki Charmaine. "Viral determinants of influenza A (H5N1) associated TNF-a hyper-induction in human primary monocyte-derived macrophages." Click to view the E-thesis via HKUTO, 2006. http://sunzi.lib.hku.hk/hkuto/record/B37659029.
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Wong, Hing-ki Charmaine, and 黃馨琦. "Viral determinants of influenza A (H5N1) associated TNF-a hyper-induction in human primary monocyte-derived macrophages." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B37659029.
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Horikawa, Naoki. "Expression of Vascular Endothelial Growth Factor in Ovarian Cancer Inhibits Tumor Immunity through the Accumulation of Myeloid-Derived Suppressor Cells." 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225478.
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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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Miller, Katherine. "Genetic susceptibility in Alzheimer's Disease and the role of lipid metabolism." Connect to text online, 2007. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=case1164830757.
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Thesis (Ph. D.)--Case Western Reserve University, 2006.[School of Medicine] Department of Epidemiology and Biostatistics. Includes bibliographical references. Available online via OhioLINK's ETD Center.
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Ma, Haisha. "Regulation of Platelet-Derived Growth Factor Receptor Signaling and its Targeting in Cancer Therapy." Doctoral thesis, Uppsala universitet, Ludwiginstitutet för cancerforskning, 2015. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-248172.
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Overactivity of platelet-derived growth factor receptor (PDGFR) is a frequent event in many types of solid tumors. Therefore, it is of great importance to uncover the mechanisms that regulate PDGF/PDGFR signalling, to develop efficient inhibitors targeting this pathway. The first step of downregulation of PDGFR activity upon ligand binding is internalization; thus we investigated how endocytosis pathways affect PDGFR signaling. We showed that in Ras-transformed fibroblasts, the internalization of PDGFR is shifted from the routine clathrin-dependent endocytosis to macropinocytosis, which results in enhanced PDGFR activity and subsequent downstream signalling, promoting anchorage-independent growth. We were also interested in how intracellular trafficking regulates signalling attenuation of PDGFR. We found that His-domain containing protein tyrosine phosphatase (HD-PTP) positively regulates phosphorylation level of the ubiquitin-ligases c-Cbl and Cbl-b; consistently, silencing of HD-PTP led to a decreased level of PDGFR ubiquitination (paper II). Consequently, internalized PDGFR could not be sorted properly and escaped degradation. This resulted in enhanced activation of phospholipase C γ (PLCγ) and changed kinetics of signal transducer and activator of transcription (STAT) 3 signalling, which further increased colony formation of HD-PTP silenced cells in soft agar, indicating a tumor suppressor role of HD-PTP. Activation of PDGFR leads to stimulation of downstream pathways. We identified Fer kinase as a critical signal transducer downstream of PDGFR in a proteomic screen. We showed that Fer kinase is essential for PDGF-induced STAT3 activation; as a result (paper III), Fer depletion severely blunted the ability of PDGFR signalling to promote anchorage-independent growth in soft agar and delayed tumor initiation in a mouse model. The crosstalk between host and tumor plays a critical role in tumor progression. At present most anti-cancer drugs are targeting tumor cells; we were interested in how targeting tumor host cells affects the efficacy of anti-tumor therapy. We found that selective PDGFRβ inhibition in host cells exerted tumor inhibitory effects on growth and vascularization of tumors with autocrine PDGF signaling, whereas tumors lacking such stimulation show only minor response on tumor growth (paper IV). Meanwhile, we demonstrated that PDGF/PDGFRβ signalling promotes expression of NG2, a marker for pericytes.
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Tudge, Ellinor. "Does crosstalk occur between neuropilin-1 and platelet-derived growth factor receptors in tumour cells?" Thesis, University of Manchester, 2013. https://www.research.manchester.ac.uk/portal/en/theses/does-crosstalk-occur-between-neuropilin1-and-plateletderived-growth-factor-receptors-in-tumour-cells(c3829d57-ed30-4025-8781-443a7a57d251).html.
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The platelet-derived growth factor (PDGF) and vascular endothelial growth factor (VEGF) families of receptor tyrosine kinases (RTKs) are evolutionarily related cell-surface receptors which regulate physiological and pathological angiogenesis. Neuropilins (NRPs) are transmembrane glycoproteins which function as co-receptors for VEGFR to mediate vascular development and angiogenesis. RTK signalling has a long established role in tumour-cell biology and downstream cellular effects of RTK activation, such as, sustained cell proliferation and invasion are known hallmarks of cancer. NRPs are also up-regulated in tumour cell lines and clinical specimens, and a major focus of NRP research has been to understand the role of NRPs in cancer, which to date has largely been attributed to NRPs contribution to VEGFR activation. Emerging evidence for NRPs in regulating the activation of adhesion molecules, growth factors and RTKs (other than VEGFR) illustrate that NRP has a much broader role in cancer. In cell types including smooth muscle cells, stem cells and tumour cells, there is now evidence that NRP-1 regulates PDGFR activation and signalling. Identification of the molecules that regulate PDGFR signalling will advance the understanding of tumour cell biology and contribute to the development of targeted therapies.To date, few studies have evaluated the role of NRP-1/PDGFR signalling in cancer. The objective of this study was therefore, to elucidate the cellular mechanisms of NRP-1/PDGFR signalling, and to investigate how this cellular crosstalk modulates PDGFR-stimulated signalling, survival and migration of tumour cells. A subset of mesenchymal tumour cell lines that expressed NRP-1 and PDGFR-α and/or PDGFR-β and were identified to investigate NRP-1/PDGFR crosstalk. In these cell lines, NRP-1 could associate with PDGFR-α and PDGFR-β independent of PDGF growth factor stimulation. NRP-1 did not regulate PDGF-stimulated phosphorylation of PDGFR-α or PDGFR-β yet, in a subset of the cell lines, NRP-1 contributed to the activation of the MAPK-ERK and PI3K pathways. NRP-1 did not regulate PDGF-stimulated cell proliferation, yet NRP-1 knockdown attenuated PDGF-stimulated cell migration in certain cell lines. Together, this study has provided evidence of NRP-1/ PDGFR crosstalk, which affects the migratory potential of a subset of mesenchymal tumour cells. In these cell lines, NRP-1 knockdown does not inhibit the overall phosphorylation of PDGFR, yet does have subtle effects on specific downstream PDGFR pathways.
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Fjällskog, Marie-Louise. "Current Medical Treatment of Endocrine Pancreatic Tumors and Future Aspects." Doctoral thesis, Uppsala University, Department of Medical Sciences, 2002. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-2709.
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We treated 16 patients with somatostatin analogs combined with α-interferon and achieved a biochemical and/or radiological response in 56% (median duration 22 months). We consider this treatment a good alternative for patients who fail during chemotherapy or who do not want to/cannot receive cytotoxic drugs.
Thirty-six patients with neuroendocrine tumors were treated with cisplatin combined with etoposide. Of 14 patients with evaluable EPTs, 50% responded radiologically and/or biochemically (median duration 9 months). We consider this treatment useful as first-line medical treatment in aggressive EPTs or in patients failing prior chemotherapy.
Twenty-eight tumor tissues from EPTs were examined with immunohistochemistry regarding expression of somatostatin receptors (ssts) 1 to 5 on tumor cells and in intratumoral vessels. We found that sst2 and sst4 were highly expressed on tumor cells and in vessels. However, sst3 and sst5 were lacking in half of the tumor tissues and in most of the vessels. Because of the variability in sst expression, we recommend analysis of each individual’s receptor expression before starting treatment.
Endocrine pancreatic tumors (EPTs) are rare with an incidence of 4 per million inhabitants. In the majority of cases they grow slowly, but there are exceptions with very rapidly progressing malignant carcinomas. First-line medical treatment is streptozotocin combined with 5-fluorouracil.
We examined 38 tumor samples regarding expression of tyrosine kinase receptors platelet-derived growth factor receptors (PDGFRs), c-kit and epidermal growth factor receptor (EGFR). We found that the receptors were expressed in more than half of the tumor tissues. Further studies will reveal if tyrosin kinase antagonists can be part of the future treatment arsenal.
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Johansson, Fredrik. "Screening for Candidate Brain Tumor Genes : Identifying Genes that Cooperate with Platelet-Derived Growth Factor in Glioma Development and Progression." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis Univ.-bibl. [distributör], 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7185.
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Valente, Vitor Bonetti [UNESP]. "Níveis dos hormônios do estresse no microambiente: influência sobre a ocorrência do tumor e modulação durante a carcinogênese quimicamente induzida em ratos." Universidade Estadual Paulista (UNESP), 2016. http://hdl.handle.net/11449/144395.
