Rozprawy doktorskie na temat „Tumorigenesis”
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1
Rocchi, Laura <1982>. "mRNAs translation and tumorigenesis". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4363/1/Rocchi_Laura_tesi.pdf.
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Translational control has a direct impact on cancer development and progression. Quantitative and qualitative changes of cap-dependent translation initiation contribute to neoplastic transformation and progression. However, the idea that “alternative” mechanisms of translation initiation, such as IRES-dependent translation, can be involved in the tumorigenesis is emerging. Because the relevance of this kind of translation initiation in cancer progression is not so well clarified, the purpose of my work was to study the impact of IRES-dependent mRNA translation on tumourigenesis and cancer progression with particular regard for breast cancer. The data obtained clarify the function of cap-independent translation in cancer. Particularly they suggested that the deregulation of IRES-dependent translation can be considered a sort of pro-oncogenic stimulus characterized by the inhibition of the expression of some proteins that block cell growth and proliferation and by the over expression of other proteins that contributed to cell survival. In addition, under stress condition, such as a hypoxia, in immortalized epithelial cell lines, changes in cap-independent translation are associated with an induction of expression of stem cell markers, and with the selection of a sub group of cells that have an increased ability to self-renewing and therefore in the acquisition of a more aggressive phenotype.
2
Rocchi, Laura <1982>. "mRNAs translation and tumorigenesis". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4363/.
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Translational control has a direct impact on cancer development and progression. Quantitative and qualitative changes of cap-dependent translation initiation contribute to neoplastic transformation and progression. However, the idea that “alternative” mechanisms of translation initiation, such as IRES-dependent translation, can be involved in the tumorigenesis is emerging. Because the relevance of this kind of translation initiation in cancer progression is not so well clarified, the purpose of my work was to study the impact of IRES-dependent mRNA translation on tumourigenesis and cancer progression with particular regard for breast cancer. The data obtained clarify the function of cap-independent translation in cancer. Particularly they suggested that the deregulation of IRES-dependent translation can be considered a sort of pro-oncogenic stimulus characterized by the inhibition of the expression of some proteins that block cell growth and proliferation and by the over expression of other proteins that contributed to cell survival. In addition, under stress condition, such as a hypoxia, in immortalized epithelial cell lines, changes in cap-independent translation are associated with an induction of expression of stem cell markers, and with the selection of a sub group of cells that have an increased ability to self-renewing and therefore in the acquisition of a more aggressive phenotype.
3
Cripps, Kathryn Jane. "Genetic events in colorectal tumorigenesis". Thesis, University of Edinburgh, 1995. http://hdl.handle.net/1842/27836.
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More is known about the genes involved in colorectal tumorigenesis than for any other human cancer. Mutations have been identified in many genes, including the K-ras oncogene and the APC, MCC, DC and p53 tumour suppressor genes. However, whilst much is known about these events there are many questions that remain unanswered. Three specific questions involving p53, MCC and APC were addressed in this thesis. Firstly, it has been previously assumed that point mutation of the p53 gene inevitably resulted in a permanently stabilised protein product. To address this question in colorectal carcinomas, the relationship between p53 mutation and stabilisation of p53 protein was assessed by comparing stabilised product detected by immunocytochemistry (ICC) using p53 specific antibodies, with mutation as detected by single strand conformational polymorphism analysis (SSCP) and sequencing. The results suggest a high correlation between p53 protein stabilisation and gene mutation, but highlight specific incidences in which concordance is not absolute. In particular, mutations in exon 6 of p53 did not result in a stabilised protein and several tumours with a high degree of staining contained no apparent mutation within the entire coding region of the gene. Secondly, although MCC (for mutated in colorectal cancer) on chromosome 5q was amongst the first colorectal cancer genes to be identified and was shown to be mutated in a small number of colon tumours, its role is still uncertain. Finally, another gene has also been located on chromosome 5q and had been shown to be mutated in about 60% of sporadic colon tumours as well as in the germline of FPC patients and hence called APC (for adenomatous polyposis coli).
4
Jonkers, Yvonne Margaretha Hendrika. "Molecular alternations during insulinoma tumorigenesis". [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Universiteit Maastricht [host], 2007. http://arno.unimaas.nl/show.cgi?fid=8685.
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Hobeika, Alice. "Notch1 signaling in mammary tumorigenesis". Thesis, McGill University, 2012. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=110389.
