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1
Wake, Naomi Catherine. « Identification and functional analysis of a novel renal cell carcinoma (RCC) susceptibility gene from an RCC associated constitutional chromosomal translocation ». Thesis, University of Birmingham, 2013. http://etheses.bham.ac.uk//id/eprint/3964/.
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Familial renal cell carcinoma (RCC) only accounts for 3% of all RCC, yet the study of these inherited forms has provided important insights into the more common sporadic RCC. Somatic VHL inactivation is found in 70% of sporadic clear cell RCC (ccRCC) though is rarely found in other forms of RCC including papillary and chromophobe types. VHL-independent RCC tumourigenesis is poorly understood and current research involves identifying novel RCC candidate genes to further understand the mechanisms involved. In this study a constitutional balanced translocation, t(5;19)(p15.3;q12), associated with familial RCC was characterised using an oligonuleotide CGH array followed by genomic sequencing and the previously uncharacterised gene, UBE2QL1, was found to be disrupted by the 5p15.3 breakpoint. UBE2QL1 expression was down-regulated in 78.6% of sporadic RCC and UBE2QL1 promoter region hypermethylation and gene deletions were detected in 20.3% and 17.3% of sporadic RCC, respectively. Re-expression of UBE2QL1 in deficient RCC cell lines suppressed anchorage independent growth and colony formation. UBE2QL1 shows homology to the E2 class of ubiquitin conjugating enzymes and was shown to possess an active-site cysteine (C88) that is monoubiquitinated in vivo. In addition, UBE2QL1 co-immunoprecipitation and co-localisation studies demonstrated a protein interaction with FBXW7 (an F box protein for the SCF E3 ubiquitin ligase) and was shown to facilitate the degradation of the known FBXW7 substrates, cyclin E1 and mTOR. These findings demonstrate that UBE2QL1 functions as a novel renal tumour suppressor gene and ubiquitin conjugating enzyme.
2
Malouf, Gabriel. « Décryptage des changements épigénétiques impliqués dans la transition épithélio-mésenchymateuse et le cancer ». Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T037.
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La transition épithélio-Mésenchymateuse (TEM) est un processus de plasticité cellulaire qui existe dans le développement embryonnaire et qui permet la formation des tissus et organes. Dans la cancérogénèse, ce processus est réactivé par des facteurs de transcription dont l’action implique très probablement un remodelage de la chromatine. La cartographie exacte de ces changements épigénétiques est peu connue à l’échelle du génome entier, même si il y a eu quelques études antérieures explorant les changements de quelques loci de façon bien ciblée. Ce mémoire traite du remodelage épigénétique médié par le facteur de transcription Twist1 dans un modèle de lignée mammaire immortalisée. L’architecture de ce remodelage a été cartographiée grâce à l’utilisation des techniques de haut-Débit pour analyser la méthylation de l’ADN (DREAM) et les modifications des histones (ChIPseq). Nos résultats montrent un changement majeur du méthylome pendant la TEM avec une hyperméthylation focale et une hypométhylation globale des corps des gènes prédominant au niveau des « domaines partiellement méthylés »; ces domaines sont déjà connus dans le développement pour gagner de façon concomitante à leur hypométhylation des marques d’histone répressives. Nous avons aussi observé un remodelage des domaines de l’histone répressive H3K27me3 avec une réduction de leur taille, et surtout le quasi doublement du nombre de gènes bivalents qui accompagne la transition. Le couplage de la méthylation de l’ADN avec le profil des microRNA nous a permis d’identifier le miR-203 comme l’unique microRNA régulé par méthylation de l’ADN durant la TEM; nous avons aussi montré que l’extinction épigénétique du miR-203 est requise pour la TEM et l’acquistion des propriétés de cellules souches. Enfin, nous avons réalisé une caractérisation génétique et/ou épigénétique de deux cancers rares, les carcinomes fibrolamellaires du foie et les carcinomes du rein à translocation. Pour les carcinomes fibrolamellaires du foie, nous avons décrit la nature endocrine de cette tumeur et établi une signature épigénétique basée sur la méthylation de l’ADN pouvant servir à différencier les formes histologiques appelées « pures » des formes « mixtes ». Pour les cancers du rein à translocation, nous avons montré les bases génétiques et épigénétiques de la différence entre les formes pédiatriques et adultes, avec la découverte fréquente du gain du bras chromosomique 17q dans les formes adultes. Nous avons aussi identifié une mutation récurrente dans le gène qui remodèle la chromatine INO80D appartenant à la famille INO80. En conclusion, ce travail explore le rôle de l’étude de l’épigénome pour comprendre la reprogrammation pendant les processus physiologiques comme la TEM d’une part et le cancer d’autre partThe epithelial-Mesenchymal transition (EMT) is a process of cellular plasticity that exists in embryonic development and which allows the formation of tissues and organs. In carcinogenesis, the process is reactivated by transcription factors whose action probably involves chromatin remodeling. The exact mapping of these epigenetic changes is poorly understood genome-Wide, although there have been some previous studies exploring changes in so few well-Targeted loci. This thesis deals with the epigenetic remodeling mediated by the transcription factor Twist1 in a model of human mammary immortalized cell line. The architecture of this remodeling has been mapped through the use of high-Throughput techniques to analyze DNA methylation (DREAM) and histone modifications (ChIPseq). Our results suggest a major change in the EMT methylome with focal hypermethylation and gene body hypomethylation predominantly within "partially methylated domains"; these areas are already known in development to gain repressive histone marks concomitantly with DNA hypomethylation. We also observed landscape remodeling of repressive histone mark H3K27me3 with a reduction in domains size, and especially the almost doubling of the number of bivalent genes. The coupling of DNA methylation with the profile of microRNA has allowed us to identify miR-203 as single microRNA regulated by DNA methylation during EMT; we have also shown that epigenetic suppression of miR-203 is both required for EMT and acquisition of stem cell properties. Finally, we performed a genetic and/or epigenetic characterization of two rare cancers, named fibrolamellar hepatocellular carcinomas and translocation renal cell carcinomas. In fibrolamellar hepatocellular carcinoma, we described the endocrine nature of this tumor and established a signature based on DNA methylation which can be used to distinguish histological forms called "pure" from "mixed" fibrolamellar hepatocellular carcinomas. Regarding translocation renal cell carcinomas, we established the genetic and epigenetic basis of differences between pediatric and adult forms, characterized by frequent gain of 17q gain chromosomal arm in adults. We also identified recurrent mutations in the chromatin remodeling gene INO80D which belongs to INO80 family. In conclusion, this work explores the impact of analyzing the epigenome to understand reprogramming during physiological processes such as EMT and cancer
3
Rashidkhani, Bahram. « Diet and renal cell carcinoma / ». Stockholm, 2005. http://diss.kib.ki.se/2005/91-7140-163-6/.
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4
Fallah, Abdul Karim. « Genomic studies in renal cell carcinoma ». Thesis, Manchester Metropolitan University, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.528380.
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5
Al-Sharhan, Mouza Abdulla. « Prognostic factors in renal cell carcinoma ». Thesis, University of Newcastle Upon Tyne, 1999. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.285788.
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6
Chagnon, Fanny. « A dendritic cell vaccine for murine renal cell carcinoma ». Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=19400.
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Renal Cell Carcinoma (RCC) has a very high rate of mortality since it does not respond to conventional therapies such as chemotherapy and radiation therapy. Furthermore, in the majority of cases, metastases are already present at the time of diagnosis. The objective of our study is to develop a noval treatment for RCC, using a dendritic cell (DC) vaccine. An animal model of RCC, RENCA, was used to develop the vaccine.
7
Giraldo-Castillo, Nicolas. « The Immune Microenvironment in Clear Cell Renal Cell Carcinoma : The heterogeneous immune contextures accompanying CD8+ T cell infiltration in clear cell Renal Cell Carcinoma ». Thesis, Paris 6, 2015. http://www.theses.fr/2015PA066321/document.
