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1
Maharjan, Rajani. „New Insights in Adrenal Tumourigenesis“. Doctoral thesis, Uppsala universitet, Institutionen för kirurgiska vetenskaper, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-326149.
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Unilateral cortisol producing adenoma (CPA) is the most common cause of ACTH-independent Cushing’s syndrome and is surgically curable. On the other hand, adrenocortical carcinomas (ACCs) are rare and aggressive tumours. Although the overall survival of the patients with ACC is very poor, the outcome can be heterogeneous and vary significantly between the patients. This thesis comprises studies showing genetic and genomic events occurring in CPAs and ACCs, their functional impact and clinical correlations. The Wnt/β-catenin and cAMP/PKA signalling pathways are crucial in adrenal homeostasis and frequent mutations in members of these pathways (CTNNB1, GNAS, and PRKACA) are found in CPAs. Mutational analysis revealed that ~60% of the CPAs harboured mutations in either of these genes. Transcriptome signature exhibited increased expression of genes involved in steroidogenesis in PRKACA/GNAS mutated (Cluster1) tumours in comparison to CTNNB1 mutated /wildtype (Cluster2) tumours. In addition we have also observed that gain of chromosome arm 9q was the most frequent arm level copy number variation (CNV) occurring in CPAs and were exclusively present in Cluster2 tumours. We also discovered novel PRKACA mutations occurring in ACCs, causing activation of cAMP/signalling pathway. Comprehensive analysis of Wnt/β-catenin signalling pathway in ACCs revealed novel interstitial deletions occurring in CTNNB1 leading to deletion of the N-terminus of β-catenin. This is a novel and yet another frequent event leading to activated Wnt/β-catenin signalling and downstream targets in ACCs. Both, mutations occurring in CTNNB1 and nuclear expression of its protein were associated with poor overall survival. Through multiregional sampling approach we discovered intra-tumour heterogeneity in ACC tumours. Although all the multiregions within a tumour showed presence of shared basal CNVs, they encompassed private CNVs, different ploidy levels and private mutations in known driver genes. We found intra-tumour heterogeneity in CTNNB1, PRKACA, TERT promoter and TP53 mutations as well as ZNRF3 and CDKN2A/2B homozygous deletions.
2
Oliver, Joseph James. „Characterizing ErbB2-induced mammary tumourigenesis“. Thesis, Kingston, Ont. : [s.n.], 2007. http://hdl.handle.net/1974/687.
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3
Tam, Kevin J. „Semaphorin 3C in prostate cancer tumourigenesis“. Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/61319.
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The full abstract for this thesis is available in the body of the thesis, and will be available when the embargo expires.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
4
Robinson, James Peter. „Tumourigenesis of Peutz-Jeghers Syndrome polyps“. Thesis, Queen Mary, University of London, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.522321.
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5
Aimls, Mark Anthony Slevin. „The role of gangliosides in tumourigenesis“. Thesis, Manchester Metropolitan University, 1993. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.359140.
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6
Blyth, Karen. „A transgenic model to study the role of oncogenes and tumour suppression genes in T cell lymphoma“. Thesis, University of Glasgow, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.321716.
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7
Johansson, Térèse A. „Pancreatic Endocrine Tumourigenesis : Genes of potential importance“. Doctoral thesis, Uppsala University, Department of Medical Sciences, 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9294.
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Understanding signalling pathways that control pancreatic endocrine tumour (PET) development and proliferation may reveal novel targets for therapeutic intervention. The pathogenesis for sporadic and hereditary PETs, apart from mutations of the MEN1 and VHL tumour suppressor genes, is still elusive. The protein product of the MEN1 gene, menin, regulates many genes. The aim of this thesis was to identify genes involved in pancreatic endocrine tumourigenesis, with special reference to Notch signalling.
Messenger RNA and protein expression of NOTCH1, HES1, HEY1, ASCL1, NEUROG3, NEUROD1, DLK1, POU3F4, PDX1, RPL10, DKK1 and TPH1 were studied in human PETs, sporadic and MEN 1, as well as in tumours from heterozygous Men1 mice. For comparison, normal and MEN1 non-tumourous human and mouse pancreatic specimens were used. Nuclear expression of HES1 was consistently absent in PETs. In mouse tumours this coincided with loss of menin expression, and there was a correlation between Men1 expression and several Notch signalling factors. A new phenotype consisting of numerous menin-expressing endocrine cell clusters, smaller than islets, was found in Men1 mice. Expression of NEUROG3 and NEUROD1 was predominantly localised to the cytoplasm in PETs and islets from MEN 1 patients and Men1 mice, whereas expression was solely nuclear in wt mice. Differences in expression levels of Pou3f4, Rpl10 and Dlk1 between islets of Men1 and wt mice were observed.
In addition, combined RNA interference and microarray expression analysis in the pancreatic endocrine cell line BON1 identified 158 target genes of ASCL1. For two of these, DKK1 (a negative regulator of the WNT/β-catenin signalling pathway) and TPH1, immunohistochemistry was performed on PETs. In concordance with the microarray finding, DKK1 expression showed an inverse relation to ASCL1 expression.
Altered subcellular localisation of HES1, NEUROD1 and NEUROG3 and down-regulation of DKK1 may contribute to tumourigenesis.
8
Small, Donna. „The role of cathepsin S in tumourigenesis“. Thesis, Queen's University Belfast, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.580089.
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Recent studies have demonstrated that cysteine cathepsin S, predominantly from tumour- associated macrophages, promotes tumour development and progression. Conversely, previous work examining human colorectal and brain biopsies have shown that the tumour cells themselves are a major source of CatS. In order to clarify the contribution of stromal- derived versus tumour cell-derived CatS in colorectal tumourigenesis, investigations were carried out using the syngeneic MC38 coloadenocarcinoma cell line, which was found to expressed and produced CatS. Loss-of-function CatS experiments performed on the MC38 cells demonstrated a reduction in invasion, lower activity level and reduced proteolysis, signifying a role for CatS in various aspects of tumourigenesis. Investigations in vivo using CatS null mice revealed a role for both tumour cell and stromal-derived CatS in MC38 tumour development and highlighted that CatS derived from either sources partially compensated for each other, and that depletion from both sources was required for the most significant retardation of tumour growth, This noted anti-tumour effect was characterised by a reduction in tumour cell proliferation and increased apoptosis, which may be attributable, at least in part, to the significant diminution in tumour neo-angiogenesis. Mean vessel number and vessel area was significantly reduced in tumours which lacked both sources of CatS, were the vessels presented with increased leakiness; suggestive of more dysfunctional tumour vessel architecture, The observation of increased lung and liver metastases in the CatS null mice was unexpected, however, this may be due to the expression of tumour cell derived CatS, thereby promoting rnetastases. This may be a result of decreased immuno-protective and anti-tumour roles due to the loss of CatS. Taken together, these findings clearly highlight a functional role for CatS in several hallmarks of tumourigenesis, particularly angiogenesis. The data also demonstrates CatS as a valid anti-angiogenic target in the treatment of cancer, at least in solid tumours.
9
Devlin, Andrea. „A study of CYP1B1 expression in tumourigenesis“. Thesis, University of Ulster, 2006. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.494336.
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10
Lynch, Catherine Anne. „Mechanisms of epigenetic gene silencing in tumourigenesis“. Thesis, University of Ulster, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.428611.
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11
Lewy, Gregory Douglas. „Novel pathways promoting thyroid tumourigenesis and growth“. Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3933/.
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Thyroid cancers are the most common endocrine malignancies and their incidence continues to rise. Over-expression of the human pituitary tumor transforming gene (hPTTG) in thyroid carcinomas is a prognostic indicator of tumour recurrence. hPTTG is multifunctional with roles in mitotic control, DNA repair, genetic instability, cell transformation and apoptosis. Importantly, hPTTG transactivates expression of growth factors implicated in proliferation and angiogenesis, and represses the sodium iodide symporter (NIS), which is essential to radioiodine treatments in thyroid cancer. hPTTG interacts with a binding factor (PBF) which is an independent transforming gene and also represses iodine uptake. Work described in this thesis provides evidence for the existence of thyroidal autocrine regulatory pathways involving hPTTG and growth factors in vitro. We directly investigated the role of hPTTG in thyroid tumourigenesis through the generation and characterisation of a murine transgenic model with thyroid-targeted hPTTG over-expression (hPTTG-Tg mice). Unexpectedly, hPTTG over-expression was not sufficient for thyroid tumourigenesis. Investigations performed in hPTTG-Tg and Pttg-/- knockout mice indicated a particularly important relationship between hPTTG and the epidermal growth factor (EGF) in vivo. hPTTG and PBF were confirmed as repressors of NIS in vivo following studies in hPTTG-Tg and PBF-Tg mice respectively. The studies described in this thesis highlight the therapeutic potential of targeting hPTTG and PBF in thyroid cancer. To this effect, specific tyrosine kinase inhibitors prevented autocrine induction of hPTTG by growth factors, and siRNA depletion of PBF restored NIS function to normal levels in hPBF-Tg thyrocytes. Based on these data, hPTTG appears to play a dual role in endocrine tumourigenesis, being involved in both tumour initiation and subsequent progression towards more aggressive phenotypes.