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Aberrant activation of Notch receptors has been implicated in breast cancer. We and other have shown that the expression of a mutant Notch transcript coding mostly for the intracellular domain of Notch1 (Notch1IC) causes transformation of cells in culture and development of tumors in transgenic mice. However, the mechanisms contributing to Notch1IC-induced tumor formation remain elusive and the long latency before the appearance of tumors in Tg mice seems to indicate that Notch requires the collaboration of secondary mutations to induce transformation and tumorigenesis. In the aim of studying direct downstream effects of Notch1IC expression, we generated a Tet-ON inducible expression system for Notch1IC in Hc11 mammary epithelial cells. In the inducible cell lines established, expression of the transgene is only activated upon addition of doxycycline (DOX) to the culture media. The inducible cells were capable of forming colonies in soft agar when subjected to continuous DOX induction and transplantation of the inducible cells in DOX-treated recipient mice caused tumor formation with metastasis to the lungs. We performed a genome-wide microarray-based expression analysis to compare gene expression following 24-hr Notch1IC induction to that of their uninduced counterparts. There were 26 genes identified as being upregulated 2-fold and more upon expression of Notch1IC, while 5 genes were found to be downregulated. Most of these genes identified represent novel candidate Notch1 targets. Of the candidate Notch1IC targets found to be upregulated, expression of the transcript for M-cadherin, also known as CDH15, was most significantly elevated with a change of over 19-fold. M-cadherin is a member of the cadherin family of type I single-pass transmembrane domain proteins that mediate calcium-dependent cell adhesion. M-cadherin, first identified in myogenic mouse cells, is found predominantly in developing skeletal muscles and is highly expressed during secondary myogenesis. In mature skeletal muscle, M-cadherin is mainly detectable in satellite cells. A role for M-cadherin in tumors of epithelial origin has not been previously documented, nor has it been associated with the Notch signaling pathway. We first confirmed that M-cadherin was significantly upregulated by semi-quantitative RT-PCR in the Notch1IC-inducible system. In a time-course experiment, M-cadherin upregulation was observed within 2 hours of Notch1IC induction. In vivo, Notch1IC expression in mammary tumors from Tg mice also correlated with strong expression of M-cadherin, whereas M-cadherin was undetectable in non-Tg mammary glands. We further determined that the transcriptional upregulation of M-cadherin occurs, at least in part, through the canonical CSL-dependent Notch1 pathway. Moreover, using shRNA-mediated depletion of M-cadherin in cell lines derived from mammary tumors from our MMTV/Notch1IC, we were able to investigate the function of M-cadherin in Notch1IC-induced oncogenesis. Through in vitro and in vivo assays, M-cadherin was shown to be required for the transformation of MMTV/Notch1IC cells as well as for their ability to form tumors in mice. In light of these findings, we also examined gene expression of M-cadherin in several human cancer cell lines, including different subtypes of breast cancers. M-cadherin expression was confirmed and appears to also be activated by Notch1IC in a number of breast cancer cell lines. A cursory survey of publicly available human cancer gene expression datasets further corroborated an implication for M-cadherin in human cancers, as well as a correlation between the levels of expression of M-cadherin and Notch1. A better understanding of the mechanisms of action of M-cadherin could shed light on targeted therapeutic approaches for the treatment of Notch1-overexpressing cancers and possibly other human carcinomas.L'activation aberrante des récepteurs Notch a été impliqué dans le cancer du sein. Notre groupe ainsi que quelques autres ont démontré que l'expression d'un transcrit Notch1 muté, codant