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Evidências mostram que os hormônios relacionados ao estresse podem influenciar a progressão do câncer, mas o papel destes mediadores sobre o processo de carcinogênese no microambiente tecidual, em condições naturais, é pouco compreendido. Neste estudo, nós utilizamos um modelo de carcinogênese bucal em ratos para testar a hipótese de que os níveis de hormônios relacionados ao estresse no microambiente tecidual em condições naturais (sem estresse) pré-indução carcinogênica influenciam a ocorrência e progressão do carcinoma espinocelular (CEC) de língua. Quarenta e oito ratos machos Wistar foram submetidos a uma biópsia de tecido lingual normal previamente à indução carcinogênica e os níveis teciduais de norepinefrina, corticosterona, ACTH e BDNF foram mensurados. Três semanas depois os animais foram tratados com o carcinógeno químico 4-nitroquinolina-1-óxido (4NQO) por 20 semanas e a ocorrência de CEC ou Leucoplasia (lesão precursora do CEC) na língua foi analisada microscopicamente. Níveis basais aumentados pré-carcinogênese de norepinefrina e BDNF e níveis reduzidos de corticosterona foram preditivos para ocorrência de CEC. Níveis basais elevados de norepinefrina foram associados à uma expressão reduzida de RNAm para CDKN2a-p16 nos CECs. Níveis teciduais de corticosterona e BDNF nas leucoplasias e corticosterona no CEC foram significativamente mais elevados em relação a mucosa normal pré-carcinogênese. Níveis elevados de norepinefrina no microambiente dos CECs foram associados a um maior volume e espessura do tumor. Da mesma forma, níveis elevados de norepinefrina, ACTH e BDNF no CEC foram associados a uma menor intensidade do infiltrado linfoplasmocitário subjacente ao tumor. Além disso, maior expressão de RNAm para IL-6 no CEC foi correlacionada à níveis elevados de corticosterona pós-carcinogênese. Este estudo mostra as primeiras evidências in vivo de que os níveis basais de hormônios do estresse no microambiente do tecido normal podem ser preditivos para a incidência do câncer quimicamente induzido. Além disso, a ação do carcinógeno pode modular os níveis hormonais no microambiente tecidual e estes podem estar associados à progressão do tumor. Em suma, estes dados sugerem que a susceptibilidade ao início e progressão do carcinoma quimicamente induzido pode ser diretamente influenciada por diferenças individuais endócrinas no microambiente pré-carcinogênese.
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El, Maï Mounir. "Rôle du Telomeric Repeat Binding Factor 2 (TRF2) au cours de l’angiogenèse tumorale et son implication dans la trans-activation du gène du récepteur PDGFRß." Thesis, Nice, 2015. http://www.theses.fr/2015NICE4063.
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Nous avons découvert que TRF2 est aussi sur-exprimée au niveau des cellules endothéliales de nombreux types de cancers humains alors qu’elle n’est pas détectable dans les vaisseaux des tissus sains adjacents. Des cellules endothéliales extraites de tumeurs ex-vivo manifestent une expression supérieure de TRF2, une migration et une prolifération accrues et une aptitude à former des tubules élevée, comparées aux endotheliums isolées de tissus sains. La sur-expression de cette protéine in vitro dans des cellules endothéliales primaires et ex-vivo entraine l’augmentation de la prolifération, de la migration et de la capacité de ces dernières à former des tubules. La diminution de l’expression de TRF2 conduit à l’effet inverse. Par ailleurs, la modulation de l’expression de TRF2 n’affecte pas la proportion de cellules apoptotiques. De même, les variations des niveaux d’expression de TRF2 n’induisent aucune réponse aux dommages à l’ADN et les modifications des facultés angiogéniques sont indépendantes d’ATM. Les effets angiogéniques de TRF2 semblent donc distincts des fonctions télomériques. Etant donné que le facteur de transcription WT1 (Wilms’ tumour suppressor 1) est fortement exprimé dans les vaisseaux de tumeurs humaines et régule les propriétés angiogéniques des cellules endothéliales, nous nous sommes penché sur la régulation potentielle de TRF2 par WT1. WT1 se lie en effet sur le promoteur de TRF2 pour activer sa transcription. Enfin, nous avons démontré que l’activité angiogénique de TRF2 réside en partie dans sa capacité à se fixer sur le promoteur du gène codant pour le récepteur angiogénique à activité tyrosine kinase PDGFRβ et à activer sa transcriptionWe discovered that TRF2 is expressed in endothelial cells of many human cancer types but not in the vessels of healthy adjacent tissues. Endothelial cells derived from tumours ex vivo exhibited a significantly increased TRF2 expression, and a higher migration, proliferation and tube formation potential as endothelium obtained from healthy tissues. In vitro TRF2 over-expression in primary or ex vivo endothelial cells resulted in an increased proliferation, migration and tube formation, while silencing of TRF2 led to the opposite results. No changes in apoptosis could be observed. Interestingly, modulation of TRF2 in endothelium does not induce DNA damage responses and the observed changes in the angiogenic behaviour are ATM –independent. The angiogenic effects of TRF2 seem therefore to be uncoupled from its telomeric function. Since the transcription factor WT1 (Wilms’ tumour suppressor 1) is highly expressed in human tumour vessels and mediates angiogenic properties of endothelial cells, we investigated whether TRF2 expression could be regulated by WT1. Indeed, WT1 binds the TRF2 promoter and activates its transcription. Finally, we demonstrated that TRF2 promotes angiogenesis by binding to the promoter of the gene encoding for the angiogenic tyrosine kinase receptor PDGFRβ and activating its transcription
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Terzi, Menderes Yusuf [Verfasser]. "The role and influence of pigment epithelium-derived factor (PEDF) on peripheral nerve tumor, brain trauma and stroke / Menderes Yusuf Terzi." Berlin : Medizinische Fakultät Charité - Universitätsmedizin Berlin, 2015. http://d-nb.info/1071088068/34.
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Pistollato, Francesca. "Oxygen Tension Controls the Expansion and Differentiation of Normal and Tumor-derived Human Neural Stem Cells. Role of oxygen in BMP responsiveness." Doctoral thesis, Università degli studi di Padova, 2007. http://hdl.handle.net/11577/3425173.
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During neural development the generation of diverse cell types involves the response of precursor cells to a wide variety of environmental cues, like soluble factors, the extracellular matrix and oxygen tension. Among these, oxygen tension and oxidation state in particular are important biophysical parameters that control neural precursor proliferation, survival and fate determination, so the dynamic control of oxygen availability regulates self renewal and the generation of cell diversity during development and throughout the life of the organism. However, the mechanisms by which oxygen acts in this manner are poorly understood.
Current evidence suggests that oxygen levels in both developing and mature brain are much lower than the 20% oxygen used in standard mammalian cell culture (Erecinska M. et al. 2001).
Previously it has been found that the sensitivity to oxygen tension is greater in mouse than in rat cells. Precursor survival and expansion is greatly improved at an oxygen tension (2-5%) closer to that measured in vivo and far lower than conditions typically used (20%) in culture studies. In the last decade much research has focused on the detrimental effect of anoxia during ischemic episodes and these results indicate that atmospheric oxygenation is incompatible with long-term precursors cell survival. Furthermore, one of the main effort is directed to maximize the culture efficiency of neural precursors for replacement therapies and also in vitro fertilization research has focused on oxygenation in order to optimize viability of the early post-fertilization embryo. It will be very important to understand the signals that control survival, proliferation and fate choice of precursor cells and it will also be necessary to investigate what subtypes of precursors are preferentially selected under normal in vitro condition. Indeed, the addition of antioxidants and other free radical scavengers is likely to be no more than a sub-optimal surrogate for culturing in lowered oxygen.
Moreover, it has been recently shown that hypoxia is a crucial component of the brain tumor niche as it positively correlates with tumor aggressiveness and over-activity of Hypoxia Inducible Factor-1? (HIF-1?) reinforces tumor progression.
Thus, the main aim of the project is to understand the role of oxygen tension in proliferation and lineage determination of Human CNS (Central Nervous System) and brain tumor derived precursor cells. We sought to understand if a lower oxygen tension (2-5%), compared to environmental 20% oxygen, promotes the expansion of a more premature and actively proliferating subtype of precursor cells, affecting cell multipotency, and which could be the molecular pathways modulated by oxygen tension.
Our results indicate that dynamic control of oxygen tension regulates different steps in fate and maturation and may be crucial for treating neurodegenerative diseases (i.e. demyelinating diseases). They also suggest that the maintenance of brain tumors stem-ness, particularly in high Grade Glioma (HGG) tumors, is correlated to a hypoxic microenvironment in which BMP signaling pathway and the pro-differentiating effects mediated by BMP are down-regulated.
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Al, Ssadh Hussain. "The role of immunological receptors CD74 and CD44 in association with the macrophage Migration Inhibitory Factor (MIF) on human breast cancer derived cells." Thesis, University of Essex, 2016. http://repository.essex.ac.uk/16169/.