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Dans cette étude, nous avons tenté de décrypter les mécanismes reliant l’augmentation de lymphocytes infiltrant les tumeurs (LIT) T CD8+ et un pronostic clinique défavorable dans le cancer du rein à cellules claires (ccRCC). Pour cela, nous avons déterminé 1) la relation entre le pronostic associé à l'expression d’immune checkpoints et l’infiltrat de cellules dendritiques (DC) et de LT CD8+ et 2) les caractéristiques phénotypiques des LIT T CD8+. L’expression des immune checkpoints a été déterminée par immunohistochimie dans une cohorte de 135 ccRCC. Nous avons constaté que les densités des cellules exprimant CD8, PD-1 et LAG-3 sont corrélées, et associées à une diminution de PFS et OS. Egalement, les patients dont les tumeurs présentent des densités élevées de cellules PD-1+ et PD-L1 et/ou PD-L2 +, ont le taux de survie le plus faible. Des densités élevées de DC immatures isolées dans le stroma tumoral sont associées à une forte expression d’immune checkpoints et à un faible taux de survie chez ces patients. En revanche, les patients présentant un taux de survie prolongé ont une densité élevée de lymphocytes CD8+, des DC matures au sein de structures lymphoïdes tertiaires, ainsi qu’une faible expression d’immune checkpoints. Nous avons analysé les LIT T CD8+ chez 21 patients ccRCC par Cytométrie de Flux. On a trouvé un groupe de patients (8/21) dont les tumeurs sont caractérisées par la surexpression de marqueurs inhibiteurs (PD1 et TIM3) et de d'activation (CD69 et CD38), par l'expansion des cellules T CD8 + mémoires effectrices et un plus grand potentiel d’agressivité. En résumé, nous avons démontré qu’une densité élevée de LIT T CD8+ dans les ccRCC est accompagnée d’une forte expression d’immune checkpoints et d’une réponse immunitaire mal coordonnée dans un sous-groupe de tumeurs agressivesTo decipher the potential mechanisms linking increased CD8+ T cell infiltration with an adverse clinical outcome in ccRCC, in this study we determined: 1) the prognosis associated with the expression of immune checkpoints and its coordination with dendritic cell (DC) and CD8+ cell infiltration, and 2) the phenotypic traits of CD8+ tumor infiltrating lymphocytes. The prognosis associated with CD8+ and DC infiltrations, in addition to the expression of immune checkpoints were investigated in a cohort of 135 ccRCC by quantitative immunohistochemistry. We found that the densities of CD8+, PD-1+ and LAG-3+ cells were closely correlated, and independently associated with decreased PFS and OS. In addition, patients whose tumors presented both high densities of PD-1+ cells and PD-L1+ and/or L2+ tumor cells, displayed the worst clinical outcome. High densities of immature DC isolated in the tumour stroma were associated with high expression of immune checkpoints and patients’ poor clinical outcome. In contrast, the presence of mature DC within Tertiary Lymphoid Structures identified, among the tumours with high CD8+-TIL densities, those with low expression of immune checkpoints and prolonged survival. We also investigated the phenotype of freshly isolated CD8+TIL in 21 ccRCC by flow cytometry. We found a group tumors (8/21) characterised by the over-expression of inhibitory (PD-1 and TIM-3) and activation markers (CD69 and CD38), the expansion of the effector memory cell subpopulation (CCR7-CD45RA-), and a trend toward more aggressive features. In summary, we demonstrated that the infiltration with CD8+ TIL in ccRCC is accompanied by the enhanced expression of immune checkpoints and a poorly coordinated immune response in a subgroup of aggressive tumors
8
Ronkainen, H. L. (Hanna-Leena). « Novel prognostic biomarkers for renal cell carcinoma ». Doctoral thesis, Oulun yliopisto, 2012. http://urn.fi/urn:isbn:9789514297731.
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Abstract Background and aims: Stage and grade are the most widely used prognostic parameters for renal cell carcinoma (RCC). The clinical course of this disease is not, however, always predictable by traditional prognostic factors. In the era of new molecular targeted therapies a more accurate prognostication of RCC patient survival is important for the individualization of treatment and follow-up of patients. Despite exhaustive research there are still no prognostic biomarkers for RCC in clinical practice. In order to find novel prognostic tissue markers for RCC, we examined the expression of 14 biomarkers involved in carcinogenesis and clarified their prognostic significance in RCC. Material and methods: Out of 189 consecutive patients who underwent surgery for kidney cancer at Oulu University Hospital in the 1990s, 152 patients with histologically verified RCC were included in this study. The stage distribution was 70 (46%), 12 (8%), 51 (34%) and 19 (12%) patients with stages I-IV, respectively. The majority of the tumours (83 tumours, 55%) were nuclear grade II and 5 (3%), 40 (27%) and 22 (15%) of the tumours were grades I, III and IV, respectively. Clinical and follow-up data were obtained from patient records, the Finnish Cancer Registry and on demand from the Population Register Centre of Finland. The biomarkers studied included markers of the oxidative and neuroendocrine systems as well as proteins related to cell adhesion and migration, invasion, metastasis, inflammation and immune responses. The expression of various biomarkers was characterized via immunohistochemical tests of archival tumour material. The staining intensity was compared to clinicopathological parameters and patient RCC-specific survival. Results: The 5-year RCC-specific survival was 77%. The expression of Toll-like receptor 9 (TLR9) was an independent marker of favourable RCC-specific survival whereas cytoplasmic myosin VI expression was found to be an independent prognostic factor of poor RCC-specific survival. Cell culture experiments showed how cyclooxygenase-2 (COX-2) expression is regulated by HuR in RCC. HuR and COX-2 immunoexpression were also related to decreased RCC-specific survival. Immunostaining of Keap1 was associated with advanced RCC and a marker of a poorer RCC-specific prognosis. The expression of different neuroendocrine markers was evaluated but we could not establish any prognostic value for them. Conclusions: In particular, TLR9, HuR and myosin VI can be regarded as promising novel prognostic biomarkers in RCC. Stage, however, is the most important single prognostic factor for RCCTiivistelmä Munuaissyöpä on vuosikymmenten ajan jatkuvasti yleistynyt. Vaikka se diagnosoidaan nykyisin useimmiten sattumalöydöksenä vatsan alueen kuvantamistutkimuksissa ja hoitomenetelmät ovat viime vuosikymmenten aikana kehittyneet, munuaissyöpäkuolleisuus ei ole laskenut. Munuaissyövän ennusteen määrittäminen voi olla haasteellista. Perinteiset ennustetekijät, levinneisyys ja erilaistumisaste, eivät riitä selittämään kaikkien potilaiden taudinkulkua, eikä munuaissyövälle vielä ole kliinisessä käytössä ennusteellista merkkiainetta. Munuaissyöpähoitojen kehittyessä taudinkulun ennustaminen on yhä tärkeämpää, jotta potilaiden hoito ja seuranta voidaan yksilöidä. Tämän väitöskirjatyön tarkoituksena oli etsiä uusia ennusteellisia kudosmerkkiaineita munuaissyöpäkasvaimille. Väitöskirjatutkimus perustuu 1990-luvulla Oulun yliopistollisessa sairaalassa leikatun 152 munuaissyöpäpotilaan aineistoon. Lähes puolet aineiston kasvaimista edusti levinneisyysluokkaa I, ja yli puolet munuaissyöpäkasvaimista oli hyvin erilaistuneita (tumagradus I ja II). Tutkimuspotilaista kerättiin kattavat seurantatiedot. Leikkauksessa poistettujen munuaissyöpäkasvainten arkistomateriaalista tutkittiin eri merkkiaineiden ilmenemistä. Tutkitut merkkiaineet käsittivät oksidatiivisen ja neuroendokriinisen järjestelmän merkkiaineita sekä valkuaisaineita, jotka liittyvät keskeisiin syövän ominaisuuksiin, kuten solujen välisiin liitoksiin ja solujen liikkumiseen sekä etäpesäkkeiden syntymiseen. Lisäksi tutkittiin merkkiaineita, jotka liittyvät tulehdusreaktioihin ja immuunipuolustukseen. Väitöskirjatutkimus paljasti useita uusia kudosmerkkiaineita, joiden ilmeneminen munuaissyöpäkasvaimessa on yhteydessä potilaan ennusteeseen. Näistä merkittävimpiä ovat myosiini VI, joka liittyy syöpäkasvainten metastasointiin, sekä immuunipuolustuksessa vaikuttava Tollin kaltainen reseptori 9 (Toll-like receptor 9, TLR9). Molemmat merkkiaineet osoittautuivat itsenäisiksi ennustetekijöiksi munuaissyövässä. Muita ennusteeseen vaikuttavia merkkiaineita ovat tutkimuksen mukaan oksidatiivista stressiä aistiva Keap1 sekä immunologisiin reaktioihin liittyvä syklo-oksigenaasi 2 (COX-2) ja sen ilmenemistä säätelevä HuR
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Lawrentschuk, Nathan Leo. « Hypoxia and angiogenesis in renal cell carcinoma ». Connect to thesis, 2009. http://repository.unimelb.edu.au/10187/6790.
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Hypoxia is one of the hallmarks of cancer. It was first postulated to occur in solid tumours by Thomlinson and Gray in 1955.1 The presence of hypoxia has been demonstrated in different types of solid tumours.2 Intratumoral hypoxia is caused by the lack of functional blood vessels in proliferating tumour tissue, resulting in low intratumoral oxygen concentrations. If hypoxia is severe or prolonged, cell death occurs.3 Malignant cells can undergo genetic and adaptive changes that allow them to escape from dying of oxygen deprivation. These changes are associated with a more aggressive malignant phenotype 4,5 conferring resistance to radiation 6,7 and chemotherapeutic agents.3,8,9 Hence hypoxia is known to be a key factor responsible for tumour resistance in humans.Invasive polarographic oxygen sensor measurements have demonstrated hypoxia in solid tumours and it is generally defined to occur at an oxygen tension less than ten mmHg.10 Perhaps of more importance is that hypoxia has been demonstrated to be a prognostic indicator for local control after treatment with radiotherapy in glioma, head and neck and cervical cancers.11-13 It has also been able to predict for survival and the presence of distant metastases in soft tissue sarcomas.14 Finally, the significance of hypoxia in the activation and induction of functional molecules such as hypoxia inducible factors (HIFs) and VEGF, the modulation of gene expression (e.g. carbonic anhydrase IX), increased proto-oncogene levels, activation of nuclear factors and accumulation of other proteins (e.g. TP53) although progressing, is yet to be defined.15,16
Thus, it is of clinical interest to understand the levels of hypoxia and numbers of hypoxic cell populations in tumours, particularly those resistant to radiation and chemotherapy. In doing so clinicians and researchers may formulate more accurate prognostic information and develop treatments targeting hypoxic cells. Renal cell carcinoma (RCC) is a tumour resistant to radiation and chemotherapy that is yet to have its oxygen status investigated.