12
Johansson, Térèse A. „Pancreatic Endocrine Tumourigenesis : Genes of potential importance /“. Uppsala : Acta Universitatis Upsaliensis : Universitetsbiblioteket [distributör], 2008. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-9294.
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13
Ip, Julian Chung Yan. „Clinical and molecular aspects of adrenal tumourigenesis“. Thesis, The University of Sydney, 2015. http://hdl.handle.net/2123/13738.
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The aims of this thesis were to examine the clinical and molecular aspects of benign and malignant adrenocortical tumours. Initial research focused on correlating KCNJ5 genotype-phenotype correlations in primary aldosteronism. It was noted that 41% patients were found to have somatic mutations in KCNJ5, G151R and L168R. Mutation carriers were predominately female and significantly younger at presentation and were more likely to be cured following surgery. Further work focussed on malignant adrenocortical carcinoma (ACC). Analysis in a cohort of patients showed that advanced age, advanced disease and the lack of preoperative endocrine investigations were poor prognostic factors. There was also a trend for improved resection margins and recurrence-free survival in patients undergoing surgery with higher-volume surgeons, suggesting that management in experienced units may result in improved outcomes. Tissue microarray technology was utilised in order to identify novel protein signatures that would be able to predict clinical outcomes in patients with ACC. A panel of previously overexpressed genes were validated at the tissue level. A novel combination of predictive and prognostic biomarkers was revealed, with over-expression of Ki-67, TOP2A and EZH2 being associated with poorer outcomes whereas over-expression of BARD1 was associated with improved outcomes. The role of microRNA-129 (miR-129) was explored in ACC tumour biology utilising an ACC cell line, a miRNA known to be under-expressed in adrenocortical tumours. It was found that restoration of miR-129 resulted in cell-cycle arrest, heralding a possible tumour-suppressor role for miR-129. Further investigations demonstrated that SOX4 was a potential downstream target of miR-129, the two having been previously described in other malignancies but not in ACC. The findings in this thesis have provided significant contributions to the understanding of both benign and malignant adrenocortical tumours. However, much work is still needed to refine our understanding of adrenal disease and the findings from this body of work provide the basis for ongoing studies.
14
Sikkink, Stephen K. „Genetic pathology of non-small cell lung cancer“. Thesis, University of Liverpool, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.250405.
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15
Su, Vi-Minh-Tri. „The role of Grb2 in HER2-mediates tumourigenesis“. Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110360.
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Grb2, an adaptor protein, is ubiquitously expressed and is involved in mediating a multitude of cellular processes in various body tissues such as development and tumourigenesis. Grb2 binds to proteins via its Src-homology domains and by doing so brings them in proximity of each other. In breast tissue, Grb2 can recruit SOS and Gab1 to the plasma membrane by binding to a specific phosphorylated tyrosine residue of HER2, a member of the epidermal growth factor receptor family. HER2 is overexpressed and activated in 20-30% of human breast cancers and correlates with poor patient prognosis. In transgenic mouse models, activated Neu, a rat analog of HER2, has shown the ability to induce mammary tumours. Given that Grb2 is a link between HER2 and tumourigenic signaling pathways, the goal of the current study was to investigate how loss of Grb2 expression affects mammary gland development and mammary tumourigenesis using a conditional Grb2 mouse model. Differences in protein expression, ductal outgrowth, delay in tumour onset, metastasis to the lung were some of the measurements taken to evaluate the role of Grb2. Also, parallel in-vivo experiments were conducted by using shRNA construct targeted to Grb2 in mammary gland tumour-derived cell lines. As expected, it was uncovered that Grb2 is required for normal mammary gland development and mammary tumour initiation in a HER2-induced mammary tumour mouse model but its mechanism of action has yet to be elucidated.Growth factor receptor bound protein 2(Grb2) est une protéine adaptatrice, exprimée demanière ubiquitaire, qui joue un rôle important dans une multitude de processus cellulaires tels que le développement mammaire et la genèse de tumeurs mammaires. Grb2 regroupe diverses protéines grâce à ses domaines d'homologie Src afin de permettre leur interaction. Dans les tissues mammaires, Grb2 peut recruter SOS et Gab1 à la membrane plasmique en se liant à une tyrosine spécifique, phosphorylée et localisée sur HER2, un membre de la famille des récepteurs du facteur de croissance épidermique. HER2 est sur exprimé et activé dans 20-30% des cancers du sein et est lié à un mauvais pronostic chez le patient. Plusieurs études effectuées à partir de modèles de souris transgéniques, ont démontrées la capacité d'ErbB2, l'analogue d'HER2 chez la souris, à induire des tumeurs mammaires. L'objectif de ma recherche est d'étudier les conséquences de l'ablation fonctionnelle et spécifique de Grb2. Un modèle de souris avec un knock-out spécifique de Grb2 au niveau des glandes mammaires permet d'étudier le rôle distinctif de la protéine dans le cadre de la genèse des tumeurs mammaires. Les différences au niveau de l'expression protéique de Grb2, la longueur des canaux lactifères, le délai au niveau de l'apparition de tumeurs et les métastases aux poumons détectés chez l'animal représentent quelques-uns des paramètres évalués afin de déterminer l'importance de Grb2 dans le développement des tumeurs mammaires. Parallèlement, des expériences in vitro tel l'utilisation de constructions shRNA ciblant l'ARN messager de Grb2 introduits dans une lignée cellulaire dérivée d'une tumeur de la glande mammaire, permettent d'élaborer sur le rôle de la protéine d'intérêt dans le développement des tumeurs mammaires.
16
Flaiz, Christine. „From merlin to tumourigenesis- the role of GTPases“. Thesis, University of Exeter, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489979.
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Rac1, Cdc42 and RhoA are small RhoGTPases, molecular switches that regulate protrusion and adhesion to other cells and the extracellular matrix. The tumour suppressor merlin controls and is itself regulated by Rac1. Merlin-deficiency has been linked to many protrusive structures like lamellipodia and ruffles, defective intercellular adhesion leading to loss of contact inhibition of growth, and increased adhesion to the extracellular matrix.
17
Basterfield, Laura. „Exercise and intestinal tumourigenesis in the Min mouse“. Thesis, University of Newcastle Upon Tyne, 2006. http://hdl.handle.net/10443/753.
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Colon cancer is the third most frequently diagnosed cancer in the UK and is often associated with a "Westenf' style of eating, high in fat and low in vegetables and fruits. There is strong epidemiological evidence that more physical activity is associated with reduced risk of colon cancer, but the amount or type of activity necessary to invoke this protection is disputed, and the mechanism responsible has not been elucidated. In this project, Min mice were used in studies of the impact of physical activity on development of intestinal neoplasia. These mice have a mutation at codon 850 in the Apc gene and develop multiple intestinal polyps spontaneously. The numbers, sizes and anatomical distribution of these lesions can be altered by dietary and pharmacological agents. From 5 weeks of age, male and female Min mice were exercised by running on a treadmill at up to 21 m/min for 30-60 min on a 5% slope for 5d/week for 10 weeks (TR). Additional groups of mice were provided with an exercise wheel (WH) or with no exercise (CON). Throughout the study, mice had ad libitum access to a Western-style high fat diet. Interleukin (IL)-6, IL-10, caecal transit time, colonic short chain fatty acids and natural killer cell cytotoxicity were investigated as potential protective mechanisms. On average, WH mice ran 2.99km/d (maximum 18.35km/d) compared with a maximum 0.96km/d for TR mice. Female mice were more willing treadmill runners and ran further in the wheels than did males. There was no significant reduction in total number of turnours or tumour burden in TR or WH compared with CON mice. Molar proportion of butyrate was significantly greater in TR mice compared with CON (P = 0.002). None of the other investigated mechanisms were different between exercise groups, although sex differences were observed for transit time. Non-exercise physical activity (NEPA) undertaken by the TR and CON mice was quantified for 23h per day (i. e. excluding period associated with treadmill running) using an Inframot device. NEPA was significantly higher for TR compared with CON mice (P=0.00 1), and for females compared with males (P<0.00 1). This study demonstrates that the turnour load in Min mice fed a high fat diet is not modulated by an exercise regime.