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Synergistic interaction between pairs of membrane-bound receptors has been linked to signalling, cell communication and tumour progression. This study has shown that cluster of differentiation (CD) 74 and CD44 act in synergy and are susceptible to the effect of the macrophage migration inhibitory factor (MIF). MIF is a 12.5 kDa chemokine-like inflammatory mediator, whose ligand is the transmembrane receptor CD74. Recent data suggests that CD74 is involved in proinflammatory responses and tumorigenesis but detailed mechanisms are not fully understood. In normal cells CD74 functions as a chaperone of human leukocyte antigen (HLA)-DR biosynthesis and is expressed in antigen presenting cells in the absence of tumours. Notably, CD44 is also a transmembrane receptor and member of a family of cell adhesion molecules responsible for adhesion between adjacent cells (e.g. antigen presenting cells) and cells in the extracellular matrix. Western blotting and flow cytometry were employed to determine the quantitative expression of CD74, MIF and CD44 in three distinct breast tumour cell lines: CAMA-1, MDA-MB-231 and MDA-MB-435. All three cell lines showed a high expression of CD74, MIF and CD44. Modulation studies showed that IFN-γ and LPS can play a significant role in regulating the expression of CD74, proliferation and cell migration in CAMA-1 and MDA-MB-231 cells; suggesting that CD74 might be involved in controlling immunogenicity and immunoediting of breast cancer cells. To investigate the interaction of CD74 with CD44 and MIF, confocal microscopy and co-immunoprecipitation techniques were used. The three molecules form a multimeric complex in cytoplasmic compartments as measured by confocal microscopy, suggesting a mechanistic mode of action; in addition CD74, MIF and CD44 showed significant quantitative variations on all breast cancer derived cells. Knockdown of CD74 by CD74 siRNA significantly reduced CAMA-1 and MDA-MB-231 cell proliferation but increased the level of apoptotic cells. These data suggests that CD74, MIF and CD44, might facilitate signalling and hence could affect tumour progression. Measuring the co-expression levels of CD74, MIF and CD44 could potentially be used as a ‘biomarker signature’ for monitoring breast cancer tumours at different stages of the disease.
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Lo, Shuk-Yee Lo. "Harnessing the immunosuppressive tumour-derived cytokine, macrophage colony-stimulating factor (M-CSF), to stimulate T lymphocyte growth and activation." Thesis, King's College London (University of London), 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398007.
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Tesz, Gregory J. "Role of MAP4K4 Signaling in Adipocyte and Macrophage Derived Inflammation: A Dissertation." eScholarship@UMMS, 2008. https://escholarship.umassmed.edu/gsbs_diss/380.
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Human obesity is increasing globally at an impressive rate. The rise in obesity has led to an increase in diseases associated with obesity, such as type 2 diabetes. A major prerequisite for this disease is the development of insulin resistance in the muscle and adipose tissues. Interestingly, experiments in rodent models suggest that adipocytes and macrophages can profoundly influence the development of insulin resistance. Accordingly, the number of adipose tissue macrophages increases substantially during the development of obesity. Numerous research models have demonstrated that macrophages promote insulin resistance by secreting cytokines, like TNFα, which impair whole body insulin sensitivity and adipose tissue function. Additionally, enhancements of murine adipose function, particularly glucose disposal, prevent the development of insulin resistance in mice on a high fat diet. Thus, mechanisms which enhance adipose function or attenuate macrophage inflammation are of interest.
Our lab previously identified mitogen activated protein kinase kinase kinase kinase 4 (MAP4K4) as a potent negative regulator of adipocyte function. In these studies, TNFα treatment increased the expression of adipocyte MAP4K4. Furthermore, the use of small interfering RNAs (siRNA) to block the increase in MAP4K4 expression protected adipocytes from some of the adverse effects of TNFα. Because MAP4K4 is a potent negative regulator of adipocyte function, an understanding of the mechanisms by which TNFα regulates MAP4K4 expression is of interest. Thus, for the first part of this thesis, I characterized the signaling pathways utilized by TNFα to regulate MAP4K4 expression in cultured adipocytes. Here I show that TNFα increases MAP4K4 expression through a pathway requiring the transcription factors activating transcription factor 2 (ATF2) and the JUN oncogene (cJUN). Through TNFα receptor 1 (TNFR1), but not TNFR2, TNFα increases MAP4K4 expression. This increase is highly specific to TNFα, as the inflammatory agents IL-1β, IL-6 and LPS did not affect MAP4K4 expression. In agreement, the activation of cJUN and ATF2 by TNFα is sustained over a longer period of time than by IL-1β in adipocytes. Finally, MAP4K4 is unique as the expression of other MAP kinases tested fails to change substantially with TNFα treatment.
For the second part of this thesis, I assessed the role of MAP4K4 in macrophage inflammation in vitro and in vivo. To accomplish this task, pure β1,3-D-glucan shells were used to encapsulate siRNA. Glucan shells were utilized because they are effectively taken up by macrophages which express the dectin-1 receptor and they survive oral delivery. I demonstrate that these β1,3-D-glucan encapsulated RNAi particles (GeRPs) are efficiently phagocytosed and capable of mediating the silencing of multiple macrophage genes in vitro and in vivo. Importantly, oral treatment of mice with GeRPs fails to increase plasma IFNγ and TNFα or alter serum AST and ALT levels. Orally administered GeRPs are found in macrophages isolated from the spleen, liver, lung and peritoneal cavity and mediate macrophage gene silencing in these tissues.
Utilizing this technology, I reveal that MAP4K4 augments the expression of TNFα in macrophages following LPS treatment. Oral delivery of MAP4K4 siRNA in GeRPs silences MAP4K4 expression by 70% and reduces basal TNFα and IL-1β expression significantly. The depletion of MAP4K4 in macrophages protects 40% of mice from death in the LPS/D- galactosamine (D-GalN) model of septicemia, compared to less than 10% in the control groups. This protection associates with significant decreases in serum TNFα concentrations following LPS/D-GalN challenge. Consistent with reduced macrophage inflammation, hepatocytes from mice treated orally with GeRPs targeting MAP4K4 present less apoptosis following LPS/D-GalN treatment. Thus, MAP4K4 is an important regulator of macrophage TNFα production in response to LPS.
The results presented here add to the knowledge of MAP4K4 action in adipocyte and macrophage inflammation substantially. Prior to these studies, the mechanism by which TNFα controlled MAP4K4 expression in adipocytes remained unknown. Considering that MAP4K4 is a negative regulator of adipocyte function, identifying the mechanisms that control MAP4K4 expression was of interest. Furthermore, the role of macrophage MAP4K4 in LPS stimulated TNFα production was also unknown. To address this question in vivo, new technology specifically targeting macrophages was needed. Thus, we developed a technology for non toxic and highly specific macrophage gene silencing in vivo. Considering that macrophages mediate numerous diseases, the application of GeRPs to these disease models is an exciting new possibility.
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Langeloh, Lars. "Expression angiogener Faktoren und ihrer Rezeptoren in Tumor und Stroma während verschiedener Stadien der humanen epithelialen Hautkarzinogenese am Beispiel von Basic Fibroblast Growth Factor [bFGF] und Platelet Derived Growth Factor B [PDGF-B] /." Inhaltsverzeichnis, 2004. http://bvbr.bib-bvb.de:8991/F?func=service&doc_library=BVB01&doc_number=013108295&line_number=0001&func_code=DB_RECORDS&service_type=MEDIA.
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Côrtes, Andréa Junqueira. "Avaliação do efeito da matriz derivada do esmalte (Emdogain®) sobre o processo de cicatrização de feridas cutâneas cirúrgicas em ratos Wistar." Universidade Federal de Juiz de Fora, 2014. https://repositorio.ufjf.br/jspui/handle/ufjf/713.
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A matriz derivada do esmalte (EMD) é um complexo proteico de origem ectodérmica, isolado de germes dentários em desenvolvimento. Originalmente utilizada na regeneração de tecidos do periodonto, vem se mostrando um excelente recurso na regeneração de outros tecidos mesenquimais como derme, tecido ósseo e tendão. No presente estudo, o potencial cicatrizante da matriz foi analisado histopatologicamente em feridas cutâneas cirúrgicas realizadas em ratos Wistar, eutanaziados nos dias 01, 03, 07, 14 e 21. Durante o experimento, as feridas foram acompanhadas macroscopicamente e, a seu término, foram removidas e submetidas ao processamento histológico. À avaliação microscópica, foi observado que as lesões tratadas com a EMD evoluíram para o remodelamento dérmico de modo mais eficaz em tempo e qualidade em relação ao grupo controle não tratado, a partir do 3º dia pós-operatório; o amadurecimento e organização do colágeno foi bastante evidente a partir do 7º dia e, destaca-se que nos dias 14 e 21 o plano muscular, na profundidade da pele, exibiu excelente regeneração, sendo que, também neste período, o amadurecimento vascular se mostrou mais significativa nas amostras tratadas. Além da análise histomorfométrica, foi realizada a avaliação da expressão de iNOS, TGF- β2 e TNF-α por imunoistoquímica. A expressão de iNOS foi significativamente mais expressiva nas amostras tratadas, aumentando progressivamente a partir do 7º dia pós-operatório. Os resultados sugerem que a EMD, aplicada em feridas cutâneas cirúrgicas, potencializa a neoformação e o remodelamento de colágeno, amadurecimento vascular e regeneração muscular possivelmente via modulação do óxido nítrico.