Although the “gold standard” of oxygen tension measurement is the Polarographic Oxygen Sensor (POS or Eppendorf pO2 histograph), non-invasive means of measuring oxygen status via imaging, immunohistochemistry or serum tumour markers are more practical. As highlighted by Menon and Fraker, it is imperative that reliable, globally usable, and technically simplistic methods be developed to yield a consistent, comprehensive, and reliable profile of tumour oxygenation. Until newer more reliable techniques are developed, existing independent techniques or appropriate combinations of techniques should be optimized and validated using known endpoints in tumour oxygenation status and/or treatment outcomes.17
Hanahan and Weinberg 18 surmised that the field of cancer research has largely been guided by a reductionist focus on cancer cells and the genes within them- a focus that has produced an extraordinary body of knowledge. Looking forward in time, they believe that progress in cancer research would come from regarding tumours as complex tissues in which mutant cancer cells have conscripted and subverted normal cell types (endothelial cells, immune cells, fibroblasts) to serve as active collaborators in their neoplastic agenda. The interactions between the genetically altered malignant cells and these supporting coconspirators will prove critical to understanding cancer pathogenesis and to the development of novel, effective therapies.18
Essentially, the background outlined here not only highlights the core aim of this thesis: to better understand the oxygen status of renal cell carcinoma and the relationship of this to angiogenesis so that better targeted therapies may be pursued in the future; but it also places this research in the context of the future proposed by Hanahan and Weinberg,18 by clearly focusing on collaborators in the neoplastic agenda, rather than just tumour cells themselves, to better understand RCC.
10
Morrissey, Catherine. « The molecular pathology of renal cell carcinoma ». Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.420407.
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11
Laird, Alexander. « Molecular prognostic markers in renal cell carcinoma ». Thesis, University of Edinburgh, 2015. http://hdl.handle.net/1842/17873.
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Renal cell carcinoma (RCC) is the most deadly of urological malignancies. While metastatic disease affects one third of patients at diagnosis, a further third of patients who undergo extirpative surgery with curative intent subsequently develop metastatic disease. Inconsistency in the clinical course ensures predicting subsequent metastasis is notoriously difficult, despite the routine use of prognostic clinico-pathological parameters in risk stratification. With greater understanding of pathways involved in disease pathogenesis, a number of biomarkers have been proposed to be of prognostic significance; however there are currently no molecular prognostic markers in clinical use. Genetic intra-tumoural heterogeneity (genetic ITH) has been described in clear cell RCC (ccRCC) and may limit the clinical translation of biomarkers. There has been no assessment of ITH at other molecular levels. The aim of this work was to define and compare proteomic, transcriptomic and DNA methylation ITH in ccRCC, and identify potential prognostic biomarkers. Using reverse phase protein arrays to study protein expression in multiple spatially separate regions of primary and metastatic ccRCC, proteomic ITH was demonstrated for the first time. Interestingly there was no significant difference in proteomic ITH in metastatic ccRCC tumour deposits compared to primary tumours. However, on analysis of differential protein expression between primary and metastatic ccRCC tissue using a tissue microarray and automated analysis of immunofluorescence, there was significantly greater expression of Ki67, p53, VEGFR1, SLUG and SNAIL in the metastases compared to the primary tumours. Subsequent profiling of gene expression and DNA methylation in multiple areas of the same primary tumours confirmed transcriptomic and methylomic ITH. On comparison of this multimolecular ITH, significantly greater proteomic ITH was seen compared to gene expression and DNA promoter methylation heterogeneity. Recent evidence suggests DNA methylation may be prognostically important in RCC and given the lower methylomic ITH in ccRCC, the identification of prognostic DNA methylation changes in ccRCC were pursued using the Infinium HumanMethylation450K Beadchip. Following development of an analysis pipeline, identification and validation of prognostic differentially methylated regions (DMR) was performed on an experimental cohort and published dataset respectively. Five DMRs, which were associated with disease recurrence in ccRCC, were identified. NEFM gene promoter methylation was the only DMR associated with cancer specific survival, independent of TNM stage and nuclear grade on multivariate analysis, which was confirmed on a third independent published dataset. This thesis therefore demonstrates multi-molecular ITH in ccRCC for the first time. Despite this, NEFM promoter methylation may be a useful independent prognostic marker of cancer specific survival.
12
Griffiths, Richard Wyn. « Strategies for the adoptive cell therapy of renal cell carcinoma ». Thesis, University of Manchester, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.503835.
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Lidgren, Anders. « Hypoxia inducible factor-1α in renal cell carcinoma ». Doctoral thesis, Umeå universitet, Kirurgisk och perioperativ vetenskap, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1462.
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Hypoxia Inducible Factor-1α in Renal Cell Carcinoma Departments of Surgical and Perioperative Sciences, Urology and Andrology; Radiation Sciences, Oncology; Medical Biosciences, Pathology; and Medical Biosciences, Clinical Chemistry, Umeå University, Umeå, Sweden Background: Renal cell carcinoma (RCC) accounts for approximately 2-3% of all human cancers. A distinguished feature of RCC is vascularisation and among the three dominating RCC types conventional RCC (cRCC) generally is more vascularised than papillary RCC (pRCC) and chromophobe RCC (chRCC). Angiogenesis is a critical step in tumour progression controlled by a balance involving molecules that have positive and negative regulatory activity. A balance distorted by metabolic stress such as hypoxia, acidosis, and inflammation. Hypoxia-Inducible Factor 1α (HIF-1α) is a key transcription factor in angiogenesis and tumour progression, targeting more than a 100 genes involved in vascular growth and regulation, iron metabolism and erythropoesis, collagen matrix formation, regulation of extracellular pH, glucose uptake and metabolism, proliferation, apoptosis, differentiation, and cell viability. Methods: Tumour tissue and corresponding kidney cortex from nephrectomised RCC patients was used in order to characterize HIF-1α expression and one of its target genes, Glucose Transporter 1 (GLUT-1). All tumour samples were thoroughly described regarding tumour type, TNM stage, nuclear grade, tumour size, vein invasion, and patient survival. Utilizing RT-PCR, Westen Blot and Tissue micro array (TMA) we studied HIF-1α mRNA and protein expression as well as GLUT-1 protein expression, correlating them to each other and clinicopathological parameters. Results: Using Western Blot, HIF-1α protein expression differed significantly between the different RCC types and kidney cortex. In cRCC, high expression of HIF-1α was an independent prognostic factor for favourable prognosis. TMA is a useful method to analyze HIF-1α protein expression in RCC. HIF-1α levels were significantly lower in locally aggressive cRCC and patients with high levels of HIF-1 tended to have a better prognosis. GLUT-1 levels were higher in cRCC than in other RCC types and for cRCC a correlation to HIF-1α was seen. HIF-1α mRNA levels were significantly lower in cRCC compared to other RCC types and kidney cortex. An inverse correlation between HIF-1α protein expression and mRNA levels was observed. Summary: These results demonstrate a discrepancy between RCC types, highlighting the need to separately evaluate biological events in different RCC types. Overexpression of HIF-1α protein is not necessarily all bad and translational regulation appears more critical than anticipated. Further studies are encouraged to clarify angiogenic pathways in RCC.
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Menezes, Ravi. « Physical activity and risk of renal cell carcinoma ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0020/MQ53351.pdf.
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Jacobsen, Jan. « Vascular endothelial growth factor in renal cell carcinoma ». Doctoral thesis, Umeå : Kirurgisk och perioperativ vetenskap, 2006. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-713.
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Alimov, Andrei. « Molecular genetic aspects of renal cell carcinoma development / ». Stockholm, 2003. http://diss.kib.ki.se/2003/91-7349-559-X/.
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Ibraheem, K. « The role of CD40 in regulating renal cell carcinoma cell fate ». Thesis, University of Huddersfield, 2018. http://eprints.hud.ac.uk/id/eprint/34515/.