18
McEvoy, Katherina Yasmin. „The role of desmosomal cadherins in colorectal tumourigenesis“. Thesis, University of Birmingham, 2012. http://etheses.bham.ac.uk//id/eprint/3466/.
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In cancer, loss of intercellular contact contributes to tumour progression and invasion. Desmosomal cadherins are essential constituents of desmosomes – intercellular junctions that confer significant adhesive strength to epithelial tissues and cardiac muscle. Although changes in desmosomal components have been noted in a variety of cancers previously, this investigation has shown for the first time altered desmocollin expression in colorectal cancer. Real-time PCR and western blotting were used to assess desmocollin expression in a series of colorectal cancer and matched normal tissue samples. Loss of desmocollin 2 expression was observed in the cancer samples. In addition, de novo expression of desmocollins 1 and 3, which are not normally expressed in the colon, was observed. Desmoglein gene expression was also altered in the cancer samples. Although classical cadherin switching is a hallmark of the epithelial-mesenchymal transition, desmocollin switching has not previously been reported. Further experiments, to investigate the effect of loss of desmocollin 2 and desmoglein 2 on the behaviour of cultured cells were performed. In addition, experiments were carried out to identify those transcription factors that regulate desmosomal cadherin gene expression in the colon. Transcription factors of the CCAAT/enhancer-binding proteins family act as transcriptional activators of desmosomal cadherin promoters in colonic cells.
19
Sharma, Neil. „Novel binding partners of PBF in thyroid tumourigenesis“. Thesis, University of Birmingham, 2014. http://etheses.bham.ac.uk//id/eprint/4766/.
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Thyroid cancer is the most common endocrine cancer, with a rising incidence. The proto-oncogene PBF is over-expressed in thyroid tumours, and the degree of over-expression is directly linked to patient survival. PBF causes transformation in vitro and tumourigenesis in vivo, with PBF-transgenic mice developing large, macro-follicular goitres, effects partly mediated by the internalisation and repression of the membrane-bound transporters NIS and MCT8. NIS repression leads to a reduction in iodide uptake, which may negatively affect the efficacy of radioiodine treatment, and therefore prognosis. Work within this thesis describes the use of tandem mass spectrometry to produce a list of potential binding partners of PBF. This will aid further research into the pathophysiology of PBF, not just in relation to thyroid cancer but also other malignancies. From this list, the interaction with three proteins was further investigated and validated by GST pull-down assays and/or co-immunoprecipitation. Thyroglobulin is an essential component of thyroid hormone synthesis. Preliminary studies suggested co-localisation with PBF within intra-cellular vesicles, although further research is needed to explore this functionally. Cortactin has a role in the cellular transport of proteins, and also promotes invadopodia formation and metastases in cancer. Co-localisation was observed in vesicles and at the membrane, with PBF additionally demonstrated in cell membrane projections – indicating a potential mechanism for the shuttling of PBF to and from the cell membrane, and its secretion. SRC is a tyrosine kinase intimately linked to cancer. SRC phosphorylated PBF, an effect abrogated by treatment with specific inhibitors, including PP1. Importantly, PP1 treatment was then found to increase iodide uptake in human primary thyroid cultures over-expressing PBF. Overall, these data describe a list of possible binding partners for PBF, and specifically identify a novel potential therapeutic strategy for iodide-refractory thyroid cancer.
20
Cox, Adam. „Exploring mechanisms of prostate tumourigenesis in mouse models“. Thesis, Cardiff University, 2015. http://orca.cf.ac.uk/70907/.
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Many cell signalling pathways contribute to prostate cancer (PCa) initiation and survival, but the interplay between them remains poorly understood. In this thesis, conditional transgenic models were employed to investigate the impact of mutating the proto-oncogenes β-catenin, and Kras, and the tumour suppressor gene PTEN, alone and in combination within the murine prostate. β-catenin and Pten single mutants display progression from PIN to invasive adenocarcinoma that appears similar to human Gleason pattern 3. Tumours demonstrate co-activation of the Wnt, PI3K/Akt/mTOR, and Ras/MAPK pathways. Kras single mutants develop PIN but do not progress to adenocarcinoma. Double and triple mutants develop more aggressive tumours comparable to Gleason pattern 4. Furthermore, double and triple mutants display upregulated Wnt, PI3K/Akt/mTOR and Ras/MAPK signalling. Expression of p63 negatively correlates with tumour grade, and moreover, progression from PIN to invasive adenocarcinoma is characterised by the synergistic elevation of AR and Ki67, which parallels human PCa. Malignant transformation of a normal prostate epithelial stem cell (PrSC) gives rise to the cancer stem cell (CSC), which may contribute to castrate-resistant PCa. In this study a 3D primary tissue culture assay was optimised to allow maintenance and expansion of prostate cells that display stem-like characteristics in vitro. PrSCs can be isolated by fluorescence activated cell sorting for the antigenic profile Lin-Sca1+CD49f+TropHi, and consistently form spherical structures in Matrigel. PrSCs can withstand multiple round of passage in vitro, and demonstrate the ability to maintain an undifferentiated state. PrSC spheres possess a basal phenotype, supporting a basal location of PrSCs in prostate epithelium. In summary, these mouse models of PCa demonstrate cooperation between important cell signalling pathways in prostate tumourigenesis, and provide a platform for testing novel therapeutics. In addition, the successful isolation and cultivation of cells with stem-like attributes will allow their unique biological properties to be explored further, providing a baseline standard with which to compare the function of CSCs.
21
Tordella, Luca. „Investigation of the role of ASPP2 in tumourigenesis“. Thesis, University of Oxford, 2012. http://ora.ox.ac.uk/objects/uuid:08fd41ee-14f4-4715-9629-b20955be4eb8.
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The skin is the site where two of the most common types of epithelial cancer, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), arise. In this work, we have investigated how ASPP2, a member of a family of proteins that interact with the p53 family, can affect skin tumourigenesis. ASPP2 is expressed in the squamous epithelia of various organs, localising exclusively in the upper and most differentiated layers. We show here that Balb/c ASPP2-null and heterozygous mice develop spontaneous SCCs. To investigate how the absence of ASPP2 from the epithelial compartment could lead to tumour formation, we analysed ASPP2’s relationship with pathways involved in the normal homeostasis of the epithelium, such as p63 and Notch. ΔNp63 is the main p63 isoform expressed in the adult epidermis, and its function is to drive the proliferation of the basal keratinocytes. Aberrant or misplaced activation of ΔNp63 in the epithelium is a known initiating cause for SCC. Consistent with this, ΔNp63 was found to be highly expressed in tumours derived from ASPP2-deficient mice. Our results indicate that ASPP2 is important in limiting ΔNp63 expression in the differentiated epithelium, preventing cell proliferation in the upper layers of the skin. This is achieved by antagonising ΔNp63 transcript and protein expression, resulting in a mutually exclusive expression pattern during differentiation of keratinocytes, as well as in epithelial cancer. ASPP2 expression was found reduced or lost in human SCC cell lines and during head and neck cancer progression, reflecting what was observed in ASPP2-deficient mice. Overall, our results indicate a possible mechanism by which p63 expression can be regulated in the skin, and provide a new model for the spontaneous formation of SCC in vivo. Additionally, we found that ASPP2 can cooperate with and enhance the activity of skin pro-differentiation pathways, such as Notch. In contrast to p63, ASPP2 and Notch1 are co-expressed in the differentiated layers of the squamous epithelium. Moreover, ASPP2 can interact with components of Notch nuclear transcriptional machinery, and it is shuttled into the nuclear compartment upon activation of Notch pathway. This recruitment results in modulation of Notch transcriptional activity on specific target genes with a differential pattern of binding sites, providing new insights into the understanding of Notch transcriptional regulation.
22
Sharfeddin, Essam. „The role of gamma-synuclein in mammary gland tumourigenesis“. Thesis, Cardiff University, 2012. http://orca.cf.ac.uk/44541/.