The enamel matrix derivative (EMD) is a protein complex of ectodermal origin, isolated from the developing tooth germs. Originally used in the regeneration of periodontal tissues, has proved to be an excellent resource in the regeneration of other mesenchymal tissues such as dermis, bone and tendon. In the present study, the healing potential of the matrix was analyzed histologically in surgical wounds made in Wistar rats, euthanized on days 01, 03, 07, 14 and 21. During the experiment, the wounds were followed macroscopically, and at its end, were removed and subjected to histological processing. For microscopic evaluation, it was observed that the lesions treated with EMD progressed to dermal remodeling more effectively in time and quality in relation to the untreated control group, from the 3th postoperative day ; the maturation and organization of the collagen was quite evident from the 7th day , and it is noteworthy that on 14 and 21 muscle -up, the skin depth, showed excellent regeneration, and also in this period, vascular maturation showed more significantly in the treated samples. In histomorphometric analysis, evaluation of iNOS, TGF- β2, and TNF-α expression was performed by immunohistochemistry. The expression of iNOS was significantly more expressive in the treated samples, increasing progressively from the 7th postoperative day. The results suggest that EMD applied on surgical wounds enhances the new formation and remodeling of collagen, vascular maturation and muscle regeneration possibly via modulation of nitric oxide.
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Haji, mansor Muhammad. "Functionalized polymer implants for the trapping of glioblastoma cells Development of a non-toxic and non-denaturing formulation process for encapsulation of SDF-1α into PLGA/PEG-PLGA nanoparticles to achieve sustained release Reversing the Tumor Target: Establishment of a Tumor Trap." Thesis, Angers, 2019. http://www.theses.fr/2019ANGE0015.
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Le glioblastome (GBM) est la forme de cancer du cerveau la plus courante et la plus meurtrière. Sa nature diffusive entraine une impossibilité d’élimination complète par chirurgie. Une récidive de la tumeur chez ≥ 90% des patients peut être provoqué par des cellules GBM résiduelles se trouvant près du bord de la cavité de résection. Un implant pouvant libérer de manière durable la protéine SDF-1α, qui se lie aux récepteur CXCR4 à la surface des cellules GBM, peut être utile pour induire le recrutement des cellules GBM résiduelles, permettre leur élimination sélective et finalement réduire la récurrence de la tumeur. Dans ce travail, le SDF-1α a été initialement encapsulé dans des nanoparticules à base d'acide poly-lactique-co-glycolique (PLGA). Une efficacité d'encapsulation élevée (76%) a pu être obtenue en utilisant un processus simple de séparation de phase. Les nanoparticules chargées de SDF-1α ont ensuite été incorporées dans un scaffold à base de chitosan par électrofilage pour obtenir des implants nanofibreux imitant la structure de la matrice extracellulaire du cerveau. Une étude de libération in vitro a révélé que l'implant pouvait fournir une libération prolongée de SDF-1α jusqu'à 35 jours, utile pour établir un gradient de concentration de SDF-1α dans le cerveau et induire une attraction des cellules GBM. Une étude de biocompatibilité in vivo à 7 jours a révélé des signes d'inflammation locale sans aucun signe visible de détérioration clinique chez les sujets animaux. Une étude à 100 jours visant à confirmer l'innocuité in vivo des implants avant de passer aux études d'efficacité dans un modèle de résection GBM approprié est actuellement en coursGlioblastoma (GBM) is the most common and lethal form of brain cancer. The diffusive nature of GBM means the neoplastic tissue can not be removed completely by surgery. Often, residual GBM cells can be found close to the border of the resection cavity and these cells can multiply to cause tumor recurrence in ≥90% of GBM patients. An implant that can sustainably release chemoattractant molecules called stromal cell-derived factor-1α (SDF-1α), which bind selectively to CXCR4 receptors on the surface of GBM cells, may be useful for inducing chemotaxis and recruitment of the residual GBM cells. This may then give access to selective killing of the cells and ultimately reduce tumor recurrence. In this work, SDF-1α was initially encapsulated into poly-lactic-coglycolicacid (PLGA)-based nanoparticles. A high encapsulation efficiency (76%) could be achieved using a simple phase separation process. The SDF-1α-loaded nanoparticles were then incorporated into a chitosan-based scaffold by electrospinning to obtain nanofibrous implants that mimic the brain extracellular matrix structure. In vitro release study revealed that the implant could provide sustainedSDF-1α release for 5 weeks. The gradual SDF-1αrelease will be useful for establishing SDF-1α concentration gradients in the brain, which is critical for the chemotaxis of GBM cells. A 7-day in vivo biocompatibility study revealed evidence of inflammation at the implantation site without any visible signs of clinical deterioration in the animal subjects. A long-term study (100 days) aiming to confirm the in vivo safety of the implants before proceeding to efficacy studies in a suitable GBM resection model is currently underway
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Welin, Staffan. "Midgut Carcinoid Tumours : New Diagnostic Procedures and Treatment." Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-7436.
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LOCATELLI, LUIGI. "Expression of aVB6 integrin by Pkhd1-defective cholangiocytes links enhanced ductal secretion of Macrophage chemokines to progressive portal fibrosis in Congenital Hepatic Fibrosis." Doctoral thesis, Università degli Studi di Milano-Bicocca, 2013. http://hdl.handle.net/10281/41733.
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BACKGROUND AND AIMS: Congenital Hepatic Fibrosis (CHF) is caused by mutations in PKHD1, a gene encoding for fibrocystin, a protein of unknown function, expressed in cholangiocyte cilia and centromers. In CHF, biliary dysgenesis is accompanied by severe progressive portal fibrosis and portal hypertension. The mechanisms responsible for portal fibrosis in CHF are unclear. The αvβ6 integrin mediates local activation of TGFβ1 and is expressed by reactive cholangiocytes during cholestasis. To understand the mechanisms of fibrosis in CHF we studied the expression of αvβ6 integrin and its regulation in Pkhd1del4/del4 mice.
METHODS: In Pkhd1del4/del4 mice we studied, at different ages (1-12 months): a) portal fibrosis (Sirius Red) and portal hypertension (spleen weight/body weight); b) αvβ6 mRNA and protein expression (RT-PCR, IHC); c) α-SMA and TGFβ1 mRNA expression (RT-PCR); d) portal inflammatory infiltrate (IHC for CD45 and FACS analysis of whole liver infiltrate); f) cytokines secretion from cultured monolayers of primary cholangiocytes (Luminex assay); g) cytokine effects on monocyte/macrophage proliferation (MTS assay) and migration (Boyden chamber); h) TGFβ1 and TNFα effects on β6 integrin mRNA expression by cultured cholangiocytes before and after inhibition of the TGFβ receptor type II (TGFβRII); i) TGFβ1 effects on collagen type I (COLL1) mRNA expression by cultured cholangiocytes.
RESULTS: Pkhd1del4/del4 mice showed a progressive increase in αvβ6 integrin expression on biliary cyst epithelia. Expression of αvβ6 correlated with portal fibrosis (r=0.94, p<0.02) and with enrichment of a CD45+ve cell infiltrate in the portal space (r=0.97, p<0.01). Gene expression of TGFβ1 showed a similar age-dependent increase. FACS analysis showed that 50-75% of the CD45+ve cells were macrophages (CD45/CD11b/F4/80+ve). Cultured polarized Pkhd1del4/del4 cholangiocytes secreted from the basolateral side significantly increased amounts of CXCL1 and CXCL10 (p<0.05). Both cytokines were able to stimulate macrophage migration (p<0.05). Basal expression of β6 mRNA by cultured Pkhd1del4/del4 cholangiocytes (0.015±0.002 2^-dCt) was potently stimulated by the macrophage-derived cytokines TGFβ1 (0.017±0.002 2^-dCt, p<0.05) and TNFα (0.018±0.003 2^-dCt, p<0.05). Inhibition of TGFβRII completely blunted TGFβ1 (0.014±0.003 2^-dCt, p<0.05) but not TNFα effects (0.017±0.001 2^-dCt, p=ns) on β6 mRNA. COLL1 mRNA expression by cultured Pkhd1del4/del4 cholangiocytes (0.0009±0.0003 2^-dCt) was further and significantly increased after TGFβ1 stimulation (0.002±0.0005 2^-dCt, p<0.05).
CONCLUSIONS: Pkhd1del4/del4 cholangiocytes possess increased basolateral secretory functions of chemokines (CXCL1, CXCL10) able to orchestrate macrophage homing to the peribiliary microenvironment. In turn, by releasing TGFβ1 and TNFα, macrophages up-regulate αvβ6 integrin in Pkhd1del4/del4 cholangiocytes. αvβ6 integrin activates latent TGFβ1, further increasing the fibrogenic properties of cholangiocytes.
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Cheradame, Stéphane. "Biomodulation du 5-fluorouracile par l'acide folinique et recherche des facteurs de prédiction de la sensibilité tumorale à cette association." Université Joseph Fourier (Grenoble ; 1971-2015), 1996. http://www.theses.fr/1996GRE10252.