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CD40 is a member of the TNF receptor (TNFR) superfamily and its expression by a variety of cell types including tumour cells has suggested a possible role for CD40 in epithelial homeostasis and potentially in the pathogenesis of cancer. CD40 ligation by membrane-presented CD40L (mCD40L), but not soluble agonists, causes extensive apoptosis in malignant epithelial cells, including bladder and colorectal cancer cells, while sparing their normal counterparts. However, the role of CD40 in renal cell carcinoma (RCC) is relatively unknown and the effect of CD40 ligation in RCC cells has not been studied previously. This thesis aimed to investigate the effect of CD40 ligation in RCC cells, compare this to their normal counterparts (HRPT cells), and identify the mechanisms of CD40-mediated effects. The experimental work described in this thesis involved optimisation of assays for the detection of cell death (based on loss of plasma membrane integrity, DNA fragmentation and caspase activation) and for the detection of pro-inflammatory cytokine secretion. Immunoblotting techniques were adapted for a co-culture system to deliver mCD40L for detection of key intracellular CD40 signalling-associated mediators. Optimisation was also carried out for functional experiments using pharmacological inhibitors of intracellular mediators and caspases and for the detection of reactive oxygen species (ROS). Expression of CD40 by RCC cells was detected in RCC lines and in their normal counterparts HRPT cells and treatment with IFN-ɣ up-regulated CD40 expression in RCC cells. Cytotoxicity assays showed for the first time that mCD40L induced massive apoptosis in human RCC cells which further increased in the presence of IFN-ɣ, whereas it caused no cytotoxic effect in their normal counterparts (HRPT cells). By contrast, the G28-5 mAb did not cause death in RCC cells, and combination of IFN-ɣ with cross-linked G28-5 antibody did not render the G28-5 antibody significantly pro-apoptotic. Moreover, induction of cell death by mCD40L was accompanied by caspase-3/7 activation and DNA fragmentation in RCC cells, while mCD40L did not induce detectable DNA fragmentation in normal HRPT cells indicating that mCD40L triggered “apoptotic” cell death in RCC cells and in a tumour cell-specific fashion. ELISA assays showed that mCD40L induced marked secretion of IL-8 and IL-6 in RCC cells, which was stronger than that triggered by soluble agonist. More importantly, mCD40L induced GM-CSF secretion in RCC cells, but soluble agonist caused little GM-CSF release. In normal HRPT cells mCD40L caused secretion of IL-8 and IL-6 and a more pronounced secretion of GM-CSF, when it was compared to agonistic G28-5 mAb, confirming that CD40 on HRPT cells was functional despite being non-apoptotic. mCD40L triggered rapid induction of TRAFs 1, 2, 3 and 6 as early as 1.5h post CD40 ligation in RCC cells. By contrast, despite up-regulation of TRAF1 at 6h post CD40 ligation, in normal HRPT cells mCD40L down-regulated TRAF2 expression and caused no induction in TRAF3 expression. In addition, CD40-mCD40L interactions in RCC cells triggered MKK4/7 activation and downstream phosphorylation of both JNK and p38. Functional inhibition experiments demonstrated that JNK and p38 phosphorylation was essential in CD40-mediated apoptosis in RCC cells, and suggested that activation of p38 may be dependent on JNK activity. By contrast, inhibition of MEK1/2 and NF-кB did not alter CD40-mediated apoptosis in RCC cells, whilst inhibition of AP-1 caused moderate (not complete) reduction in apoptosis. This study demonstrated that induction of Bak and Bax occurred by 6h post CD40 ligation in RCC cells. Inhibition of caspase-9 significantly attenuated CD40-mediated apoptosis in RCC cells, while caspase-8 and 10 inhibition caused non-significant effects whilst no induction of death ligands was detectable, suggesting that CD40-induced apoptosis in RCC cells occurs via a direct, intrinsic apoptotic pathway. mCD40L triggered ROS production in RCC cells within 1h post CD40 ligation and ROS production were critical in the induction of death, as apoptosis was inhibited by the antioxidant NAC. Moreover, mCD40L triggered phosphorylation of the NOX subunit p40phox and the NOX inhibitor DPI attenuated apoptosis suggesting that a ROS-dependent NOX-triggered pathway may occur in RCC cells. By contrast, non-apoptotic CD40 agonist (G28-5 mAb) did not induce ROS production in RCC cells. Equally importantly, mCD40L caused rapid ASK-1 phosphorylation and down-regulated Trx-1 expression in all RCC lines. Collectively, this study has for the first time reported that mCD40L induced extensive apoptosis in RCC cells while sparing their normal cell counterparts. However, agonistic anti-CD40 antibody G28-5 did not cause cell death in RCC cells. Although additional functional experiments would be necessary to fully elucidate the functional mechanisms of apoptosis, it appears that CD40-mediated killing in RCC cells occurs via a TRAF3-p40phox-ASK-1-MKK4/7-p38/JNK pathway leading to caspase-9 and effector caspase-3/7 activation and intrinsic apoptosis. Importantly, whilst increasing ROS levels in RCC cells, mCD40L actively down-regulated Trx-1 expression. These findings have provided novel observations on the role of CD40 in regulating human RCC cell fate, and have also reinforced the importance of the quality of CD40 signal in determining functional outcome. Equally importantly, the findings have also assisted in the formulation of novel therapeutic avenues that may exploit CD40 for anticancer therapy and specifically for renal cell carcinoma.
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Handa, Kiren. « Dietary patterns and the risk of renal cell carcinoma ». Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1999. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp04/mq45404.pdf.
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Young, Alison Claire. « Significance of VHL changes in sporadic renal cell carcinoma ». Thesis, University of Leeds, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.581867.
Texte intégralRésumé :
The von Hippel-Lindau (VHL) tumour suppressor gene is central to the development of sporadic conventional clear cell renal cell carcinoma (ccRCC). The role VHL plays as part of a ubiquitin ligase targeting HIF-a for proteasomal degradation underpins many changes seen in ccRCC but the importance of other VHL functions and the clinical significance of specific genetic/epigenetic changes are not clear. Genetic and epigenetic analysis of VHL gene in 86 tumours from patients with ccRCC was carried out, adding to the 96 tumours already analysed in an ongoing study within the group. Overall, loss of heterozygosity (LOH) was found in 89.2%, mutation in 74.6% and methylation in 30.9%. Evidence of biallelic inactivation (LOH and mutation or methylation alone) was "found in 84.9% whilst no involvement of VHL was found in only 4% of samples, consistent with VHL involvement in the majority of conventional ccRCCs. Associations between mutation and gender (p=0.0189), LOH and grade (p=0.0097) and methylation and grade (p=0.0159) were found with a possible association between methylation and gender (p=0.0835). There was a suggestion of LOH and mutation correlating with a better overall survival compared to patients with no VHL involvement and a similar relationship was seen with methylation; however sample numbers were small in the no VHL group and neither reached statistical significance.
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Chen, Dong. « Identification of new prognostic markers in renal cell carcinoma ». Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-168397.
Texte intégralRésumé :
The clinical course of renal cell carcinoma (RCC) shows a high variability. Prognostic markers are essential to enable an individualized therapeutic strategy. The objective of this study was the identification of novel independent prognostic markers and potential therapeutic targets in RCC. The focus was on genes involved in epithelial-mesenchymal transition (EMT) and cancer stem cell biology.
EMT enhances tumor cell motility and hence plays a critical role in invasion and metastasis in various carcinomas. A set of transcription factors acts as master regulators of EMT. Whether EMT is important for tumor progression in clear cell renal cell carcinoma (RCC) is unknown. Therefore, EMT-related genes were selected from the literature, and their role and prognostic relevance in RCC were analyzed. The known cancer stem cell marker CXCR4 and the associated TPBG gene were also analyzed in this project. Additionally, a novel filter strategy was used to analyze RCC oligonucleotide microarray data for identification of potential prognostic markers: genes with increasing expression during tumor progression (normal kidney < primary tumor < metastases) were selected for outcome analysis because they could be crucial for RCC biology.
Expression of 46 EMT-related genes was analyzed using oligonucleotide microarrays and gene set enrichment analysis (GSEA) in tissue samples from normal kidney and G1 and G3 primary RCC, 14 samples each. Expression of selected EMT genes was validated by real-time polymerase chain reaction (PCR) in normal kidney, primary RCC and metastases in an independent cohort of 112 patients and then combined with follow-up data for survival analysis. Immunohistochemistry, Western blot and flow cytometry were performed to further examine the expression of CXCR4 and co-expression of CXCR4 and TPBG on the surface of RCC cells. GSEA and dChip software were used for microarray data analysis.
The EMT gene set was preferentially expressed in primary tumors compared to normal tissue (false discovery rate FDR=0.01), but no difference between G1 and G3 tumors was found. Quantitative RT-PCR showed down-regulation of critical EMT genes like CDH2 and ZEB1 in metastases which suggests reversal of EMT during metastasis. Kaplan-Meier analysis demonstrated a significant better outcome for patients with low CXCR4, vimentin, fibronectin and TWIST1 mRNA levels. Multivariate analysis revealed that CXCR4 and vimentin up-regulation represent independent prognostic markers for poor cancer-specific survival of RCC patients. The microarray approach using filtering and further RT-PCR validation of progression-associated genes revealed that ATAD2, TET3, HELLS and TOP2A are independent and previously unknown predictors of poor outcome in RCC patients.