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Abstract y-synuclein is the third and last discovered member of the synuclein family, it is expressed mostly in the nervous system and its physiological function is still unknown. y-synuclein has been claimed to play a role in mammary gland tumourigenesis as its overexpression in cancer cells was shown to inhibit apoptosis and stimulate growth, proliferation, survival, motility and metastasis. However, the role of endogenous y-synuclein in mammary gland tumourigenesis has not been studied in an appropriate in vivo model. The results obtained in this study show that y-synuclein is not required for the normal development of the mammary gland at any developmental stage - embryonic, pubertal or reproductive. Furthermore, ablation of y-synuclein did not prevent induction of mammary gland tumours by activated ErbB2 transgene in mammary gland epithelium. Unexpectedly, transgenic activated ErbB2 hemizygous, y-synuclein knockout female mice developed slightly more tumours with a significantly shorter tumour latency than the wild type littermates. These animals also exhibited similar tumour growth rates and metastases to the lungs, and a slightly shorter survival. Overall, a trend for accelerated tumourigenesis in the absence of y-synuclein was observed. Thus, it is feasible that the aberrant expression of y-synuclein reported in advance-stage tumours and metastases reflects activation of pathways aimed at repressing rather than enhancing tumourigenesis, as widely thought. Future studies will clarify the role of y-synuclein in ErbB2-induced mammary gland tumourigenesis.
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Qin, Xiao. „The role of ASPP2 in intestinal homeostasis and tumourigenesis“. Thesis, University of Oxford, 2017. https://ora.ox.ac.uk/objects/uuid:a2d76d06-4361-4a39-8050-fd8a66a29218.
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The intestinal epithelium represents one of the most actively renewing tissues in the body, and is widely used as a model system to study epithelial cell biology. ASPP2, a member of the ASPP (apoptosis stimulating protein of p53) protein family, has been shown to act as a regulator of epithelial cell polarity and tumour suppressor. This study investigated whether the dual function of ASPP2 is involved in the regulation of intestinal homeostasis and tumourigenesis, with a particular interest in the distinction between epithelial cell autonomous and non-autonomous mechanisms. Germline and intestinal epithelial cell-specific ASPP2 conditional knockout mice were employed in this study. Deficiency of ASPP2 in the intestinal epithelium resulted in delayed recovery from dextran sulfate sodium (DSS)-induced acute colitis, concurrent with a reduction in the expression of proinflammatory cytokines such as interleukin (IL)-1β and IL-6. Moreover, ASPP2-deficient mice showed increased susceptibility to Azoxymethane/DSS-induced colorectal tumourigenesis. While wild-type and ASPP2-deficient crypts showed similar incidence of tumour formation, the local immune microenvironment of ASPP2-deficient mice favoured tumour progression. The intestinal organoid culture was established to supplement in vivo experiments. The feasibility of the system was demonstrated with small intestinal organoids, in the context of proliferation, differentiation, and cell death. Using the established workflow, a colonic organoid-based tissue regeneration model was developed. The intrinsic susceptibility of organoids to DSS-induced cell death was not affected by the loss of ASPP2. However, ASPP2-deficient colonic organoids were less responsive to the pro-proliferative effects of IL-6, but were more sensitive to tumour necrosis factor-α-induced cell death in the presence of IL-22. In conclusion, this project undertook parallel examinations of animal models and organoids, demonstrating that a deficiency of ASPP2 in the intestinal epithelium results in dysregulated epithelial-immune cell interactions. This may partially explain the pathological conditions observed in ASPP2-deficient mice. Importantly, this study highlights the possibility of using organoids to investigate epithelial cell non-autonomous factors implicated in intestinal pathogenesis.
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Perrett, Rebecca Mary. „The human germ cell lineage : pluripotency, tumourigenesis and proliferation“. Thesis, University of Southampton, 2008. https://eprints.soton.ac.uk/66010/.
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25
Silva, Lara Marques Loureiro. „ASPP2 regulating p63/p73 and Notch pathways in tumourigenesis“. Master's thesis, Universidade de Aveiro, 2012. http://hdl.handle.net/10773/10878.
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Mestrado em Biotecnologia MolecularNa pele surgem dois dos tipos mais comuns de cancro epitelial, o carcinoma basocelular (BCC) e o carcinoma escamoso da pele (SCC). Neste trabalho, investigámos como ASPP2, membro da família de proteínas que interage com a família p53, pode afectar a tumurigénese da pele. Estudou-se a regulação por ASPP2 das vias de sinalização envolvidas na homeostasia normal do tecido epitelial, tais como as vias de p63 e Notch. A activação anormal de ΔNp63 no epitélio é uma causa conhecida para o surgimento do SCC e os nossos resultados indicam que a ASPP2 é importante a limitar a expressão de ΔNp63 no epitélio diferenciado, prevenindo a proliferação das células na pele. Para além disso, observámos que ASPP2 coopera com vias de sinalização pró-diferenciação, tais como as de Notch e p73. Os nossos resultados mostram um possível mecanismo pelo qual a expressão de p63 pode ser regulada na pele e sugerem um novo modelo para a formação espontânea de SCC.
The skin is where two of the most common types of epithelial cancer, basal cell carcinoma (BCC) and squamous cell carcinoma (SCC), arise. In this work, we have investigated how ASPP2, a member of a family of proteins that interact with the p53 family, can affect skin tumourigenesis. We analysed the regulation of ASPP2 in pathways involved in the normal homeostasis of the epithelium, such as the p63 and Notch. Aberrant or misplaced activation of ΔNp63 in the epithelium is a known initiating cause for SCC and our results indicate that ASPP2 is important in limiting ΔNp63 expression in the differentiated epithelium, preventing cell proliferation in the skin. Additionally, we found that ASPP2 can cooperate with skin pro-differentiation pathways, such as Notch and p73. Overall, our results indicate a possible mechanism by which p63 expression can be regulated in the skin, and provide a new model for the spontaneous formation of SCC.
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Stefanatos, Rhoda Katerina Anne. „Modelling tumourigenesis and the stress response in Drosophila melanogaster“. Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4865/.
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Chung, Ho Ki Kathryn. „Investigating the role of iASPP in skin homeostasis and tumourigenesis“. Thesis, University of Oxford, 2014. http://ora.ox.ac.uk/objects/uuid:60af22a6-c9d6-41a7-bd60-f6795e75d882.
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Heroux, Devon. „The role of an ErbB2 splice form in mammary tumourigenesis“. Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=107895.
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Breast cancer is the second most common cancer in women, after skin cancer. Of particular severity in the disease is the ErbB2 subgroup, which represents 20-30% of all breast cancers, and has poor clinical prognosis. Various isoforms of ErbB2 exist, including an exon 16 removed form denoted ErbB2ΔEx16. This splice isoform has shown to play a role in drug resistance of the ErbB2 targeted therapeutic antibody Herceptin. Understanding the role this splice form has in resistance to other drugs is therefore essential for an effective regimen of therapeutics. Dasatinib, lapatinib and bosutinib are three examples of inhibitors currently being studied in breast cancer. This study aims to characterize the resistance that ErbB2ΔEx16 confers to these inhibitors, through differences in microscopic characteristics, signaling pathways, inhibitory concentrations, apoptosis, and proliferation. Taken together, these properties demonstrate the need for ErbB2ΔEx16 status to be taken into account during clinical treatment and in the design of novel therapeutics.Cancer du sein est le cancer le plus fréquent chez les femmes après le cancer de peau. D'une particulière gravité de la maladie est le sous-groupe ErbB2, qui représente 20-30% des cancers du sein, et a mauvais pronostic clinique. Différentes isoformes de ErbB2 existent, y compris un exon 16 forme enlevée désignée ErbB2ΔEx16. Cette isoforme d'épissure joue un rôle dans la résistance aux medicaments. Cette isoforme d'épissure joue un rôle dans la résistance aux médicaments de l'Herceptin ErbB2 d'anticorps thérapeutiques ciblées. Comprendre le rôle que cette forme d'épissage a dans la résistance aux autres médicaments est donc essentiel pour un traitement efficace des thérapies.Le dasatinib, le lapatinib et bosutinib sont trois exemples d'inhibiteurs actuellement étudiés dans le cancer du sein. Cette étude vise à caractériser la résistance que lui confère ErbB2ΔEx16 à ces inhibiteurs, à travers les caractéristiques microscopiques, et les différences dans les voies de signalisation, les concentrations inhibitrices, l'apoptose et la prolifération. Pris ensembles, ces propriétés montrent la nécessité de l'état de ErbB2ΔEx16 d'être pris en compte lors du traitement clinique et dans la conception de nouveaux traitements.