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Le principal effet cytotoxique du 5-fluorouracile (5fu) s'exerce par inhibition de la thymidylate synthetase (ts). La formation d'un complexe ternaire intracellulaire entre la ts, un anabolite du 5fu le fluorodeoxyuridine monophosphate (fdump) et un folate reduit, le 5,10-methylenetetrahydrofolate (ch2fh4), bloque la synthese de thymidine et donc la formation d'adn. L'acide folinique (af) potentialise l'effet du 5fu en augmentant le pool intracellulaire de ch2fh4. Une concentration optimale de ch2fh4 sous forme polyglutamatee via la folylpolyglutamate synthetase (fpgs) est necessaire pour une inhibition maximale de la ts. Le 5fu est catabolise par la dihydropyrimidine deshydrogenase (dpd), qui diminue la concentration intratumorale de fdump. Les objectifs de cette etude etaient de tester sur des lignees cellulaires tumorales et des biopsies tumorales de patients, la valeur predictive des activites ts, dpd, fpgs et du ch2fh4 vis a vis de la sensibilite au 5fu et a l'af. Dans les lignees cellulaires, la fpgs est le seul facteur predictif de la sensibilite au 5fu seul ou en presence d'af. L'effet potentialisateur de l'af sur le 5fu est d'autant plus important que le taux de ch2fh4 de base et l'activite fpgs basale sont eleves. Le ch2fh4 intratumoral n'est pas le facteur limitant de l'effet potentialisateur. Dans les tumeurs orl, les patients repondeurs au 5fu ont un taux de ch2fh4 plus eleve et une activite dpd normalisee (dpdtumorale/dpdtissu sain) plus faible que les patients resistants. Au dessus de 1,6 pmole/mg de proteine de ch2fh4, tous les patients sont repondeurs au traitement. Au dessous de 1,6 pmole/min/mg de proteine 52% des patients sont resistants au traitement. Dans le cas des metastases hepatiques de cancers colorectaux, les patients resistants au 5fu ont une activite fpgs plus faible que les repondeurs. 96% des metastases hepatiques dont l'activite fpgs < 1,1 pmole/min/mg de proteine ou dont l'activite ts > 0,32 pmole/min/mg de proteine, sont resistantes a une chimiotherapie a base de 5fu - af
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SHRENI, SAKSHI DWADASH. "IDENTIFICATION OF ACTIVE COMPONENTS DERIVED FROM NK RESISTANT CELL LINE RESPONSIBLE FOR NK CELL MODULATION." Thesis, 2016. http://dspace.dtu.ac.in:8080/jspui/handle/repository/14794.
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1. ABSTRACT
There are various mechanism by which, tumors are able to escape from the immune attack of NK cells. The various mechanisms are related to the NK cell adhesion or activation interventions, triggered inhibition and NK cell modulation of effector functions through the interplay of huge pool of receptors on NK cell surface. NK cells are blessed with the innate ability to kill target cell. Thus, they have a major role to defend tumors as well as cells infected by viruses. The sensitivity of infected cell to NK cell lysis may open new prospectives for NK cell-based immunotherapy. Natural Killer cells have been known so far to act against many murine tumors used in experimentation, but in humans their antineoplastic attribute is not agreed upon always. A detailed concept of the mechanisms imposed by the tumor microenvironment in the modulation of cytotoxic immune cells is essential before approving their use in cancer therapies. The multifacet recognition pattern of tumor derived proteins by NK activating receptors and every accessible surface involved in this binding event should be explored. The knowledge of affinity of NK cell receptor with tumor ligands will help in understanding the binding patterns required for the activation of NK cell activity. The interactions between these tumor ligands with their activators are potentially addressable by computational approaches and can further help to develop NK based cancer therapeutic strategies. This thesis aims at investigating new factors released from respective NK sensitive cell line, and to further study the NK cell modulation that results from such factors that can be a potential targets of NK cell based therapy as well as also demonstrated the growth kinetics and growth pattern of the NK sensitive cell line. Various proteins factors were isolated from the supernatants, lysates and whole membrane preparation and separated using SDS-PAGE, which further need to be studied through NK receptor profiling
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Iachini, Maria Chiara. "Effect of soluble factors released by different cancer cell lines on the bone marrow-derived mesenchymal stem cells (BM-MSCs) behavior. Role of Sphingosine Kinases and Lemur Tyrosine Kinase activity." Doctoral thesis, 2022. http://hdl.handle.net/2158/1275150.
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The tumor microenvironment (TME) is a key factor for cancer biology and progression. In particular, it supports cancer cell survival, local invasion and metastatic dissemination (Tsuchida J. et al. 2017; Hui L. et al. 2015). During cancer progression, roles and functions of TME may be different and dynamic, and can shift according to the needs of the tumor. The composition and structure of TME varies among different cancer types and their specific localization (Anderson N.M. et al. 2020). Therefore, TME is not just a silent bystander, but rather an active promoter of tumor progression (Truffi M. et al. 2020).
In addition to the tumor bulk, TME principally consists of two main components: (1) the non-malignant cellular component (mainly stromal and immune cells that surround cancerous tissue) and (2) the non-cellular component (extracellular matrix and metalloproteinases, soluble factors, microvesicles, exosomes, and interstitial fluid) (Atiya H. et al 2020; Anderson N.M. et al. 2020; Truffi M. et al. 2020; Arneth B. 2019). The tumor bulk is able to control both components throughout complex signalling networks that involve direct cell-to-cell contacts and soluble factors. The non-malignant cellular component includes normal stromal cells that are present in the tumor tissue: immune cells, macrophages, fibroblasts, myofibroblasts, pericytes and endothelial cells, adipocytes, stellate cells and bone marrow-derived mesenchymal stem cells (BM-MSCs) (Rhee K.J. et al. 2015).
Several studies have recently underlined that MSCs have a crucial role influencing the development and functions of TME (Atiya H. et al. 2020; Ridge S.M. et al. 2017). Notably, MSCs have a dynamic and ambiguous role in TME and cancer progression. Indeed, they can either support or suppress tumor growth through a large variety of mechanisms (Papait A. et al. 2020; Ridge S.M. et al. 2017). For example, MSCs sustain tumor progression by differentiating into other pro-tumorigenic components of the TME, or by suppressing the immune response; by promoting angiogenesis, or by enhancing Epithelial-to-Mesenchymal Transition (EMT), or increasing tumor cell survival and tumor metastasis. On the contrary, other studies have shown that MSCs act in anti-tumorigenic manner by modulating the immune responses, by inhibiting angiogenesis or regulating cellular signaling, and/or leading to apoptosis (Ahn S.Y. et al. 2020; Atiya H. et al. 2020; Hass R. et al. 2020; Timaner M. et al. 2019). Therefore, further studies are required to completely understand the complex crosstalk between MSCs, tumor, immune and other stromal cells in order to identify new molecular targets or biomarkers as well as to better characterize MSCs for their use as therapeutics agents (Atiya H. et al. 2020).
Accordingly, the aim of this study was to further investigate MSCs behavior in the TME by analyzing their responses to soluble factors released in the conditioned medium (CM) collected from several cancer cell types. In particular, we used different human and murine cell lines obtained from multiple sources: lung cancer (T84-human cell line and LLC-murine cell line), colon cancer (C26-murine cell line), melanoma (SSM2c-human cell line), hepatoma (HuH7-human cell line), neuroblastoma (SH-SY5Y-human cell line) and breast cancer (MCF7,
i
T47D, MDA-MB-231 human cell lines). All the analysis has been carried out in two different experimental conditions, in the presence or not of serum in order to mimic early or late stages of cancer progression. In fact, in the early stage of tumor development, the nutrients supplied through the bloodstream, are sufficient for the growth of tumor cells, while later, during cancer progression, these cells undergo oxygen and nutrient deficiency. In these distinctive experimental conditions, the production of diversified soluble factors secreted by tumor cell lines differently influences MSCs behavior. In particular, we examined the proliferation rate, the cell cycle progression, and the differentiation processes of murine bone marrow-derived mesenchymal stem cells (BM-MSCs) into myofibroblasts or cancer- associated fibroblasts. In addition, we evaluated the release of MMP-2, which multiple studies have reported to be overexpressed in the TME of lung, ovaries, breast and prostate cancer (Kaczorowska A. et al. 2020). Interestingly, we found that released factors of only some particular cell lines could affect MSCs behavior in terms of cell proliferation and differentiation, suggesting a distinct role for specific secreted soluble factors.