Taken together, this study provides strong evidence that EMT occurs in RCC. Modulation of EMT in RCC, therefore, might represent a future therapeutic option. Expression levels of a number of EMT-related genes (like the genes encoding the cancer stem cell marker CXCR4 and vimentin) could be identified as independent prognostic markers. Using a novel filtering approach on array data, additional novel prognostic markers could be identified. These findings contribute to a better risk stratification of RCC patients that can support an individualized and optimized therapeutic strategy.Der klinische Verlauf des Nierenzellkarzinoms (RCC) zeigt eine hohe Variabilität. Prognostische Marker sind unerlässlich, um eine individuelle Therapiestrategie zu ermöglichen. Das Ziel dieser Studie war die Identifizierung neuer unabhängiger prognostischer Marker und potentieller therapeutischer Targets beim RCC. Der Schwerpunkt lag auf Genen, die bei der Epithelial-Mesenchymalen Transition (EMT) und Tumorstammzellenbiologie beteiligt sind. EMT steigert die Beweglichkeit von Tumorzellen und spielt eine entscheidende Rolle bei der Invasion und Metastasierung bei verschiedenen Karzinomen. Eine Reihe von Transkriptionsfaktoren fungiert als die Hauptregulatoren von EMT. Ob EMT wichtig ist für die Tumorprogression beim klarzelligen Nierenzellkarzinom (RCC), ist unbekannt. Daher wurden EMT-Gene aus der Literatur ausgewählt und ihre Rolle und prognostische Relevanz bei RCC wurden analysiert. Der bekannte Tumorstammzellmarker CXCR4 und das damit assoziierte TPBG-Gen wurden auch in diesem Projekt analysiert. Zusätzlich wurde eine neuartige Filter-Strategie bei RCC-Microarray-Daten verwendet, um mögliche prognostische Marker zu identifizieren: Gene mit zunehmender Expression während der Tumorprogression (normale Niere < Primärtumor < Metastasen) wurden für die Outcome-Analyse ausgewählt, weil sie entscheidend für die RCC-Biologie sein könnten. Die Expression von 46 EMT-Genen wurde mit Oligonukleotid-Microarrays und Gene Set Enrichment Analysis (GSEA) an Gewebeproben von normaler Niere und G1 und G3 Primärtumoren (jeweils 14 Proben) analysiert. Die Expression von ausgewählten EMT-Genen wurde mittels RT-PCR in normaler Niere, primärem RCC und Metastasen an einer unabhängigen Kohorte von 112 Patienten validiert und dann mit Follow-up-Daten für die Survivalanalyse kombiniert. Immunhistochemie, Western Blot und Durchflusszytometrie wurden durchgeführt, um die Expression von CXCR4 und die Co-Expression von CXCR4 und TPBG auf der Oberfläche von RCC-Zellen weiter zu untersuchen. Die Software GSEA und dChip wurde für die Analyse der Microarray-Daten verwendet. Das EMT-gene set wurde bevorzugt in Primärtumoren exprimiert, verglichen mit dem Normalgewebe (false discovery rate FDR = 0,01), es wurde aber kein Unterschied zwischen G1- und G3-Tumoren gefunden. Quantitative RT-PCR zeigte Herunterregulation von kritischen EMT-Genen wie CDH2 und ZEB1 in Metastasen, was eine Umkehrung der EMT während der Metastasierung vermuten lässt. Die Kaplan-Meier-Analyse zeigte signifikant bessere Ergebnisse für die Patienten mit niedriger CXCR4, Vimentin, Fibronectin und TWIST1 mRNA Expression. Die multivariate Analyse zeigte, dass eine Hochregulierung von CXCR4 und Vimentin unabhängige prognostischer Marker darstellen für ein schlechtes tumorspezifisches Überleben von RCC-Patienten. Der Microarray-Ansatz mit Filtern und weiterer RT-PCR-Validierung der Progressions-assoziierten Gene ergab, dass ATAD2, TET3, HELLS und TOP2A unabhängige und bisher unbekannte Prädiktoren für schlechtes Outcome bei RCC-Patienten sind. Insgesamt liefert diese Studie deutliche Hinweise, dass EMT bei RCC vorkommt. Die Modulation von EMT bei RCC könnte daher eine zukünftige therapeutische Option darstellen. Die Expressionsstärke einiger EMT-Gene (z.B. die Gene für den Tumorstammzellmarker CXCR4 und Vimentin) konnten als unabhängige prognostische Marker identifiziert werden. Mit Hilfe eines neuartigen Filter-Ansatzes bei Array-Daten konnten zusätzliche neue prognostische Marker identifiziert werden. Diese Ergebnisse tragen bei zu einer besseren Risikostratifizierung von RCC-Patienten, was eine individualisierte und optimierte Therapiestrategie unterstützen kann.
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Volk, Andreas, Stephan Kersting, Ralf Konopke, Frank Dobrowolski, Stefan Franzen, Detlef Ockert, Robert Grützmann, Hans Detlev Saeger et Hendrik Bergert. « Surgical Therapy of Intrapancreatic Metastasis from Renal Cell Carcinoma ». Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136489.
Texte intégralRésumé :
Background: Pancreatic métastases from renal cell carcinoma (RCC) are clinically rare but highly resectable. The aim of this article is to identify patients who profit from pancreatic resection of RCC despite the invasiveness of the surgery. Methods: Between January 1996 and December 2007, data from 744 patients were collected in a prospective pancreatic surgery database, and patients with metastasis into the pancreas from RCC were identified. Results: Resective surgery was performed in 14 patients with metastasis to the pancreas from RCC. Most patients were clinically asymptomatic. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 94 months (range 32–158). The morbidity rate was 42.8%. Patients with a metastasis size <2.5 cm had a much better survival after resection (100 months) than those with a metastasis size >2.5 cm (44 months). Moreover, the number of métastases predicts the survival after resection. Conclusions: In patients with pancreatic métastases from RCC who have only limited disease, complete resection of all lesions can be successfully performed with a low rate of complications. Thus, patients with a history of RCC should be monitored for more than 10 years after nephrectomy to detect recurrenceDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Fröhner, Michael, Andreas Manseck, Arndt Lossnitzer et Manfred P. Wirth. « Late Local and Pulmonary Recurrence of Renal Cell Carcinoma ». Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133953.
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Locally recurrent renal cell carcinoma and multiple pulmonary metastases were successfully resected in a patient 20 years after nephrectomyDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Foster, Keith. « Molecular genetic analysis of non-familial renal cell carcinoma ». Thesis, University College London (University of London), 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.289811.
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Jafri, Mariam. « Molecular characterisation of renal cell carcinoma and related disorders ». Thesis, University of Birmingham, 2016. http://etheses.bham.ac.uk//id/eprint/6996/.
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Over the last two decades genetic advances have provided novel insights into the molecular basis of familial and sporadic cancers and provided the basis for the development of novel therapeutic approaches. For example, the identification of the gene for von Hippel Lindau disease provided seminal insights into its role in most clear cell renal carcinomas (RCC) and led to new treatments for RCC. In this thesis I investigated three related genetic aspects of neoplasia. Firstly, I analyzed the results of genetic testing for inherited phaeochromocytoma and investigated how clinical features could be used to stratify patients and improve the cost effectiveness of genetic testing. Secondly, I sought to identify novel causes of inherited neoplasia. Through exome sequencing of familial RCC kindreds, \(CDKN2B\) was identified as a novel familial RCC gene. The role of \(CDKN2B\) mutations in neoplasia was evaluated in familial and sporadic RCC and phaeochromocytoma. \(In\) \(vitro\) assays confirmed that germline \(CDKN2B\) mutations associated with inherited RCC caused an abrogation of tumour suppressor function. Finally, I explored how a gene-based strategy might be used to identify novel therapeutic strategies, Thus, using a siRNA library screen, in RCC cells with inactivated \(VHL\), potential candidate targets (e.g. \({PLK1/STK}\)-\(10\)) were identified for selectively decreasing the viability of RCC cells with inactivated \(VHL\).
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Qayyum, Tahir. « The role of Src kinase in renal cell carcinoma ». Thesis, University of Glasgow, 2014. http://theses.gla.ac.uk/5600/.
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Renal cancer is a malignancy which is not only increasing in incidence but there has also been an increase in mortality rates. There are various prognostic factors in renal cell cancer. We have demonstrated that some of these such as nuclear grading, tumour necrosis and systemic inflammatory response can be further refined to aid in prognosis but cannot be utilised at present to assess which would benefit from therapeutic agents when recurrence occurs. We investigated if SFK members are expressed in renal cancer. Eight SFK members were found to be expressed in renal cancer and were present to varying degrees. Furthermore, expression differed in organ confined disease and metastatic disease. Immunohistochemistry was employed to assess protein expression and activation of c-Src and SFK activity as well as the downstream marker FAK Y861. Analysis demonstrated that c-Src expression was associated with improved survival and expression of the downstream marker FAK Y861 was associated with poor survival and demonstrated a positive relationship with known prognostic factors. This would suggest that another SFK member was associated with poor survival. Dasatinib, a SFK inhibitor was utilised on renal cell lines, demonstrating a dose dependant reduction on cellular metabolic activity as well an increase in apoptotic rates. This would support that Dasatinib may be a useful therapeutic drug for RCC. Treatment with Dasatinib also demonstrated that expression of c-Src, SFK activity and FAK Y861 reduced in a dose dependant manner. It was necessary to further assess that another SFK member was responsible for poor prognosis and this was undertaken by silencing c-Src. Cellular metabolic activity rates increased following silencing c-Src and assessment of SFK activity (Src Y416) and FAK Y861 on cell pellets demonstrated no change suggesting that another SFK member is responsible for the phosphorylation of FAK Y861 and therefore responsible for poor survival. This would suggest that another SFK inhibitor and not c-Src inhibitors may play a role in the treatment of renal cell cancer and further work is required to ascertain which SFK member is responsible so that this can be targeted for treatment.
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Fröhner, Michael, Andreas Manseck, Arndt Lossnitzer et Manfred P. Wirth. « Late Local and Pulmonary Recurrence of Renal Cell Carcinoma ». Karger, 1998. https://tud.qucosa.de/id/qucosa%3A27552.
Texte intégralRésumé :
Locally recurrent renal cell carcinoma and multiple pulmonary metastases were successfully resected in a patient 20 years after nephrectomy.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Volk, Andreas, Stephan Kersting, Ralf Konopke, Frank Dobrowolski, Stefan Franzen, Detlef Ockert, Robert Grützmann, Hans Detlev Saeger et Hendrik Bergert. « Surgical Therapy of Intrapancreatic Metastasis from Renal Cell Carcinoma ». Karger, 2009. https://tud.qucosa.de/id/qucosa%3A27708.