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Ranger, Jill. „Stat3 as a multifaceted regulator of mammary tumourigenesis and metastasis“. Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110488.
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Many forms of cancer express activated Stat3, a pleiotropic transcription factor that is implicated in pro-tumourigenic signaling in a variety of cancer cell lines, revealing that it may be important for tumour onset, progression, and malignancy. Yet, the role of Stat3 in the context of tumourigenesis in vivo is still unclear. Downstream of an activated form of ErbB2, we have demonstrated that Stat3 is dispensable for in vivo tumour initiation but is crucial for metastasis. Conversely, the loss of Stat3 in a novel inducible model of PyVMT-driven tumourigenesis revealed that Stat3 is necessary for tumour initiation downstream of this oncogene suggesting that the role of Stat3 may be dependent on oncogenic context.The metastatic phenotype observed in the activated-ErbB2 animals was attributed to both tumour cell intrinsic and microenvironmental interactions which are regulated downstream of Stat3. Indeed, Stat3 ablation causes these tumours to grow more slowly and produce less vasculature. Even when introduced directly into the vasculature, tumour cells lacking Stat3 were impaired in lung colonization, a defect that occurs early in the establishment of metastatic lung lesions. Although activated-ErbB2 tumours lacking Stat3 have reduced levels of proliferation, cell lines established from these tumours grow at the same rate regardless of Stat3 status. However, Stat3-null tumour cells do not migrate or invade a matrix to the same extent as the wildtype tumour cells. In addition, Stat3-deficient cells had stronger E cadherin localization at adherens junctions and appear to have more stable focal adhesions. These cell-autonomous changes show that Stat3 plays a role within the tumour cells in vitro. In addition to the in vitro changes we observed, we also suspect that Stat3 expression in tumour cells in vivo alters the immune microenvironment. Loss of Stat3 caused a decrease in a number of cytokine factors, including CCL5, a leukocyte chemotactic factor. Using an immunophenotyping protocol, the infiltration of major immune cell subtypes were assessed in both wildtype and Stat3-null tumours. Additionally, fewer macrophages were recruited to growing ErbB2-type tumours in the absence of Stat3.We believe that Stat3 may regulate tumour cell intrinsic activities, such as cell proliferation, while also mediating interactions between the tumour cells and the tumour microenvironment, particularly the immune microenvironment. Therefore, Stat3-targeted therapies may not only inhibit growth of the tumour cells at a cell-autonomous level, but may also impair communication between tumour cells and the pro-tumour immune microenvironment.Plusieurs formes de cancers expriment le facteur de transcription pléiotropique Stat3 sous une forme active. Stat3 est impliqué dans les voies de signalisation pro-tumorales de plusieurs lignées cellulaires, révélant son rôle clef dans l'apparition, la progression et la malignité cancéreuse. Cependant, le rôle de Stat3 dans le développement du cancer du sein in vivo reste à être élucidé. Nous avons démontré que Stat3, dans un modèle murin exprimant une forme active du récepteur ErbB2 (ErbB2-actif), n'est pas essentiel à l'apparition de tumeurs, mais est crucial à la formation de métastases. Inversement, la perte de Stat3 dans le modèle inductible tumoral PyVMT révèle que Stat3 est nécessaire à l'initiation de tumeurs en aval de cet oncogène, suggérant que le rôle de Stat3 puisse être dépendent du contexte tumorigène.Le phénotype métastasique observé dans les animaux ErbB2-actif est attribuable aux interactions dans les cellules tumorales elles-mêmes, mais aussi aux interactions entre les cellules tumorales et leur microenvironnement, interactions régulées en aval de la protéine Stat3. En effet, l'ablation de Stat3 provoque le ralentissement de la croissance de ces tumeurs et la diminution de la vascularisation. Même introduites directement dans la veine caudale des souris, les cellules tumorales dépouvues de Stat3 ne s'établissent pas dans les poumons avec la même ampleur que les cellules exprimant Stat3 et sont ainsi affectées à des stades précoces de la colonisation métastastique. Bien que les tumeurs ErbB2-actif dépourvues de Stat3 ont des niveaux réduits de prolifération, les lignées cellulaires établies de ces tumeurs croissent à la même vitesse que les cellules exprimant Stat3. Cependant, les cellules provenant des tumeurs privées de Stat3 montrent des niveaux de migration et d'invasion cellulaire diminués par rapport aux cellules contenant Stat3. De plus, les cellules déficientes en Stat3 arborent une localisation de la protéine E-Cadhérine plus marquée aux jonctions adhérentes et semblent posséder des adhésions focales plus stables. Ces changements cellulaires indiquent que Stat3 joue un rôle considérable dans les cellules tumorales in vitro.En plus des changements in vitro observés, nous croyons que l'expression de Stat3 dans les cellules tumorales modifie le microenvironnement immunitaire. En effet, la perte de Stat3 cause une diminutions de plusieurs cytokines incluant CCL5, une chimiokines. À l'aide d'un protocol d'immunophénotypique, nous avons établi les niveaux relatifs des sous-types de cellules immunitaires dans les tumeurs exprimant ou déficientes en Stat3. De plus, en absence de Stat3, moins de macrophages est recruté dans les tumeurs ErbB2-actif en croissance.Nous croyons que Stat3 pourrait contrôler les activités intrinsèques des cellules tumorales telles que la prolifération, mais aussi les interactions entre cellules tumorales et leur microenvionnement, en particulier le microenvionnement immunitaire. Des thérapies ciblant Stat3 pourraient non seulement inhiber la croissance des cellules tumorales elles-mêmes, mais aussi annihiler la communication entre les cellules tumorales et le miroenvionnement immunitaire pro-tumoral, conduisant ainsi à un traitement plus efficace pour les patients atteints de cancers du sein.
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Lees, Nicholas Peter. „DNA alkylation damage and repair in human colorectal mucosal tumourigenesis“. Thesis, University of Oxford, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.393518.
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Daly, Carl S. „The roles of the Apc proteins in homeostasis and tumourigenesis“. Thesis, Cardiff University, 2013. http://orca.cf.ac.uk/51008/.
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The adenomatous polyposis coli (APC) gene encodes a multifunctional tumour suppressor protein that is essential for normal development. The most characterised role of APC is its ability to mediate the Wnt signaling pathway, a pathway disrupted in the majority of human cancers. The identification of a second adenomatous polyposis coli gene (APC2) which possesses many shared structural characteristics with APC and potentially comparable functions raises the possibility that APC2 also functions both in development and in tumour suppression, and that some redundancy may exist between the two proteins. Analysis of these proteins in the mouse has been hampered due to the lethality of the Apc mutation and the lack of a suitable Apc2 mutation. However, to circumvent the first of these difficulties, Cre-lox technology was employed to conditionally delete Apc in adult mouse tissues and so study its function in vivo. To circumvent the second difficulty, a novel Apc2 null allele had become available from the laboratory of Professor Hans Clevers. Remarkably, constitutive deletion of Apc2 does not lead to embryonic lethality, permitting study of the effects of Apc2 deficiency within adult tissues. In this thesis I aimed to characterise the consequences of Apc2 loss alone, and in the context of tissue specific Apc loss, in a range of tissues. Apc2 deficiency led to subtle changes in Wnt signaling in the intestines and liver however, no detectable differences of this pathway were apparent within the mammary gland. Phenotypically, altered homeostasis was only observed within the intestines. Apc2 deficiency led to an increase in epithelial cell division, an increase in markers of intestinal stemness and increases in intestinal cell migration. However, loss of Apc2 failed to induce tumourigenesis in the intestines or indeed any other tissue. In the context of Apc loss, the effect was dependent upon the tissue. Within the intestines, additional loss of Apc2 altered the immediate phenotype of Apc loss but failed to modify Apc induced tumourigenesis. Within the mammary gland, whilst either Apc protein alone was dispensable, combined loss synergised to disrupt homeostasis and drive tumourigenesis. Contrary to this, in the liver the additional loss of Apc2 attenuated tumourigenesis induced by reduced levels of Apc. Together, these studies highlight the importance of these proteins and their interactions and redundancies in homeostasis and tumourigenesis.
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Stratford, Anna. „Molecular mechanisms of the PTTG Binding Factor (PBF) in tumourigenesis“. Thesis, University of Birmingham, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433637.
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Pollock, Claire B. „The role of oncogenic K-Ras signalling in colorectal tumourigenesis“. Thesis, University of Glasgow, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.398766.