Successively, the study has been focused on the involvement of distinct effectors in MSCs response to CM obtained from the different tumor cell lines. In fact, as noted above, cancer and non-cancer cells, including MSCs, can provide soluble factors that influence cancer progression (Takabe K. et al. 2014; Wiig H. et al. 2012; Haslene-Hox H. et al. 2011). In the past years, the most studied soluble factors released from both malignant and non- malignant cells, have been cytokines and chemokines. Recently, numerous evidences showed that also other molecules such as bioactive sphingolipids (SLs), as sphingosine 1- phosphate (S1P), can play a key role in cancer progression (Riboni L. et al. 2020; Kunkel G.T. et al. 2013; Nagahashi M. et al. 2014). In particular, in the past couple of decades, many studies have demonstrated that SLs are not exclusively structural components of biological membranes, but also play a crucial role in signaling pathways. S1P is a pleiotropic bioactive metabolite produced and secreted both by tumor and non-malignant cells, including MSCs (Schneider G. 2020; Sassoli C. et al. 2014). This bioactive lipid is produced by Sphingosine Kinase 1 (SphK1) and Sphingosine Kinase 2 (SphK2), two distinct isoforms with different function and localization (Pyne N.J. et al. 2010), often overexpressed in cancer and involved in its progression (Gomez-Brouchet A. et al. 2022; Gachechiladze M. et al. 2019; Zhang L. et al. 2016). These observations point out the possibility that SphK overexpression and, in turn the increase in S1P content, may be involved in the inflammatory processes in TME (Gupta P. et al. 2021). Although these considerations, much less is known about the role of SphK/S1P axis on the non-malignant cellular component of the TME.
Thus, we examined the role of SphK/S1P system, by pharmacological and specific inhibition of SphK1 and SphK2, in MSCs response to the soluble factors released by different cancer cell lines already described. Notably we found an isoform-specific role in MSCs proliferation and MMP-2 release after incubation with the CM obtained from different cancer cell lines.
Similarly to SphKs, other kinases and kinase-related proteins, involved in tumor progression, have been reported and investigated as targets for the development of new anti-cancer therapies (Wang X. et al. 2020; Hasanifard L. et al. 2019; Cicenas J. et al. 2018).
ii
Among these kinases, Lemur Tyrosine Kinase 3 (LMTK3) has been identified as a novel established cancer driver known to act through diverse mechanisms (reviewed in Giamas G. et al. 2011). LMTK3 is overexpressed in several tumor subtypes, contributing to the progression of the disease (Vella V. et al. 2021). Therefore, it is considered a key component of a variety of oncogenic pathways and a useful predictive and prognostic biomarker (Ditsiou A. et al. 2021). It has been reported that treatment of different breast cancer cell lines with increasing concentrations of a recently identified inhibitor of LMTK3 (C28) resulted in time- and dose-dependent degradation of LMTK3 (Ditsiou A. et al. 2020).
In order to establish the involvement of LMTK3 in our study, we evaluated MSCs behavior in response to soluble factors released by the abovementioned breast cancer cell lines, and in the same cell lines overexpressing LMTK3 (MCF7 cl2, T47D cl1, and MDA-MB- 231 109 human cell lines) and subsequently, in response to SphK2 specific inhibition. Preliminary results suggest that a possible functional crosstalk between SphK2 and LMTK3 may exist.
Finally, we analyzed the paracrine action mediated by soluble factors released from MSCs incubated with CM-derived from the different cancer cell lines on a second set of MSCs. Notably, in these experimental conditions, we identified the formation of tunneling nanotubes (TNTs) among MSCs. Indeed, the development of TNTs, a novel cargo route among cells, may represent a rescue mechanism. In the TME, MSCs can promote cancer progression through the constitution of these structures, by which cells exchange mitochondria, microRNA, soluble factors and nutrients. TNTs formation may a be a cause of tumor cell chemoresistance enhancement (Charreau B. 2021). The data here reported demonstrated a specific involvement of SphK2 activity and S1PR1-S1PR3 mediated-signaling in the generation of TNTs.
In order to achieve optimal clinical outcomes, recently it has been suggested that cancer-oriented therapies should be also associated to TME-targeting treatments. Unlike cancer cells, stromal populations within the TME are genetically stable and with minimal risk of treatment resistance and disease relapse (Hass R. et al. 2020; Yang J. et al. 2015). Therefore, all the findings here reported, mainly focusing on MSCs responses, may contribute to the identification of potential targets, thus opening new windows in the field of cancer therapeutic strategy.
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Parlee, Sebastian Demian. "Tumor necrosis factor-{alpha} amplifies adipose-derived chemerin production and bioactivation." 2011. http://hdl.handle.net/10222/21406.
Full textAbstract:
Due to its escalating prevalence, obesity is becoming a leading cause of morbidity and mortality worldwide. Obesity is a complex health problem accompanied by metabolic abnormalities and low-grade inflammation that increases the risk for developing comorbidities including type 2 diabetes. Recent evidence supports a role for fat (adipose) tissue derived factors, called adipokines, in the development of obesity and obesity-related metabolic pathologies.
Chemerin is an adipokine that mediates immune and metabolic effects through the chemokine-like receptor 1 (CMKLR1). Chemerin is secreted as an inactive proform, prochemerin, which subsequently undergoes enzymatic cleavage into multiple chemerin products that differentially activate CMKLR1. Multiple studies have reported elevated total chemerin (a combination of prochemerin and various chemerin products) in obese humans suggesting chemerin involvement in obesity pathophysiology. However, the observational nature of these human studies have restricted them from identifying specific forms of chemerin that are elevated in obesity and the mechanisms that govern them.
Herein, I have reported that the levels of both serum total chemerin and chemerin products capable of activating CMKLR1 are elevated in obese mice and in wild type mice following treatment with an obesity-associated inflammatory mediator tumor necrosis factor-? (TNF?). Likewise, cultured adipocytes produced active chemerin under basal conditions and highly active chemerin following TNF? treatment as measured by CMKLR1 activation. The current belief is that prochemerin circulates through blood primed for activation by immune and fibrinolytic enzymes present within injured tissues. My results challenge this theory, identifying adipocytes as cells alone produce and proteolytically activate chemerin. Under basal conditions, a balance between activating serine proteases and deactivating aminopeptidases governed the amount of CMKLR1-activating chemerin formed by adipocytes. Treatment of adipocytes with TNF? elevated the levels of serine proteases elastase and tryptase, which cumulatively shifted the proteolytic balance toward the production of chemerin products that highly activate CMKLR1.
Taken together, my results are the first to identify that local TNF? triggers increased adipocyte production of chemerin providing an explanation for the elevated concentrations of chemerin in obese animals and humans. Furthermore, adipocyte processing represents a novel mechanism that likely governs the amount and type of circulating chemerin in obesity.
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KHOKHAR, VIKRANT. "REGULATION OF EXPRESSION OF NK CELL RECEPTOR BY TUMOUR DERIVED TRANSCRIPTION FACTOR." Thesis, 2018. http://dspace.dtu.ac.in:8080/jspui/handle/repository/16214.
Full textAbstract:
Natural killer (NK) cells were identified 30 years ago based on their ability to
"spontaneously" kill tumour cells. The NK cell recognition and activation is due to presence
of receptors that binds to specific ligands on tumour cells and normal cells. These receptors
have the ability to modulate and activate NK cell function. NK cell response is regulated by
the balance between the signals by activating and inhibitory receptors. The outcome of
immune response is determined by the extent of strength of activating and inhibitory signals.
The expressions of inhibitory receptor were found to be up regulating and activating receptor
is down regulating against tumour cell. Tumour cell had reported in escape NK mediated
recognition by down regulating the expression of ligands for activating receptors and over
expressing the ligand for inhibitory receptors. NK cell inhibitory function can be a means for
promotion and regression of tumour and exploring means of blockade of NK cell inhibitory
receptors is a way to promote immune response against tumour. Cancer therapies are being
developed based on preventing NK cell inhibition or activation of NK cell receptors and
modulation of T cell function. Transcription factors (TFs) are key molecules in the regulation of gene transcription and have a significant influence on immune cells growth and development. Many primary and modified genes leading to cancer, participate in many
pathways of NK cell development and maturation. Tumours are essentially tissues that have
overcome normal regulation mechanisms, and therefore the ability to distinguish normal cells
from abnormal cells is a key part of selectively attacking tumour cells. TF derived from tumour cells like GATA -3, ER β, Helios A, bind on the 5’UTR region of NK cell inhibitory
receptor genes and modulate their normal regulation by affecting their signaling pathways.
These tumour derived TF up regulate and down regulate the signaling of NK cell and
abnormalities in signaling pathway leads to progression of tumour cells. Understanding the
NK cell receptors and their recognition mechanisms provides new ways for the development
of immunotherapies against cancer.
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Ganey, John. "Determining the role of tumor-derived leukemia inhibitory factor in cancer cachexia using a genetic approach." Thesis, 2018. https://hdl.handle.net/2144/32732.
Full textAbstract:
Cachexia is a multifactorial metabolic wasting syndrome that affects a large percentage of cancer patients and results in the involuntary loss of skeletal muscle and adipose tissue. The consequences of this condition include metabolic imbalances and fatigue, which are strongly associated with poor prognosis. While the specific mechanism for skeletal muscle wasting is still undefined, LIF secreted by C26 colon carcinoma cells has recently be found to induce atrophy in treated myotubes. The purpose of this study is to determine the necessity of LIF for inducing atrophy in mouse myotubes by producing a knockout of Lif in C26 cells using CRIPSR-Cas9. Media was collected from these cells and used to treat myotubes. Measurements of myotube diameters were made and atrophy was compared between myotubes that received medium from C26 and C26Lif-/- cells. A dosage of recombinant mouse LIF was also added to LIF-deficient medium in order to determine if LIF alone was sufficient to induce atrophy. At study endpoint, myotubes that were treated with media taken from C26 cells showed significant signs of atrophy compared to myotubes that were treated C26Lif-/- media. LIF was also shown to be sufficient to induce myotube atrophy on its own, with atrophy being rescued in myotubes that received a dosage of LIF added to C26Lif-/- media. These results demonstrate that LIF is required for atrophy to be induced in mouse myotubes treated with media taken from cancer cells, and can do so independent of other secreted factors.