Texte intégralRésumé :
Background: Pancreatic métastases from renal cell carcinoma (RCC) are clinically rare but highly resectable. The aim of this article is to identify patients who profit from pancreatic resection of RCC despite the invasiveness of the surgery. Methods: Between January 1996 and December 2007, data from 744 patients were collected in a prospective pancreatic surgery database, and patients with metastasis into the pancreas from RCC were identified. Results: Resective surgery was performed in 14 patients with metastasis to the pancreas from RCC. Most patients were clinically asymptomatic. The median interval between primary treatment of RCC and occurrence of pancreatic metastasis was 94 months (range 32–158). The morbidity rate was 42.8%. Patients with a metastasis size <2.5 cm had a much better survival after resection (100 months) than those with a metastasis size >2.5 cm (44 months). Moreover, the number of métastases predicts the survival after resection. Conclusions: In patients with pancreatic métastases from RCC who have only limited disease, complete resection of all lesions can be successfully performed with a low rate of complications. Thus, patients with a history of RCC should be monitored for more than 10 years after nephrectomy to detect recurrence.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Mastrandrea, Nicholas Joseph. « Pentoxifylline As An Adjuvant Treatment In Renal Cell Carcinoma ». Diss., The University of Arizona, 2014. http://hdl.handle.net/10150/337293.
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Cyclin D1, a proto-oncogene, is required for progression from the G1 phase into the S phase of the cell cycle. Over-expression of cyclin D1 causes an increase in cell cycle progression and cell proliferation, implicating it in a variety of cancers including renal cell carcinoma (RCC). The rodent RCC cell model, QTRRE, and human RCC cell models, ACHN, 786-O and Caki-2, exhibit elevated levels of cyclin D1. Pentoxifylline (PTX), a non-specific phosphodiesterase inhibitor, is an FDA-approved hemorheologic agent used to treat intermittent claudication, stemming from peripheral vascular diseases, as well as other diseases involving defective locoregional blood flow. Treatment of QTRRE, ACHN, 786-O and Caki-2 with PTX caused a time- (0-24 hrs) and dose- (0-1.0 mg/mL) dependent decrease of cyclin D1 protein and p-Rb levels in whole cell lysate as well as cytosolic and nuclear fractions, albeit, to different extents within the models. Concomitant with cyclin D1 and p-Rb decrease, enhanced G1 phase cell cycle arrest was observed in the RCC models. Mechanistic studies in these RCC cell models were carried out to determine PTXs mechanism of action with regard to cyclin D1 protein level decrease. RT-PCR analysis showed no significant changes in cyclin D1 mRNA copy number in time- (0-24 hrs) and dose- (0-1.0 mg/mL) dependent PTX treatments. However, such treatments caused decrease in p-4EBP1 (Ser65), p-4EBP1 (Thr70), and p-4EBP1 (Thr37/46). Because PTX's ability to decrease cyclin D1 protein was prevented in the presence of the proteasome inhibitor, MG-132, studies were performed to determine whether cyclin D1 stability was decreased during PTX treatment. Cyclin D1 degradation is initiated by phosphorylation of residue Thr286 by GSK-3β. Inhibition of GSK-3β with LiCl or knockdown via siRNA in the presence of PTX failed to block cyclin D1 decrease. Moreover, PTX treatment in the presence of MG-132 revealed no significant increase in cyclin D1 p-Thr286 compared to control. Finally, using the protein synthesis inhibitor, CHX, PTX caused no significant decrease in cyclin D1 t₁/₂ (wt-HA and T286A-HA) compared to control. Sorafenib, a broad-spectrum (cRAF, bRAF, KIT, FLT-3, VEGFR-2, VEGFR-3, and PDGFR-β) kinase inhibitor, is FDA-approved for the treatment of RCC. Studies with sorafenib and PTX in the ACHN cell model were carried out to determine PTXs possible adjuvant role in inhibiting cell growth via cyclin D1 decrease and G1 phase arrest. MTS data showed PTX potentiates the anti-proliferative effects of sorafenib. PTX pre-treatment for 24 hrs was also lowered the effective dose of sorafenib from 50 μM to 5 μM. Further, ACHN xenograft tumor volumes from mice treated with PTX and sorafenib displayed significantly higher tumor growth inhibition compared to either drug treatment alone or vehicle. Finally, drug treated ACHN xenograft tissue displayed significantly lower cyclin D1, p-RB and p-4EBP1 levels. These results demonstrate a novel anti-cancer property of PTX and suggest its use as a possible adjuvant therapy in RCC treatment should be further explored.
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Winegard, Billie. « Renal Cell Carcinoma in Arizona American Indians/Alaska Natives ». Thesis, The University of Arizona, 2012. http://hdl.handle.net/10150/221595.
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A Thesis submitted to The University of Arizona College of Medicine - Phoenix in partial fulfillment of the requirements for the Degree of Doctor of Medicine.OBJECTIVE – This study assesses trends in the incidence of cancers of the kidney and renal pelvis (K&RP) with focus on renal cell carcinoma (RCC) from 1995-2009 among American Indian/Alaska Natives (AI/AN) residing in Arizona. RESEARCH DESIGN AND METHODS – Using the Arizona Cancer Registry (ACR), we obtained the total number of new cases of cancers of the K&RP from 1995 through 2009. The incidence rates of these cancers, as well as the sub-group of RCC, were age-adjusted to the 2000 U.S. population for comparison between populations. Comparisons between demographic and tumor characteristics were also completed between AI/AN and non-Hispanic white cases. RESULTS – Between 1995 and 2009, 502 cases of K&RP were diagnosed in AI/AN in Arizona, with a majority of these cases (463, 92.23% of cases) being RCC of the kidney parenchyma. Over the study period, the age-adjusted incidence per 100,000 population was 19.18 for all tumors of the K&RP and 17.65 for RCC. Comparing the average age-adjusted rate over the first third (1995-1999) of the study period versus the last third (2005-2009), the rate of RCC among AI/AN increased 12.30% from 16.55 to 18.58 per 100,000 population. When this rate was stratified by sex, AI/AN males showed the most striking increase - 54.56% (19.22 to 29.70 cases of RCC per 100,000 population). While AI/AN females showed a decrease in the rate of 28.24% (14.20 to 10.19 cases per 100,000 population). CONCLUSIONS – The incidence rate of RCC has increased dramatically in Arizona AI/AN males. Research looking at this disease in this group is needed to determine which risk factors may be associated and to determine if any steps can be taken toward prevention or if there is a need for screening in this population.
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Bulmer, Bronwyn. « Prostate specific antigen-like expression in renal cell carcinoma ». Thesis, Queensland University of Technology, 2002.
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Vemuri, Bhargav R. « Identification of prognostic metabolic classifier in localized clear cell renal cell carcinoma ». University of Cincinnati / OhioLINK, 2020. http://rave.ohiolink.edu/etdc/view?acc_num=ucin161710619577556.
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Kanno, Toru. « JunB promotes cell invasion and angiogenesis in VHL-defective renal cell carcinoma ». Kyoto University, 2012. http://hdl.handle.net/2433/152497.
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Shibasaki, Noboru. « Role of IL13RA2 in Sunitinib Resistance in Clear Cell Renal Cell Carcinoma ». Kyoto University, 2016. http://hdl.handle.net/2433/215954.
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Arakaki, Ryuichiro. « CCL2 as a potential therapeutic target for clear cell renal cell carcinoma ». 京都大学 (Kyoto University), 2017. http://hdl.handle.net/2433/225490.
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Lee, Wing-sang, et 李榮生. « The prognostic significance of DJ-1 in patients with renal cell carcinoma of clear cell type ». Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B42925095.
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Lee, Wing-sang. « The prognostic significance of DJ-1 in patients with renal cell carcinoma of clear cell type ». Click to view the E-thesis via HKUTO, 2009. http://sunzi.lib.hku.hk/hkuto/record/B42925095.
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Bartrolí, Comellas Mariona. « Prognostic markers and therapeutic targets for metastatic renal cell carcinoma ». Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664198.
Texte intégralRésumé :
Targeting cancer metastasis has gained considerable importance in the recent years when aiming to increase patients’ overall survival. In Renal Cell Carcinoma (RCC), the discovery of metastatic biomarkers and targets is still required, as most patients present metastatic disease at the time of diagnosis.
Therefore, the aim of this thesis is the discovery of new biomarkers and targets of metastatic RCC using two variants of a patient-derived orthoxenograft (PDOX) animal model of clear cell RCC (ccRCC). Indeed, PDOX models have recently gained significant relevance for studying the progression of cancer and metastasis, due to their better mimicking of the histology, the metastatic capacity and treatment responses of human cancers. To this purpose, previous results had sequenced the two variants of this PDOX model, both at DNA and at RNA level, and had performed a FISH analysis.
Firstly, Carboxypeptidase E (CPE), which was one of the highest expressed genes in the metastatic variant, has demonstrated to play a role in invasion when it is secreted to the medium, even though its overexpression alone is not sufficient to generate metastasis in vivo. In addition, it has showed a clear association to ccRCC and an inverse correlation with the overall survival of these patients. Secondly, we have studied two molecules of the coagulation pathway due to its relevance as one of the most upregulated pathways at RNA level. On the one hand, Factor XIII (FXIII or F13) has shown to be related to CPE in vivo, despite the overexpression of both molecules is not sufficient to develop all the metastatic cascade. However, it also affects the overall survival of ccRCC patients, highlighting these two molecules as possible biomarkers for this type of cancer. On the other hand, Coagulation Factor II Thrombin Receptor (F2R or PAR1) has demonstrated to play a role in metastasis, since its inhibition reduces both the early and late phases of this process. With the use of F2R inhibitors and the clinical association of the coagulation pathway to worse prognosis, this thesis opens new opportunities for the treatment of metastasis and cancer malignization.