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Cooke, James C. „Molecular investigations of phaeochromocytoma tumourigenesis in von Hippel-Lindau disease“. Thesis, University of Newcastle Upon Tyne, 2005. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.417558.
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Pantazi, Eleni. „The role of GLI2 in human basal cell carcinoma tumourigenesis“. Thesis, Queen Mary, University of London, 2010. http://qmro.qmul.ac.uk/xmlui/handle/123456789/508.
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Abnormal Sonic Hedgehog (SHH) signalling leads to increased transcriptional activation of its downstream effector, GLI2, which is implicated in the pathogenesis of a variety of human tumours, including human basal cell carcinoma (BCC). However, little is known about the molecular mechanisms underlying the tumourigenic role of GLI2 in human skin keratinocytes. This study examines the effects of inducible and stable expression of constitutively active GLI2 (GLI2:N) oncogenic transcription factor, on immortalised human epidermal keratinocytes. It is shown here that GLI2:N overexpressing N/TERT keratinocytes display gene expression patterns and phenotypic characteristics reminiscent of those observed in human BCC in vivo. It is also shown for first time, that expression of GLI2:N in N/TERT keratinocytes is sufficient to induce accumulation of binucleated/tetraploid cells as evidenced by an increase in G2/M phase of the cell cycle and binucleate cell counting, and to promote polyploidy and aneuploidy, in the absence of increased cell death or apoptosis. This cell cycle deregulation is accompanied by strong activation of anti-apoptotic protein BCL-2 and simultaneous suppression of important cell-cycle regulators such as 14-3-3σ and CDK inhibitor p21WAF1/CIP1, with no change in p53 protein levels, indicating uncontrolled proliferation of cells with ploidy abnormalities and/or DNA damage. Consistently, it is shown that p21WAF1/CIP1 protein is also absent in human BCC tumours and that forced overexpression of GLI2:N renders human keratinocytes resistant to apoptosis mediated by ultraviolet B (UVB, 290-320 nm), one of the most important etiological factors in BCC formation. Karyotype analysis of GLI2:N N/TERT keratinocytes further demonstrates that overexpression of GLI2:N induces numerical (tetraploidy, polyploidy, aneuploidy) and structural instability in N/TERT keratinocytes including chromosomal translocations and double minute chromosomes. Furthermore, β-catenin activation is the most common alteration observed during aberrant WNT signalling, and is often implicated in the development of human carcinogenesis and metastasis. In this study it is shown that GLI2:N induction induces nuclear accumulation of β-catenin in keratinocyte cell culture and in the basal layer of organotypic skin rafts, similar to human BCCs. In addition, several WNT genes were found to be upregulated upon GLI2:N induction, while β-catenin transcriptional activity is increased upon stable and conditional expression of GLI2:N. Overall these data give new insights for the possible mechanisms that mediate the tumourigenic potential of GLI2.
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Niederreiter, Lukas. „Endoplasmic reticulum (ER) stress transcription factor Xbp1 in intestinal tumourigenesis“. Thesis, University of Cambridge, 2015. https://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.708846.
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Benedykcinska, A. M. „Multiple roles of β-catenin in brain development and tumourigenesis“. Thesis, University College London (University of London), 2014. http://discovery.ucl.ac.uk/1436079/.
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β-catenin is a multifunctional protein with roles in Wnt pathway signal transduction and in cell adhesion. While the normal function of β-catenin is important for CNS development, Wnt pathways have also been intrinsically linked to cancer. Here, the multiple roles of β-catenin in CNS development and in brain tumour pathogenesis were investigated. All experiments used a mouse model where a dominant active form of β-catenin can be induced by Cre mediated recombination of the exon 3 of the CATNNB gene. Three models were established to analyse the effects of dominant active β-catenin: (i) during development with En2Cre, in the midbrain-hindbrain regions, (ii) in mature (L7Cre) Purkinje neurons, and (iii) in adult stem cells using Cre delivery into the SVZ using an established and a specifically developed novel method. En2Cre;β‐cateninlox(ex3) mice express mutant β-catenin in the midbrain-hindbrain junction during early brain development. Although En2 is expressed between E8 and E12.5, the precise timing and duration of stabilized β‐catenin is not known. At later stage, these mice showed decreased motor performance, caused by a significant defect in the vermis region. This phenotype could be rescued by deletion of p53 gene, pointing at a potential role of p53/β-catenin cross-talk. In contrast, constitutive activation of β-catenin in mature cerebellar Purkinje neurons using the L7Cre; β-cateninlox(ex3) model, does not cause cell death or dysfunction of these neurons. To target SVZ stem/progenitor cells, we used an established model with adenovirus-Cre mediated recombination and we developed a highly selective approach through direct, intraventricular injection of Endoxifen into GLAST-Cre(ERT2) mice. Both approaches resulted in similar phenotypes and latencies to tumour development, and required at least one additional tumour suppressor to be inactivated simultaneously to cause brain tumours. The results suggest that β-catenin has diverse effects during different developmental stages. During early development, it causes widespread cell death, whilst no effect is seen in mature cells. In adult SVZ progenitor cells it has no effect unless tumour suppressor genes such as p53 or PTEN are concomitantly inactivated, resulting in formation of brain tumours.
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Grant, Nicola Joan. „Reassessing the role of Cyclin-dependent kinase 5 in tumourigenesis“. Thesis, University of Dundee, 2014. https://discovery.dundee.ac.uk/en/studentTheses/e642934d-14f9-4f12-b476-a22629d4b89e.
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The discovery of Cyclin-dependent 5 (Cdk5) added a new member to the mammalian Cdks, appearing uncharacteristic of its family members despite strong sequence homology. In contrast to the mitotic Cdks, Cdk5 exerts no apparent role in cell cycle regulation therefore its potential role in cancer is subject to much controversy. Cdk5 is heavily depicted as a neuronal-specific kinase, due to its association with neuronal activators, and dysregulation of Cdk5 activity is thought to contribute to the pathogenesis of several neurodegenerative diseases, including Alzheimer’s disease. Nonetheless, the physiological functions of this kinase are being complicated by an upsurge in potential substrates that implicate Cdk5 activity in extra-neuronal functions and diseases such as cancer. However, the predicted substrates fail to meet a general consensus sequence and are yet to be fully validated in vivo. Furthermore, the involvement of Cdk5 in pathophysiological pathways is only partially understood. Adding further complexity, truncation of the Cdk5 cofactor, p35 is thought to increase the catalytic ability of the Cdk5 complex and alter its substrate specificity profile, although little evidence has been provided to support this claim. In the present study, in vitro peptide analysis was performed in an attempt to identify a consensus sequence that regulates Cdk5 substrate phosphorylation, as a consensus for Cdk5 substrate selection is generally considered degenerative. Despite this theory, Cdk5 displayed high peptide selectivity that was shown to be distinct from other members of the CMGC family of proteins to which it belongs. While Cdk5 showed a preference for basic residues, interestingly, it was the presence of a proline residue located N-terminally (-2) relative to the phosphoacceptor residue that appeared to dictate substrate phosphorylation. Further in vitro analysis using full-length proteins confirmed a correlation between substrates possessing the optimal consensus residues and substrate phosphorylation; those containing these residues were phosphorylated to a greater extent in vitro compared to those lacking these residues. Furthermore, both Cdk5 complexes displayed similar substrate profiles and inherent catalytic ability, as determined by comparison of phosphorylation kinetic parameters between complexes, despite the notion of a hyperactive complex with altered substrate specificity following activator truncation. Following manipulation of Cdk5 activity in cell lines and intact tissue, tau and CRMP2 were confirmed as Cdk5 targets. Subsequently, a panel of total and phospho-specific antibodies to each substrate was assessed for compatibility with the immunohistochemistry protocol to serve as a surrogate for examining Cdk5 activity in tumours. For the first time, this study presents abnormal CRMP2 phosphorylation at a Cdk5 sensitive site in the nuclei of lymphoma, lung, and breast tumour cells, implicating Cdk5 activity in tumourigenesis. Furthermore, this is the first implication of long-form CRMP2 (CRMP2A) in the nucleus and potentially the isoform associated with cancer. Overall, the data presented in this study provides a platform in which to improve mechanistic insight into tumourigenesis in specific forms of cancer, which will potentially provide new diagnostic and therapeutic strategies for cancer in the near future.