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WU, HAN-HSUAN, and 吳翰玄. "The Role of Stromal Cell-derived Factor 1 in Tumor Microenvironment Contributes to the Promotion of Colorectal Cancer." Thesis, 2016. http://ndltd.ncl.edu.tw/handle/28519976744342247148.
Full textAbstract:
碩士國防醫學院
病理及寄生蟲學研究所
104
Colorectal cancer (CRC) is one of the leading causes of cancer-related death worldwide. The prognosis of CRC is usually poor because of its propensity for extensive invasion, local recurrence and frequent regional lymph node metastasis. Researches have shown Carcinoma-associated fibroblasts (CAFs), a major type of tumor-surrounding stromal cell, generate mediators, such as Stromal Cell-Derived factor 1 (SDF-1), through which they interact with tumors and contribute to the progression and increase of stemness of cancer. The orchestration between CAFs and CRC cells is complex. Despite recent studies demonstrating the paracrine effect of stromal cells in the tumor microenvironment on initiation and progression of colorectal cancer cells, the major mediator related to CAFs and its underlying mechanism still remain unknown. Based on our present study, we found that the expression of SDF-1 and its receptor C-X-C chemo receptor type 4 (CXCR4) are stronger when co-cultured with CAFs than with NFs. In addition, ELISA assay also validates the presence of SDF-1 that is responsible for the crosstalk between fibroblasts and CRC cells via the paracrine effect. Furthermore, the mediator SDF-1 not only triggers epithelial-mesenchymal-transition (EMT), showing upregulation of EMT markers in RNA and proteins levels, but also improves the capabilities of migration and invasion. CRC cells treated with recombinant SDF-1, mimics the CAFs-CRC paracrine route, increased capabilities of sphere formation in ten days. To simulate SDF-1-induced autocrine signaling, we established stable clones of SDF-1-overexpressing CRC cells. Stable clone CRC cells exhibited the epithelial-mesenchymal-transition, increased mobility and upregulation of drug-resistant genes. In vivo study reconfirmed the functional role of SDF-1 in tumor initiation. Immunohistochemistry of tumor dissected from mouse confirmed that autocrined-SDF-1 enhances CSCs properties through different pathways than paracrine. Besides the paracrine signaling, we clearly verified that CAFs-induced SDF-1 reciprocally triggered cancer cells to produce SDF-1 in an autocrine manner, which resulted in the binding to CXCR4 and cancer progression. Further studies include evaluations of the mechanism of autocrine signaling. Meanwhile, validates in clinical patients. Our results verify that CAFs promote cancer invasiveness via paracrine and autocrine effects on microenvironmental SDF-1 signaling, and suggest that SDF-1 is a potentially biomarker which contributes to the expression of CSC properties, and may provide as a therapeutic option for improving prognosis in patients with CRC.
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Hu, Tsung-Hui, and 胡琮輝. "The prognostic role and cellular function of hepatoma-derived growth factor and tumor suppressor gene PTEN in hepatocellular carcinoma." Thesis, 2004. http://ndltd.ncl.edu.tw/handle/03058926542819168233.
Full textAbstract:
博士長庚大學
臨床醫學研究所
92
Hepatocellular carcinoma (HCC) is the most common and devastating malignant tumor in Taiwan. Transformation of hepatocytes to the malignant phenotype may be induced by chronic liver injury and regeneration, with genetic mutations. Increasing evidence suggests that additional oncogenes, tumor suppressor genes and certain growth factors (through the regeneration) were involved in the progression of hepatoma. In the present study, we set forth to explore the role of the newly identified growth factor, HDGF and tumor suppressor gene, PTEN in the pathogenesis of hepatocellular carcinoma Hepatoma-derived growth factor (HDGF) was originally isolated from the cultured media of human hepatoma cell line, HuH-7 cells. Previous studies indicated that HDGF participates in many cellular processes including astrocytes proliferation, renal development, vascular lesion formation, and cardiovascular differentiation. To explore the role of HDGF in the carcinogenesis of hepatocellular carcinoma (HCC), in vitro functional analysis in hepatoma cell lines and immunohistochemical studies on 105 HCC specimens were performed. We found that HDGF was upregulated in malignant hepatoma cell lines. Besides, malignant hepatoma cells exhibited higher mitogenic responses to exogenous HDGF, which might be attributed to their higher capability to uptake HDGF into nucleus. Immunohistochemical studies indicated that HDGF immunostaining was detected in nucleus and cytoplasm of hepatocytes and hepatoma cells in HCC specimens. The HDGF labeling index (LI) in hepatoma tissues were significantly higher than that in the adjacent non-tumor tissues (P < 0.05). Statistical analysis revealed that elevated nuclear HDGF LI correlated with HCC dedifferentiation (P = 0.033), absence of tumor capsules (P = 0.008), and high alpha-fetoprotein (a-FP) level (P = 0.045). Besides, the nuclear HDGF LI was strongly associated with that of proliferating cell nuclear antigen (PCNA) (P < 0.001). Kaplan-Meier analyses indicated that patients with high nuclear HDGF LI had poor survival and increased recurrence (P < 0.001). By multivariate analysis, nuclear HDGF LI is an independent prognostic factor for overall and disease free survival of HCC patients. To further explore the roles of HDGF in angiogenesis and tumorigenesis, recombinant HDGF was generated and shown to stimulate the proliferation and migration of human umbilical vein endothelial cells (HUVEC) in a dose-dependent manner. Besides, treatment of HUVEC with HDGF increased the secretion of matrix metalloproteinase-9 (MMP-9) by up to ten-fold. Implantation of hydron pellets containing HDGF induced dose-dependent neovascularization in rat corneas. Further, non-malignant NIH3T3 cells were transfected with HDGF expression vector and selected for HDGF-overexpressing stable clones. HDGF transfectants proliferated at a higher rate than that of NIH3T3 cells in serum-containing or -deprived media. Moreover, HDGF transfectants were capable of forming colonies in soft agar and inducing tumor formation when injected into nude mice. Histological analysis revealed prominent angiogenic and mitogenic activities in tumors derived from HDGF transfectants. Inactivation of tumor suppressor genes or activation of oncogens in HCC has been widely explored. The inactivation of tumor suppressor gene PTEN, located on chromosome 10q23, is a common event in advanced stage of diverse human cancers. Although the mutation rates of PTEN were low (< 5%) in HCC, there have been 20~30% allelic loss of chromosome 10q in HCC. However, the role of PTEN in HCC is not characterized yet. Analysis of PTEN expression in hepatoma cell lines revealed that loss of PTEN expression was found in one hepatoma cell line, Mahlavu cells. Restoration of PTEN expression resulted in significant reduction in colonies formation, proliferation and migration of Mahlavu cells, indicating that PTEN gene delivery suppressed tumorigenicity of hepatoma cells. Furthermore, adenoviral gene transfer of PTEN gene into Mahlavu cells also suppressed its tumor growth in nude mice. Immunohistochemical analysis of 105 HCC tissues revealed that decreased or absence of PTEN immunostaining was found in 43 (40.9%) cases. The reduced PTEN expression correlated with increased grades (P = 0.017), advanced stages (P = 0.016), and elevated serum alpha-fetoprotein (aFP) levels (P = 0.001). Kaplan-Meier analysis indicated that patients with reduced PTEN level had shorter overall survival (P = 0.001) and higher recurrence rates (P = 0.0007) than that of patients with intact PTEN expression. Examining p53 expression unveiled an inverse correlation between p53 overexpression and PTEN reduction in HCC patients (P = 0.004), implicating that PTEN inactivation frequently occurred in HCC with p53 mutation. Besides, patients with p53 overexpression had shorter overall survival comparing to that of patients without p53 overexpression (P = 0.0014). Finally, the univariate and multivariate analysis revealed that reduced PTEN expression and high nuclear HDGF are two independent prognostic factors for survival of HCC. In summary, the present study provided in vitro and in vivo evidences supporting that upregulation of HDGF and loss of PTEN expression participates in liver carcinogenesis. Both of them may hold potential for future treatment of HCC. The relationship between the two genes in HCC needs to be further elucidated.
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Kunder, Christian. "Interactions of Mast Cells with the Lymphatic System: Delivery of Peripheral Signals to Lymph Nodes by Mast Cell-Derived Particles." Diss., 2009. http://hdl.handle.net/10161/1307.