In summary, we have discovered new metastatic biomarkers and targets which, together with further validations, especially in the clinical setting, are proposed to be useful for RCC patients in the future.Recentment, l’estudi de la metàstasi ha guanyat importància amb l’objectiu d’augmentar la supervivència dels pacients amb càncer. En el càncer renal (RCC), el descobriment de biomarcadors metastàtics i dianes terapèutiques és necessari degut a que la majoria de pacients presenten metàstasi en el moment del diagnòstic. L’objectiu d’aquesta tesi ha estat el descobriment de nous biomarcadors i dianes terapèutiques pel càncer renal metastàtic a través de dues variants d’un model animal orthoxenograft (PDOX) de RCC de cèl·lula clara (ccRCC). Els models PDOX han guanyat molta importància en l’estudi de la progressió del càncer i la metàstasi, ja que mimetitzen la histologia, la capacitat metastàtica i la resposta als tractaments. Prèviament, s’havien seqüenciat les dues variants d’aquest model PDOX tant a nivell de DNA com de RNA, juntament amb un anàlisi FISH. En primer lloc, la Carbxoxipeptidasa E (CPE), un dels gens més expressats en la variant metastàtica, ha demostrat ser important en la invasió quan és secretada al medi, tot i no ser suficient per generar metàstasi in vivo. A més, s’ha associat amb el ccRCC i anti-correlacionat amb la supervivència d’aquests pacients. En segon lloc, hem estudiat dues molècules de la cascada de coagulació, una de les més alterades en nivells de RNA. Hem demostrat que el Factor XIII (FXIII o F13) està relacionat amb CPE in vivo, malgrat que l’expressió de les dues molècules no és suficient per a que es desenvolupi la metàstasi. Tot i així, el F13 afecta la supervivència de pacients amb ccRCC, suggerint aquestes dues molècules com a possibles biomarcadors d’aquest tipus de càncer. A més, la inhibició del Receptor del Factor de Coagulació II (F2R) ha demostrat reduir les fases inicials i finals del procés metastàtic. Així doncs, l’ús d’inhibidors de F2R, juntament amb el fet que la cascada de coagulació es relaciona amb el pronòstic dels pacients, fa que aquesta tesi obri noves oportunitats per al tractament de la metàstasi i la malignització del càncer. En resum, hem descobert nous biomarcadors i dianes terapèutiques que, juntament amb futures validacions, sobretot en clínica, poden ser útils per als pacients metastàtics de ccRCC.
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Carter, Jessica. « Epigenetic basis for Tensin3 dysregulation in human renal cell carcinoma ». Thesis, University of Portsmouth, 2013. https://researchportal.port.ac.uk/portal/en/theses/epigenetic-basis-for-tensin3-dysregulation-in-human-renal-cell-carcinoma(e39a962d-9c23-4265-8318-bf5fd296148c).html.
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The Tensins are a family of intracellular cytoskeleton interacting proteins that are involved in the regulation of cell motility and migration. Downregulation of Tensins has been observed in several cancers, indicating that it may be advantageous for tumour progression. In this study, an epigenetic basis for the observed downregulation of Tensin3 in human renal cell carcinoma (RCC) has been investigated, specifically the methylation state of the TNS3 gene promoter. The aims of this study were to: 1. Identify and validate a functional promoter for the human TNS3 gene that contains a CpG island within it; 2. quantify the methylation level of this region in RCC; 3. determine whether expression of Tensin3 could be altered through DNA demethylation treatment. Bioinformatic analysis revealed there to be a putative promoter for the human TNS3 gene, housing an 826-bp CpG island. A luciferase reporter assay demonstrated a functional minimal promoter activity for a 2000 bp sequence containing this island. For quantification of methylation in the TNS3 promoter, genomic DNA from RCC patients (tumour and adjacent non tumour) and a normal control group were analysed by bisulphite conversion followed by pyrosequencing analysis. This enabled quantitative determination of DNA methylation of individual CpG dinucleotides within the TNS3 gene promoter, out of a total of 43 analysed. Across the entire CpG stretch, RCC DNA showed significantly higher methylation level than non-tumour kidney DNA and normal control DNA (tumour n=12, non-tumour n=3; normal n=12; P<0.01, tumour vs. non-tumour; P<0.0001, tumour vs. normal). Out of the CpGs analysed, two CpG dinucleotides, CpGs 2 and 8, showed the most pronounced increases in methylation in tumour samples (P<0.0001). Furthermore, CpG 2 methylation negatively correlated with Tensin3 gene expression levels in RCC samples (P<0.005). In addition, pharmacological demethylation of cultured HK2 kidney cells with 5-aza-2’deoxycytidine caused a threefold upregulation of Tensin3 expression as measured by qRT-PCR. In conclusion, these results reveal a differential methylation pattern in the TNS3 promoter region occurring in human RCC, suggesting at least in part an epigenetic basis for the observed aberrant downregulation of Tensin3 in this disease.
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Sandlund, Johanna. « Angiogenesis in human renal cell carcinoma : hypoxia, vascularity and prognosis ». Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1331.
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Fonseca, Cátia Isabel Correia dos Reis. « Vaccine Targets in a Murine Model of Renal Cell Carcinoma ». Doctoral thesis, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7210.
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Fonseca, Cátia Isabel Correia dos Reis. « Vaccine Targets in a Murine Model of Renal Cell Carcinoma ». Tese, Instituto de Ciências Biomédicas Abel Salazar, 2007. http://hdl.handle.net/10216/7210.
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Rae, Fiona Karen. « Identification and characterisation of genes expressed in renal cell carcinoma ». Thesis, Queensland University of Technology, 2001.
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Arévalo, Bautista Jazmine Paola. « The role of stat3 phosphorylation state in clear cell renal cell carcinoma (ccRCC) ». Doctoral thesis, Universitat Autònoma de Barcelona, 2019. http://hdl.handle.net/10803/669570.
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STAT3 (signal transducer and activator of transcription 3) és un factor de transcripció latent que regula la transcripció de gens relacionats amb processos biològics essencials tals com: la diferenciació cel·lular, la proliferació, la migració, la inhibició de l’apoptosi i la supervivència. L’activació anormal d’STAT3 s’ha relacionat amb el desenvolupament d’aproximadament el 50% dels càncers humans, incloent el carcinoma renal de cèl·lula clara (ccRCC). Actualment, les propietats oncogèniques d’STAT3 s’atribueixen a la fosforilació del seu residu Tyr705; no obstant, recentment, la fosforilació de la Ser727 ha sorgit com un esdeveniment capaç d’amplificar l’activitat transcripcional d’STAT3, juntament a activitats no genòmiques que promouen el desenvolupament del càncer. El nostre grup va ser un dels pioners en assenyalar la importància de la fosforilació de la Ser727, demostrant que els nivells d’expressió de la pSer727 al nucli (en mostres de teixit de pacients de ccRCC) correlacionaven amb un mal pronòstic i una baixa supervivència global. Donat que el ccRCC és el subtipus histològic de carcinoma renal més prevalent i letal, i que els mecanismes subjacents al seu desenvolupament no han estat determinats fins el moment, l’objectiu d’aquest treball va ser elucidar el paper de l’estat de fosforilació d’STAT3 en el desenvolupament del ccRCC i, específicament, en estudiar la contribució de la pSer727 en la progressió tumoral. Amb aquesta finalitat, es varen generar fosfomutants simples i dobles d’STAT3 (Tyr705Phe, Ser727Ala, Ser727Asp, Tyr705Phe/Ser727Ala, i Tyr705Phe/Ser727Asp) que van ser transduïdes en línies cel·lulars humanes derivades de ccRCC (769-P i 786-O) per avaluar el seu comportament funcional, així com la conseqüent expressió gènica diferencial mitjançant l’anàlisi de microarray. Els nostres resultats han demostrat que les mutants d’STAT3 que contenien una substitució fosfomimètica de la Ser727 (Ser727Asp) promouen un fenotip pro-tumoral in vivo de manera independent a la Tyr705. A més, es descriu que l’estat de fosforilació global d’STAT3 determina l’expressió de diferents subconjunts de gens associats a diversos processos biològics, essent els gens dependents de la pSer727 els més relacionats amb processos característics amb el desenvolupament del càncer. En resum, aquest treball constitueix el primer anàlisi de quin és el paper de l’estat de fosforilació global d’STAT3 en el ccRCC, i demostra que la pSer727 activa la senyalització d’STAT3 a través de la transcripció d’un subconjunt específic de gens que són clínicament rellevants com potencials dianes terapèutiques i nous biomarcadors del ccRCC.STAT3 (signal transducer and activator of transcription 3) es un factor de transcripción latente que regula la transcripción de genes relacionados con procesos biológicos esenciales, tales como: diferenciación celular, proliferación, migración, inhibición de la apoptosis y supervivencia. La activación anormal de STAT3 ha sido relacionada con el desarrollo de cerca del 50% de todos los cánceres humanos, incluyendo el carcinoma renal de célula clara (ccRCC). Actualmente, las propiedades oncogénicas de STAT3 se atribuyen a la fosforilación de su Tyr705; sin embargo, recientemente, la fosforilación de su Ser727 ha surgido como un evento capaz de amplificar la actividad transcripcional de STAT3, aunada a actividades no genómicas que promueven el desarrollo del cáncer. Nuestro grupo fue uno de los pioneros en señalar la importancia de la fosforilación de la Ser727, al demostrar que los niveles de expresión de pSer727 en el núcleo (en muestras de tejidos de pacientes con ccRCC) correlacionaban con un mal pronóstico y baja supervivencia global. Dado que el ccRCC es el subtipo histológico de carcinoma renal más prevalente y letal, y los mecanismos subyacentes a su desarrollo aún no han sido determinados, el objetivo de este trabajo fue elucidar el rol del estado de fosforilación de STAT3 en el desarrollo del ccRCC, y específicamente, en estudiar la contribución de la pSer727 en la progresión tumoral. Para ello, generamos fosfomutantes simples y dobles de STAT3 (Tyr705Phe, Ser727Ala, Ser727Asp, Tyr705Phe/Ser727Ala, y Tyr705Phe/Ser727Asp) que fueron transducidas en líneas celulares humanas derivadas de ccRCC (769-P y 786-O) para evaluar su comportamiento funcional, así como la consecuente expresión génica diferencial a través de un análisis de microarray. Nuestros resultados demostraron que las mutantes de STAT3 que contenían una substitución fosfomimética para la Ser727 (Ser727Asp) promueven un fenotipo pro-tumoral in vivo de forma independiente de la Tyr705. Además, describimos que el estado de fosforilación global de STAT3 determina la expresión de diferentes subconjuntos de genes asociados a distintos procesos biológicos, siendo los genes dependientes de la pSer727, los más relacionados con procesos característicos del desarrollo del cáncer. En resumen, este trabajo constituye el primer análisis acerca del rol del estado de fosforilación global de STAT3 en el ccRCC, y demuestra que la pSer727 activa la señalización de STAT3 a través de la transcripción de un subconjunto específico de genes que son clínicamente relevantes como potenciales dianas terapéuticas y nuevos biomarcadores para el ccRCC.