principalement pour le domaine intracellulaire de Notch1 (Notch1IC) provoque la transformation des cellules en culture et le développement de tumeurs chez les souris transgéniques. Cependant, les mécanismes contribuant à la tumorigénèse induite par Notch1IC demeurent méconnus et la longue période de latence avant l'apparition de tumeurs chez les souris Tg semble indiquer que Notch nécessite la collaboration des mutations secondaires pour engendrer la transformation cellulaire et la formation de tumeurs. Dans le but d'étudier les effets directs en aval de l'expression de Notch1IC, nous avons généré un système d'expression inductible Tet-ON pour Notch1IC dans les cellules épithéliales mammaires Hc11. Dans les lignées cellulaires inductibles établies, l'expression du transgène n'est activée que lors de l'addition de doxycycline (DOX) au milieu de culture. Les cellules inductibles sont capables de former des colonies en agar lorsqu'elles sont induites à la DOX en continu, et elles forment des tumeurs avec métastases aux poumons lorsque transplantées dans des souris traitées à la DOX. Nous avons effectué une analyse de l'expression du génome entier par micropuce dans le but de comparer l'expression des gènes à la suite de l'induction Notch1IC durant 24 heures, à celle de cellules homologues non-induites. 26 gènes ont été identifiés comme étant régulés à la hausse (2 fois et plus) suite à l'expression de Notch1IC, tandis que 5 gènes ont été identifiés comme étant régulés à la baisse. La plupart des gènes ainsi identifiés représentent de nouvelles cibles candidates de Notch1.Parmi ces cibles candidates, l'expression du transcrit pour M-cadhérine (CDH15) a été le plus significativement élevée (19 fois). M-cadhérine, une molécule d'adhésion cellulaire, a été identifiée dans les cellules myogéniques de souris; la protéine est principalement exprimée durant le développement de muscles squelettiques et au cours de la myogenèse secondaire. Dans le muscle squelettique mature, M-cadhérine est principalement détectable dans les cellules satellites. Fait intéressant, un rôle pour M-cadhérine dans les tumeurs d'origine épithéliale n'a pas été précédemment documenté, d'autant plus que M-cadhérine n'a pas été associée à la voie de signalisation Notch.Nous avons d'abord confirmé la surexpression de M-cadhérine par RT-PCR semi-quantitatif dans les cellules Notch1IC-inductibles. In vivo, l'expression de Notch1IC dans les tumeurs mammaires de souris Tg corrélait également avec une forte expression de M-cadhérine. Nous avons également déterminé que la régulation de la transcription de M-cadhérine se produit, au moins en partie, par la voie de signalisation canonique (CSL-dépendante) de Notch1. Par ailleurs, en utilisant des shRNA pour supprimer l'expression de M-cadhérine dans des lignées cellulaires dérivées de tumeurs mammaires provenant de nos souris MMTV/Notch1IC, nous avons pu étudier la fonction de M-cadhérine dans l'oncogénèse induite par Notch1IC. Par le biais d'essais in vitro et in vivo, nous avons démontré que M-cadhérine était requise pour la transformation des cellules MMTV/Notch1IC ainsi que pour leur capacité à former des tumeurs chez la souris. Par la suite, nous avons également confirmé l'expression de M-cadhérine dans plusieurs lignées cellulaires de cancer du sein. Un bref survol de bases de données d'expression génique dans des cancers humain suggère que M-cadhérine serait impliquée dans plusieurs types de cancers, et qu'il y aurait une corrélation entre les niveaux d'expression de M-cadhérine et de Notch1 dans certains cancers du sein.Une meilleure compréhension des mécanismes d'action de M-cadhérine pourrait mener à de nouvelles approches thérapeutiques ciblées pour le traitement des cancers surexprimant Notch1.
6
Hong, Karen H. (Karen Hsiao-Ying) 1971. "Mouse modifiers of intestinal tumorigenesis". Thesis, Massachusetts Institute of Technology, 2001. http://hdl.handle.net/1721.1/8585.
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Thesis (Ph.D.)--Massachusetts Institute of Technology, Dept. of Biology, 2001.Includes bibliographical references.