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Ma, Jingyi. „Investigating the role of factor inhibiting HIF (FIH) in tumourigenesis“. Thesis, University of Oxford, 2017. http://ora.ox.ac.uk/objects/uuid:5a3100e0-7875-4c05-9a63-494932d44335.
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The tumour microenvironment (TME) is frequently hypoxic and inflammatory, leading to the activation of the Hypoxia-Inducible Factor (HIF) family of transcription factors. HIF has been shown to exert broad, and sometimes controversial, effects on tumour progression through the induction of over 70 effector genes. Factor Inhibiting HIF (FIH), an oxygen-dependent hydroxylase of HIF, inhibits the transcription of selective HIF target genes, and is hence a potential therapeutic target to fine-tune HIF activity. However, how FIH may affect tumourigenesis has not been comprehensively investigated. By monitoring the spontaneous tumour formation in mice, it was found that a lack of FIH expression does not profoundly affect the lifespan but accelerates the development of low-grade B cell lymphomas. To investigate whether FIH could suppress tumourigenesis via modulating the TME, syngeneic tumour models were employed on FIH-deficient animals. Reduced FIH expression in the host promotes tumour growth, which is recapitulated by FIH deletion only in the myeloid compartment. Tumours in mice deficient of myeloid FIH exhibit an altered immune profile, reflected by the increased expression of programmed death-ligand 1 (PD-L1) and Arginase 1 (ARG1) in tumour-associated macrophages (TAMs) and a reduced CD4 T cell population. In vitro characterisation of FIH-deficient macrophages reveals that FIH suppresses cell migration to C5a and CCL5, and affects the expression of several inflammatory mediators including PD-L1 and ARG1. Importantly, the transcription of FIH is upregulated in macrophages by tumour cell-conditioned media as well as bacterial infection. Altogether, this study provides the genetic evidence for the role of FIH in tumour suppression, which may result from its influence on the myeloid-mediated immune response. Therefore, FIH represents a new candidate regulator of the TME and can be implicated in other inflammatory conditions such as infection.
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Gan, Pei Pei Children's Cancer Institute Australia for Medical Research Faculty of Medicine UNSW. „Determining the role of β-tubulin isotypes in drug resistance and tumourigenesis in lung cancer cells“. Publisher:University of New South Wales. Children's Cancer Institute Australia for Medical Research, 2009. http://handle.unsw.edu.au/1959.4/43357.
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Non-small cell lung cancer (NSCLC) is the leading cause of cancer-related death worldwide and in its advanced stage, has a poor clinical outcome. Resistance to chemotherapeutic agents, either intrinsic or acquired, is the primary cause of treatment failure in NSCLC. Tubulin binding agents (TBAs), such as paclitaxel and vinorelbine are important components in the treatment of NSCLC. Upregulation of the neuronal specific class III β-tubulin (β-III-tubulin) is frequently found in drug resistant cancer cell lines and human tumours, lending support that βIII-tubulin might play a role in the development of drug resistance in cancer cells. However, to date, compelling evidence supporting its direct role in drug resistance and response has been lacking. To address its role in NSCLC, RNA interference (RNAi) was employed to knock down βIII-tubulin expression in two drug naive NSCLC cell lines, Calu-6 and H460. Specific knockdown of βIII-tubulin resulted in increased sensitivity to TBAs and DNA damaging agents, two classes of agents that are commonly used in the treatment of NSCLC. Increased sensitivity to TBAs and DNA damaging agents in the βIII-tubulin knockdown cells was due to an increased propensity of the cells to undergo apoptosis, suggesting that this tubulin isotype may be a cellular survival factor. Interestingly, specific knockdown of βII- or βIVb-tubulin hypersensitised the cells to Vinca alkaloids but not taxanes, demonstrating that each isotype is unique in terms of drug-target interactions. Moreover, the β-tubulin isotype composition of a cell can influence response, and therefore resistance to TBAs. To determine whether βIII-tubulin differentially regulates microtubule behaviour and influences cell proliferation via an effect on microtubule dynamics, siRNAs were used to knockdown βIII-tubulin expression in H460 cells stably expressing GFP-βI-tubulin and the dynamic instability behaviour of individual microtubules was measured by time-lapse microscopy. In the absence of drug, silencing of βIII tubulin alone did not significantly affect the dynamic instability of interphase microtubules. However, at the IC50 for proliferation of either paclitaxel or vincristine, the overall dynamicity was suppressed significantly in the βIII-tubulin silenced cells as compared to the control, indicating that βIII-tubulin knockdown induces paclitaxel or vincristine sensitivity by enhancing the ability of these agents to suppress microtubule dynamics. At a concentration of drug that represented the IC50 for mitotic arrest, for either paclitaxel or vincristine, increased apoptosis induction was found to play a dominant role in βIII-tubulin knockdown, further supporting a role for βIII-tubulin as a cellular survival factor. Collectively, when βIII-tubulin is overexpressed in tumours cells, it is highly likely to be promoting cellular survival and resistance to TBAs. In addition to its proposed role in drug resistance, high expression of βIII-tubulin in tumours of non-neuronal origin such as NSCLC, has been positively correlated with the degree of tumour aggressiveness. H460 cells are known to display substrate- independent growth in soft agar and tumourigenicity in nude mice and provided an ideal model to investigate the role of βIII-tubulin in tumourigenesis. To address the role of βIII-tubulin, H460 cells stably expressing βIII-tubulin shRNA were generated, validated and examined using both in vitro and in vivo methods of tumourigenesis. Colony formation of H460 cells stably expressing βIII-tubulin shRNA was dramatically reduced in soft agar and significantly delayed tumour growth and reduced tumour incidence of subcutaneous xenografted tumours in nude mice when compared to respective controls. These results provide new insights into the function of βIII-tubulin and suggest that βIII-tubulin may play an important role in tumour development and progression in lung cancer. In conclusion, β-tubulin isotype status can serve as a valuable molecular marker capable of distinguishing patients with differential sensitivity to TBAs. These results not only shed new light on the role of specific β-tubulin isotypes in the response to TBAs, but also the role of βIII-tubulin in the biology of cancer that will lead to new treatment strategies for NSCLC.
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Park, Hyun-Sook. „Crypt fission in the spread of muted clones in the intestinal epithelium“. Thesis, Imperial College London, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.266423.
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Coy, Joanna Lucy. „Epstein Barr nuclear antigen 1 induced lymphoma in transgenic mice“. Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241746.
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Miao, Yu Rebecca. „The role of c-Myb in mammary gland development and tumourigenesis“. Connect to thesis, 2009. http://repository.unimelb.edu.au/10187/7069.
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c-Myb/MYB is an established and key player in hematopoietic malignancies but more recently a strong case for c-Myb as an oncogene in breast cancer has emerged. c-Myb and its transcriptional target genes have direct bearing on tumour initiation and progression and thus this has opened new opportunities to the development of therapeutic approaches in a range of cancer types with the aim of treating cancer at its various stages. In this study, the requirement of c-Myb during mammary gland tumourigenesis is being examined. In addition a direct therapeutic approach to targeting c-Myb-driven gene grp78/GRP78 in the context of primary and metastatic breast cancer was assessed.The first aim of this study is to examine the expression of c-Myb during normal mammary gland development. The expression of c-Myb is extensively characterised in a temporal and spatial fashion. Nuclear staining of c-Myb by immunohistochemisty was found to be most elaborately expressed in the ductal epithelium during early mammary gland development. Mouse mammary gland lacking c-myb showed disorganised ductal structure in virgin mice, but did not affect subsequent pregnancy and lactation.
To extend the view that c-Myb is involved in mammary tumourigenesis c-myb-transduced immortalised mammary epithelial cells and two mammary tumour prone transgenic mouse models were examined. NMuMG cells transduced with c-myb showed enhanced proliferation and reduced Annexin V staining consistent with the protection from apoptosis. This reduced apoptosis is consistent with, and perhaps contingent upon, the elevated expression observed for bcl-2 and grp78. The data assembled by expression studies raised the possibility that c-Myb is essential for the establishment of mammary gland tumor in both MMTV-Neu and MMTV-PyMT spontaneous mammary gland tumor models. Loss of c-Myb expression in these models significantly delayed and in most instances completely abolished the onset of mammary gland tumours in both models. Preliminary evidence also indicated that Stat3 phosphorylation may underpin the elevated c-Myb expression in mouse mammary tumour cells.