The signal transducer and activator of transcription 3 (STAT3) is a latent transcription factor that regulates downstream genes involved in essential biological processes such as cell differentiation, proliferation, migration, apoptosis inhibition, and survival. The aberrant activation of STAT3 has been related to the development of near 50% of all human cancers including clear cell renal cell carcinoma (ccRCC). To date, the oncogenic properties of STAT3 are attributed to the phosphorylation of its Tyr705, however, the phosphorylation of its Ser727 has recently emerged as an event that enhances STAT3 transcriptional activity, in addition to non-genomic activities that promote cancer development. Our group was one of the pioneers in bringing the Ser727 phosphorylation to light by demonstrating that nuclear pSer727 expression levels, in tissue samples of ccRCC patients, correlated with poor prognosis and low overall survival. Since ccRCC is the most prevalent and lethal histological subtype of renal cell carcinoma (RCC) and the molecular mechanisms behind its tumorigenesis remain unclear, we aimed to elucidate the role of STAT3 phosphorylation state in ccRCC development, and especially the contribution of pSer727 to tumor progression. For that purpose, we generated simple and double STAT3 phosphomutants (Tyr705Phe, Ser727Ala, Ser727Asp, Tyr705Phe/Ser727Ala, and Tyr705Phe/Ser727Asp) transduced in human-derived ccRCC cell lines (769-P and 786-O), and we evaluated their functional behavior as well as their differential gene expression through microarray analysis. Our data demonstrated that STAT3 mutants carrying a phosphomimetic substitution for Ser727 (Ser727Asp) promote a pro-tumoral phenotype in vitro in a Tyr705-independent manner. Moreover, we describe that the overall STAT3 phosphorylation state determines the expression of different subsets of target genes associated with distinct biological processes, being pSer727-dependent genes the most related to cellular hallmarks of cancer development. In summary, the present study constitutes the first analysis on the role of overall STAT3 phosphorylation state in ccRCC and demonstrates that pSer727 activates STAT3 signaling through transcription of a specific subset of target genes that are clinically relevant as potential therapeutic targets and novel biomarkers for ccRCC.
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Weber, Thomas, Matthias Meinhardt, Stefan Zastrow, Andreas Wienke, Kati Erdmann, Jörg Hofmann, Susanne Füssel et Manfred P. Wirth. « Stage-dependent prognostic impact of molecular signatures in clear cell renal cell carcinoma ». Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-147292.
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Purpose: To enhance prognostic information of protein biomarkers for clear cell renal cell carcinomas (ccRCCs), we analyzed them within prognostic groups of ccRCC harboring different tumor characteristics of this clinically and molecularly heterogeneous tumor entity. Methods: Tissue microarrays from 145 patients with primary ccRCC were immunohistochemically analyzed for VHL (von Hippel-Lindau tumor suppressor), Ki67 (marker of proliferation 1), p53 (tumor protein p53), p21 (cyclin-dependent kinase inhibitor 1A), survivin (baculoviral IAP repeat containing 5), and UEA-1 (ulex europaeus agglutinin I) to assess microvessel-density. Results: When analyzing all patients, nuclear staining of Ki67 (hazard ratio [HR] 1.08, 95% confidence interval [CI] 1.04–1.12) and nuclear survivin (nS; HR 1.04, 95% CI 1.01–1.08) were significantly associated with disease-specific survival (DSS). In the cohort of patients with advanced localized or metastasized ccRCC, high staining of Ki67, p53 and nS predicted shorter DSS (Ki67: HR 1.07, 95% CI 1.02–1.11; p53: HR 1.05, 95% CI 1.01–1.09; nS: HR 1.08, 95% CI 1.02–1.14). In organ-confined ccRCC, patients with high p21-staining had a longer DSS (HR 0.96, 95% CI 0.92–0.99). In a multivariate model with stepwise backward elimination, tumor size and p21-staining showed a significant association with DSS in patients with "organ-confined" ccRCCs. The p21-staining increased the concordance index of tumor size from 0.75 to 0.78. In patients with "organ-confined" ccRCC, no disease-related deaths occurred in the group with p21-expression below the threshold of 32.5% p21-positive cells (log rank test: P=0.002). Conclusion: The prognostic information of the studied protein biomarkers depended on anatomic tumor stages, which displayed different acquired biological tumor characteristics. Analysis of prognostic factors within different clinical ccRCC groups could help to enhance their prognostic power. The p21-staining was an independent prognostic factor and increased prognostic accuracy in a predictive model in "organ-confined" ccRCC.
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Polanski, Radoslaw. « Identification of MDM2-interacting proteins in renal cell carcinoma and characterization of phenotypic properties acquired by renal cell carcinoma cells which over-express MDM2 and p53 ». Thesis, University of Liverpool, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.533936.
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Reid, Janet Louise. « The mechanism of action of captopril in human renal cell carcinoma / ». [St. Lucia, Qld.], 2003. http://www.library.uq.edu.au/pdfserve.php?image=thesisabs/absthe17182.pdf.
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Gutteridge, Robert. « Caveolin-1 is a modulator of clonogenicity in renal cell carcinoma ». Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/91911/.
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Renal cell carcinoma (RCC) represents a group of aggressive tumours of the kidney. These tumours have a high propensity for metastasis and are extremely treatment refractive after disease relapse. Therefore, the identification of new therapeutic targets is of great importance. One such potential target for therapy are cancer stem cells (CSCs). CSCs are populations of cells imbued with a stem cell-like phenotype capable of driving tumour formation, metastasis and chemoresistance. As such, reliable methods for the identification of CSC populations and defining targets important to their functionality, in hopes of developing more potent therapeutics is of great importance. Previous work has found CAV1 to play a significant role in the malignant progression of RCC and also in the maintenance of adult stem cell populations. As such, this work aimed to understand if common markers of CSC phenotype in combination with CAV1 can act indicators of poor prognostic outcome in clinically confined RCC. Furthermore, this work sought to identify CSC populations from RCC cell lines using a panel of surface markers common to embryonic, mesenchymal and cancer stem cells. Then, understand if CAV1 is responsible for driving the CSC phenotype in these CSC populations by regulating one of the major characteristics of CSC biology, self-renewal. Co-expression of CD44 and CAV1 in RCC tumours indicated greatly reduced disease free survival in clinically confined RCC. Additionally, CD44/CAV1 was found to be the most significant covariate in predicting disease recurrence. In vitro analysis, using a panel of CSC related markers, was unable of identifying a putative CSC population. However, CAV1 expression in the VHL positive CAKI-1 cell line was important for the maintenance of clonogenicity. Incubation of CAV1 deficient CAKI-1 cells under hypoxic conditions was able to restore lost clonogenicity. Further iv work revealed that CAV1 maintains clonogenicity in CAKI-1 through activation of STAT3 and -catenin. This suggests an important role for CAV1 in the maintenance of clonogenicity through STAT3 activation in VHL competent RCC.
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Iranparvar, Alamdari Farhood. « Renal cell carcinoma : factors of importance for follow-up and survival ». Doctoral thesis, Umeå : Univ, 2007. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-1418.
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Aggelis, Vassilis. « Proteomic identification of differentially expressed membrane proteins in renal cell carcinoma ». Thesis, University of Leeds, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.530852.
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Wolfe, Kara. « The Role of Purine Nucleotide Metabolism in Renal Cell Carcinoma Migration ». University of Cincinnati / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1563872926565308.
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