Colorectal cancer involves a series of molecular alterations as a normal cell progresses to malignancy. A large body of evidence points to the mutation of the APC gene as the pivotal event initiating intestinal tumorigenesis. Apdmin, an induced mutation in mouse homologue of APC, was identified several years ago by Moser et al., providing a genetic model system to study this process. We used the Apdmin system to identify additional genes influencing tumorigenesis. One of these genes,. Mom1 (Modifier of Min-1), involves the effect of genetic background on the Apdmin phenotype. On C57BL/6 (B6), the strain on which Apdmin arose, mice develop approximately 100 tumors. However, B6 X AKR Fl hybrids develop five-fold fewer tumors. Mom1 was identified as the major locus controlling this variation and localized to a 15 cM region on distal mouse chromosome 4 by Dietrich et al. To positionally clone Mom1, Gould et al created a B6.Mom1 AKR congenic strain isolating Mom1 from other AKR resistance factors. Separated from other loci, a single copy of Mom1 AKR reduced tumor number by 50% and two copies produced a 70% reduction. We have used recombinant lines derived from B6.Mom1 AKR to mapMom1 to a 4-cM interval containing one candidate gene, the group IIA secretory phospholipase a2 (sPLA2-IIA). Only tumor prone Mom1 strains, such as B6, contain a mutation in sPLA2-IIA abolishing expression. In order to rigorously measure the effect of sPLA2-IIA on the Apdmin tumor phenotype, we have created and analyzed transgenic lines that restore sPLA2-IIA expression. While we conclude that sPLA2-IIA is indeed protective, tumor number is only reduced by approximately 30%, suggesting that sPLA2-IIA is only part of Mom1. Analysis of additional Moml AKR recombinant strains containing and lacking sPLA2-IIA also implicates a separate distal modifier that accounts for the remaining resistance. To further probe how phospholipases impinge on intestinal cancers, we have studied tumorigen-sis in mice lacking group IV cytosolic phospholipase a2 (cPLA2). Crossing ApcMin into this background produces an 83% reduction in tumor number in ApcMin, cPLA2 -/- homozygotes, suggesting that cPLA2 expression promotes tumorigenesis, most likely via the production of arachidonic acid for downstream eicosanoid synthesis.
by Karen H. Hong.
Ph.D.
7
Tam, Mandy Chi-Mun. "Genomic analysis of mouse tumorigenesis". Thesis, Massachusetts Institute of Technology, 2006. http://hdl.handle.net/1721.1/37454.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2006.Includes bibliographical references.
The availability of the human and mouse genome sequences has spurred a growing interest in analyzing mouse models of human cancer using genomic techniques. Comparative genomic studies on mouse and human tumors can be valuable in two major ways: in validating mouse models and in identifying genes that are common to mouse and human tumorigenesis. Many analytic tools have emerged in recent years for human genome mining. Some of these tools have been translated to the murine versions. The work in this thesis described the application of two new whole-genome analytic techniques to study mouse tumorigensis: Representational Oligonucleotide Microarray Analysis (ROMA) for tumor DNA copy number asessment and single nucleotide polymorphism (SNP) genotyping using the SNaPshotM system (Applied Biosystems) to detect loss of heterozygosity (LOH) in mouse tumors. The murine version of ROMA was tested on DNA from early-stage KrasGJ2D-derived lung cancers and metastatic retinoblastoma in mice with retinal-specific Rb and p130 deletions. We were interested in identifying the additional genetic lesions that got positively selected during tumorigenesis of these mice.
(cont.) Several recurrent chromosomal copy number gains and losses were observed in the DNA of KrasGJ2D-derived lung tumors. In addition, a focal amplification of the murine N-Myc locus was detected in the metastatic retinoblastomas, demonstrating the capability of ROMA to detect copy number changes at a single-gene resolution. For genome-wide allelotyping, a panel of 147 mouse SNPs were individually validated in 129S4/SvJae vs. C57BL/6J strains and were chosen as markers in the genotyping panel. We worked out a multiplex protocol to genotype the SNPs in an efficient manner. Through this protocol, we generated low-density global LOH maps of lung tumors from mice expressing KrasG12D. LOH that spanned entire chromosomes was seen in a subset of the tumors. A loss of the wild-type p53 allele was also observed in some cases.
by Mandy Chi-Mun Tam.
Ph.D.
8
Cabrerizo, Granados David 1993. "Endothelial Snail1 in angiogenesis and tumorigenesis". Doctoral thesis, Universitat Pompeu Fabra, 2020. http://hdl.handle.net/10803/670305.
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Snail1 is a transcriptional factor with a great relevance in tumor development as it is
required for epithelial to mesenchymal transition and activation of cancer-associated
fibroblasts (CAF). In this thesis, we reported that tumor endothelial cells did also express
Snail1, being key for angiogenesis, by promoting endothelial cell migration, invasion and
tubulogenesis in vitro. Those roles are associated to Snail1 induction by FGF2 and VEGFA, leading to gene expression profile change in endothelial cells and modulation of their
activation status. Specific Snail1 depletion in the endothelium of adult mice does not
promote an overt phenotype; however, it controls angiogenesis and vessel morphology
in Matrigel plug assay. Moreover, endothelium-specific Snail1 depletion in the MMTVPyMT breast cancer murine model delays the initiation of neoplasms, being less
advanced and with a papillary morphology, which was corroborated by orthotopic
breast tumor inoculation model. These in vivo effects are associated to the inability of
Snail1-deficient endothelial cells to promote a full in vitro and in vivo activation of
fibroblasts through a reduced FGF2 and CXCL12 signaling; as well as to sustain a
complete in vivo angiogenesis, with wider and less invasive neo-vessels. Similar changes
on tumor onset and morphology are observed by pretreatment on MMTV-PyMT mice
with the angiogenic inhibitor bevacizumab. Checking those results in human breast
tumor samples, we could recapitulate most of the findings of our mouse models.