The focus of my thesis then shifted to examining ways to exploit elevated c-Myb target gene GRP78 expression on the cell surface of mammary tumour cells. To do this I employed a GRP78 binding pro-apoptotic chimera peptide that specifically binds to GRP78 where I examined its efficacy against primary and metastatic breast cancer models. My results demonstrated the anti-tumour activity of the GRP78-chimera peptide both in vitro and in vivo. More importantly, the peptide is also effective at prolonging disease-free survival in mice with established metastatic disease.
Evidence obtained within these studies suggests that c-Myb plays an important role in mammary gland development and tumourgenesis. Although it may be difficult to directly target c-Myb in malignant disease, alternative anti-tumoural therapy may be developed against c-Myb-regulated target genes that are also implicated in mammary tumours. Collectively my thesis studies have advanced our understanding of c-Myb in mammary cancer initiation, progression and as a direct or indirect therapeutic target.
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Tho, Lye Mun. „Investigating the role of Chk1 in mouse skin homeostasis and tumourigenesis“. Thesis, University of Glasgow, 2011. http://theses.gla.ac.uk/2504/.
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Chk1 is a key regulator of DNA damage response and genome stability in eukaryotes. To better understand how checkpoint proficiency affects cancer development particularly tumours induced by chemical carcinogens in murine skin, I investigated the effect of conditional genetic ablation of chk1. I found that complete deletion of chk1 immediately prior to carcinogen exposure strongly suppressed papilloma formation, and the few, small lesions that did form always retained Chk1 expression. Remarkably, chk1 deletion was accompanied by spontaneous cell proliferation followed by DNA damage and cell death within the hair follicle. This also affected and led to proliferation and ultimately depletion of label-retaining stem cells (LRCs) within the bulge region of hair follicles, the principal source for carcinogen-induced tumours. At later times, ablated skin became progressively repopulated by Chk1-expressing cells and normal sensitivity to tumour induction was restored if carcinogen treatment was delayed. In marked contrast, papillomas formed normally in chk1 hemizygous skin but showed an increased propensity to progress to carcinomas. I conclude that Chk1 is essential for the survival of incipient cancer cells but that partial loss of function (haploinsufficiency) fosters tumour progression.
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Mohamed, Noha-Ehssan. „Characterizing the roles of APC2 protein in ovarian homeostasis and tumourigenesis“. Thesis, Cardiff University, 2017. http://orca.cf.ac.uk/105634/.
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Canonical WNT signalling plays a critical role in the regulation of ovarian development during embryogenesis; dysregulation of this pathway in adult ovary is associated with subfertility and tumourigenesis. The aim of the current study was to elucidate the previously unexplored roles of Adenomatous polyposis coli 2 (APC2), a WNT signalling pathway regulator, in the ovary using an Apc2 constitutive knockout mouse. For the first time, the current work demonstrated essential roles of APC2 in regulating ovarian WNT signalling and ovarian homeostasis. In early adulthood, APC2-deficiency resulted in WNT signalling activation and sub-fertility driven by intra-ovarian defects. Follicular growth was perturbed, resulting in a reduced rate of ovulation and corpora lutea formation, which was not rescued by administration of gonadotrophins. The current study provides fundamental new knowledge on the role of APC2 in ovarian tumourigenesis. APC2-deficiency (on the background of a hypomorph Apc- allele) resulted in a predisposition to granulosa cell tumour (GCT) formation, accompanied by acute tumour-associated WNT-signalling activation and expression of a histologic pattern and molecular signature seen in human adult GCTs. Hence, APC2 has an important tumour-suppressor activity within ovarian granulosa cells. However, APC2 is dispensable for ovarian surface epithelium (OSE) homeostasis. APC2 loss on its own, or combined with PTEN or APC loss in the OSE, failed to cause tumour development. Introducing APC2-deficiency to an ovarian endometrioid adenocarcinoma (OEA) mouse model, driven by loss of PTEN and APC in the OSE, resulted in early initiation of tumourigenesis, but attenuated tumour growth. This attenuation was accompanied by squamous metaplasia, decreased mitosis, decreased p-ERK1/2 expression and disrupted immune/inflammatory signalling. Thus, for the first time, an APC2 functional dualism in initiation and progression of WNT-driven OEA in mice is reported. RNA sequence analysis unraveled 2 transcripts (HAL and HUNK) associated with OEA progression and should be considered for future research.
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Veerakumarasivam, Abhimanyu. „Integromic analysis of urothelial cell carcinoma identifies key targets in tumourigenesis“. Thesis, University of Cambridge, 2009. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.611565.
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Podmore, Lauren. „The role of the p66-Shc adapter protein in mammary tumourigenesis“. Thesis, McGill University, 2013. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=119690.
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The ShcA adaptor protein is a key signaling molecule in the regulation of survival, angiogenesis, immune suppression and metastasis in breast cancer cells. The mammalian ShcA gene encodes three isoforms which are produced through alternative translation initiation (p46Shc, p52Shc) or different promoter usage (p66Shc). Although p46Shc and p52Shc are constitutively expressed and confer pro-tumorigenic signals, p66Shc levels vary in cancer cell lines. While activation of p66Shc through phosphorylation of its serine-36 (S36) is known to induce reactive oxygen species (ROS) formation, the role it plays in tumourigenesis is poorly understood. Our objective was to characterize the impact of p66Shc expression on mammary tumourigenesis both in vitro and in vivo. To this end, p66Shc-expressing vectors were stably transfected into two cell lines low in endogenous p66Shc; one driven by oncogenic ErbB2 activation (NIC-4360) and one lacking ErbB2 expression altogether (MDA-MB-231). These cells were characterized in vitro before being injected into the mammary fat pad (MFP) of immune-compromised mice for characterization in vivo. Our data revealed that while increased p66Shc expression promotes tumour initiation by way of increased angiogenesis, sustained p66Shc activation serves to decrease tumour cell proliferation. Our observation that p66Shc delayed tumour outgrowth in ErbB2-expressing cells also indicates a link between p66Shc activation and ErbB2 expression. The results of this study demonstrate that p66Shc confers both pro- and anti-tumourigenic properties, and that its role in mammary tumourigenesis is largely dependent on its ability to induce production of ROS.La protéine adaptatrice ShcA est une molécule clé dans la régulation de la survie, de l'angiogénèse, de la suppression tumorale et des métastases des cellules cancéreuses du sein. Le gène ShcA, chez les mammifères, encode trois isoformes qui sont produites par site d'initiation alternatif pour la transcription (p46Shc, p52Shc) ou l'utilisation d'un différent promoteur (p66Shc). Malgré le fait que p46Shc et p52Shc soient constitutivement exprimés et confèrent un signal bénéfique aux tumeurs, les niveaux de p66Shc varient dans les lignées cellulaires cancéreuses. L'activation de p66Shc via la phosphorylation de Sérine36 (S36) est connue pour induire la formation de dérivés réactifs de l'oxygène (ROS), toutefois le rôle que cela joue dans la tumorigénèse est mal compris. Notre objectif était de caractériser l'impact de l'expression de p66Shc sur la tumorigénèse mammaire, à la fois in vitro et in vivo. À cette fin, des vecteurs exprimant p66Shc ont été transfectés, de façon stable, dans deux lignées cellulaires ayant une expression endogène faible en p66Shc : une mû par l'activation de l'oncogène ErbB2 (NIC-4360), l'autre complètement exempte de ErbB2 (MDA-MB-231). Ces cellules ont été caractérisées in vitro avant leur injection dans les tissus graisseux mammaires de souris immunodéficientes pour la caractérisation in vivo. Nos données démontrent qu'une augmentation de l'expression de p66Shc promouvoit l'initiation tumorale via une augmentation de l'angiogénèse, toutefois une activation soutenue de p66Shc entraîne une diminution de la prolifération des cellules tumorales. Notre observation que p66Shc retarde la croissance tumorale dans les cellules exprimant ErbB2 dénote un lien entre l'activation de p66Shc et l'expression de ErbB2. Les résultats de cette étude démontrent que p66Shc confèrent des propriétés à la fois bénéfiques et néfastes pour les tumeurs, et que son rôle dans la tumorigénèse mammaire est largement dépendante de son habilité à induire la production de ROS.
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Wu, Xuemei. „Genetic control of tumour susceptibility in mouse skin carcinogenesis“. Thesis, University of Glasgow, 2000. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.312688.
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Davoodi-Semiromi, Abdoreza. „Molecular pathology of the hMSH2 mutator gene and its transcripts in patients with colorectal cancer in the west of Scotland“. Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.241714.
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Suaeyun, Ratchada. „The cellular roles of MDM2 and its alternatively spliced variants“. Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.340667.
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