Full textAbstract:
Mast cells, best known for their pathologic role in allergy, have recently been shown to have key roles in the initiation of adaptive immune responses. These cells are located throughout the body just beneath barriers separating host from environment, possess multiple pathogen recognition systems, and store large quantities of fully active inflammatory mediators. These key features make them uniquely situated to act as sentinels of immunity, releasing the very earliest alarm signals when a pathogen is present. As a testament to the importance of these cells, mast cell-deficient mice have suboptimal immune responses, and mast cell activators can act as potent adjuvants for experimental immunizations. Specifically, mast cells have been shown to enhance the number of naive lymphocytes in infection site-draining lymph nodes, and to encourage the migration of dendritic cells to responding lymph nodes.
Although infections usually occur at peripheral sites, adaptive immune responses are initiated in distant lymph nodes. Despite the distance, signals from the site of infection result in dramatic, rapid reorganization of the node, including massive recruitment of naive lymphocytes from the circulation and extensive vascular restructuring to accommodate the increase in size. How such signals reach the lymph node is not well understood.
When mast cells degranulate, in addition to releasing soluble mediators such as histamine, they expel large, stable, insoluble particles composed primarily of heparin and cationic proteins. The work presented herein demonstrates that these particles act as extracellular chaperones for inflammatory mediators, protecting them from dilution into the interstitial space, degradation, and interaction with non-target host cells and molecules. The data show clearly that mast cells release such particles, that they are highly stable, that they contain tumor necrosis factor (a critically important immunomodulator), and that they can traffic from peripheral sites to draining lymph nodes via lymphatic vessels. Furthermore, extensive biochemical characterization of purified mast cell-derived particles was performed. Finally, evidence is presented that such particles can elicit lymph node enlargement, an infection-associated phenomenon that favors the development of adaptive immunity, by delivering peripheral TNF to draining lymph nodes.
This signaling concept, that particles may chaperone signals between distant sites, also has important implications for adjuvant design. The evidence presented here shows that encapsulation of TNF into synthetic particles similar to mast cell-derived particles greatly enhances its potency for eliciting lymph node enlargement, an indication that adaptive immunity may be improved. This delivery system should ensure that more adjuvant arrives in the draining lymph node intact, where it would lead to changes favorable to the development of the immune response. Such a system would also facilitate the delivery of multi-component adjuvants that would act synergistically at the level of the lymph node when gradually released from microparticle carriers. An additional advantage of microparticle encapsulation is that vaccine formulations of this type may require much lower doses of expensive antigen and adjuvants.
The delivery of inflammatory mediators to lymph nodes during immune responses may be an important general feature of host defense. Although the action of mediators of peripheral origin on draining lymph nodes has been described before, this is the first demonstration of a specific adaptation to deliver such mediators. Not only is the characterization of mast cell-derived particles important to basic immunology, but mimicking this adaptation may also lead to improved therapeutics.
Dissertation
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Sud, Reeteka. "Brain-derived tumor necrosis factor-alpha (TNF) mediates the antinociceptive effect of amitriptyline and modulates brain-body interactions during neuropathic pain." 2005. http://proquest.umi.com/pqdweb?did=888850581&sid=5&Fmt=2&clientId=39334&RQT=309&VName=PQD.
Full textAbstract:
Thesis (Ph.D.)--State University of New York at Buffalo, 2005.Title from PDF title page (viewed on May 12, 2006) Available through UMI ProQuest Digital Dissertations. Thesis adviser: Spengler, Robert N., Ignatowski, Tracey A. Includes bibliographical references.
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Su, Chin-Chuan, and 蘇金泉. "The stromal cell-derived factor-1(SDF-1) receptor, CXCR4 expression in oral squamous cell carcinoma and risk of tumor progression." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/02952770574830572553.
Full textAbstract:
碩士長榮大學
醫學研究所
100
Back ground: The oral cavity is one of the most common locations of squamous cell carcinoma in head and neck region. Oral cancer is ranked as the fourth leading cause of cancer death among males. Over the last decade, a significant rise in incidence and mortality of oral cancer has been noted in Taiwan, and in oral cancer there is largest increase in incidence rate and mortality rate among all cancers . In recent years, chemokines are found to be an important factor associated with tumor formation and metastasis. Moreover, it is recently reported that SDF-1 and its receptor CXCR4 are involved in tumor proliferation, neoangiogenesis, lymph node metastasis and distant dissemination. The purposes of this study were to investigate CXC chemokine receptor 4 (CXCR4) expression on oral squamous cell carcinoma and elucidate the association of CXCR4 receptor expression with clinicopathological factor and with the prognosis of survival of oral squamous cell carcinoma. Methods: From August 1999 to December 2007, patients with oral cancer treated with primary surgical approach in Changhua Christian Hospital were enrolled in this study. CXCR4 expression was evaluated by immunohistochemical staining using a tissue microarray (TMA) containing samples from 298 oral tumors. The association between CXCR4 expression and several clinicopathological factor, including tumor size, lymph node metastasis, distant metastasis, and survival were assessed. Results: A total of 289 consecutive patients (operated between August, 1999 and December 2007) with a median age of 55.5 (range 31 to 80) years were retrospectively evaluated. CXCR4 was expressed in 27.7% of oral primary tumor (80 of 289). The association between CXCR4 expression and several clinicopathological factors were evaluated. The expression of CXCR4 was associated with tumor size (P = 0.05), but not lymph node metastasis, distant metastasis or clinical stage. Cumulative survival was analyzed with the Kaplan–Meier method. There was also no statistical significance between CXCR4 and cumulative survival. Conclusion: Our study demonstrates that the CXCR4 receptor is expressed in 27.7% of oral tumor samples, and that this expression is associated with tumor progression (P=0.005). This finding confirms observations from previous preclinical studies that CXCR4 and its ligand, SDF-1 can modulate tumor cell proliferation and invasiveness.
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Haji, Mansor Muhammad. "Functionalized polymer implants for the trapping of glioblastoma cells." Thesis, 2019. http://www.theses.fr/2019ANGE0015.
Full textAbstract:
Le glioblastome (GBM) est la forme de cancer du cerveau la plus courante et la plus meurtrière. Sa nature diffusive entraine une impossibilité d’élimination complète par chirurgie. Une récidive de la tumeur chez ≥ 90% des patients peut être provoqué par des cellules GBM résiduelles se trouvant près du bord de la cavité de résection. Un implant pouvant libérer de manière durable la protéine SDF-1α, qui se lie aux récepteur CXCR4 à la surface des cellules GBM, peut être utile pour induire le recrutement des cellules GBM résiduelles, permettre leur élimination sélective et finalement réduire la récurrence de la tumeur. Dans ce travail, le SDF-1α a été initialement encapsulé dans des nanoparticules à base d'acide poly-lactique-co-glycolique (PLGA). Une efficacité d'encapsulation élevée (76%) a pu être obtenue en utilisant un processus simple de séparation de phase. Les nanoparticules chargées de SDF-1α ont ensuite été incorporées dans un scaffold à base de chitosan par électrofilage pour obtenir des implants nanofibreux imitant la structure de la matrice extracellulaire du cerveau. Une étude de libération in vitro a révélé que l'implant pouvait fournir une libération prolongée de SDF-1α jusqu'à 35 jours, utile pour établir un gradient de concentration de SDF-1α dans le cerveau et induire une attraction des cellules GBM. Une étude de biocompatibilité in vivo à 7 jours a révélé des signes d'inflammation locale sans aucun signe visible de détérioration clinique chez les sujets animaux. Une étude à 100 jours visant à confirmer l'innocuité in vivo des implants avant de passer aux études d'efficacité dans un modèle de résection GBM approprié est actuellement en coursGlioblastoma (GBM) is the most common and lethal form of brain cancer. The diffusive nature of GBM means the neoplastic tissue can not be removed completely by surgery. Often, residual GBM cells can be found close to the border of the resection cavity and these cells can multiply to cause tumor recurrence in ≥90% of GBM patients. An implant that can sustainably release chemoattractant molecules called stromal cell-derived factor-1α (SDF-1α), which bind selectively to CXCR4 receptors on the surface of GBM cells, may be useful for inducing chemotaxis and recruitment of the residual GBM cells. This may then give access to selective killing of the cells and ultimately reduce tumor recurrence. In this work, SDF-1α was initially encapsulated into poly-lactic-coglycolicacid (PLGA)-based nanoparticles. A high encapsulation efficiency (76%) could be achieved using a simple phase separation process. The SDF-1α-loaded nanoparticles were then incorporated into a chitosan-based scaffold by electrospinning to obtain nanofibrous implants that mimic the brain extracellular matrix structure. In vitro release study revealed that the implant could provide sustainedSDF-1α release for 5 weeks. The gradual SDF-1αrelease will be useful for establishing SDF-1α concentration gradients in the brain, which is critical for the chemotaxis of GBM cells. A 7-day in vivo biocompatibility study revealed evidence of inflammation at the implantation site without any visible signs of clinical deterioration in the animal subjects. A long-term study (100 days) aiming to confirm the in vivo safety of the implants before proceeding to efficacy studies in a suitable GBM resection model is currently underway