Altogether, these findings establish a new role for Snail1 in endothelial cells, not only in
angiogenesis but also in tumor onset, development and phenotypeSnail1 es un factor de transcripción con gran relevancia en el desarrollo tumoral, siendo necesario para la transición epitelio-mesénquima y la activación de fibroblastos asociados al cáncer (CAF). En esta tesis, hemos reportado la expresión de Snail1 en células endoteliales de tumor, jugando un papel fundamental en angiogénesis, promoviendo su migración, invasión y tubulogenesis in vitro. Estas funciones están asociadas a la inducción de Snail1 por FGF2 y VEGF-A, que generan un cambio en el perfil de expresión génica en las células endoteliales y modulan su estado de activación. La depleción específica de Snail1 en el endotelio de ratones adultos no supone un cambio fenotípico evidente; sin embargo, sí controla la angiogénesis y la morfología de los vasos en ensayos de plugs de Matrigel. Además, la eliminación específica de Snail1 en el endotelio del modelo murino de tumores de mama espontáneos MMTV-PyMT provoca el retraso en la iniciación de tumores, siendo éstos menos avanzados y con una morfología papilar. Estos efectos in vivo están asociados a la incapacidad de las células endoteliales sin Snail1 de promover una activación completa de fibroblastos in vitro e in vivo, debido a una señalización reducida de las vías de FGF2 y CXCL12; ni de generar una angiogénesis completa in vivo, con neovasos más anchos y menos invasivos. Cambios similares en la aparición de tumores y en su morfología se observaron en ratones MMTV-PyMT pretratados con el antiangiógenico bevacizumab. En muestras humanas de cáncer de mama pudimos recapitular la mayoría de los descubrimientos de los modelos animales usados. En resumen, estos hallazgos establecen un nuevo papel para Snail1 en las células endoteliales, no solo en angiogénesis, sino también en la aparición tumoral, el desarrollo y el fenotipo del tumor.
9
Andræ, Johanna. "PDGF in cerebellar development and tumorigenesis". Doctoral thesis, Uppsala : Acta Universitatis Upsaliensis : Univ.-bibl. [distributör], 2001. http://publications.uu.se/theses/91-554-4987-5/.
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Ball, Elizabeth Louise. "Molecular mechanisms of human thyroid tumorigenesis". Thesis, Cardiff University, 2008. http://orca.cf.ac.uk/55767/.
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Thyroid cancer is the commonest endocrine malignancy. Several of the initiating genetic events in thyroid tumorigenesis have been identified, although the exact molecular mechanisms are unclear. Our thyrocyte model has demonstrated that p16INK4A is up-regulated in RAS-induced colonies which resemble follicular adenomas. Affymetrix microarrays revealed that many interferon-stimulated genes (ISGs) are also up-regulated in these colonies. I hypothesised that p16 expression would be induced in follicular adenomas and lost in follicular cancers, consistent with their escape from growth control, and that ISG expression (HLA-DR, PKR, MxA) would be induced in follicular adenomas. I tested these hypotheses using immunohistochemistry, and correlated p16 expression with cyclin D1 and p21 expression to further investigate growth control. My original research demonstrates that p16 is expressed in adenomas, and surprisingly up-regulated in well-differentiated cancers. Loss of expression was only seen in poorly-differentiated carcinomas. Cyclin D1 expression increased during the transition from a benign to a malignant tumour, whereas p21 protein was expressed at a lower level in both adenomas and carcinomas. Unexpectedly, ISGS were not up-regulated in either the adenomas or carcinomas, but were expressed in some papillary carcinomas. PKR expression was positively correlated with p16 expression. I speculate that there must be two or more growth inhibitory pathways involved in thyroid tumorigenesis, one of which involves p16, and both must be inactivated for progression to a more aggressive phenotype. The cyclin D1 result is explained as a result of growth stimulation during tumorigenesis, whereas the basis and implication of p21 expression is uncertain. Thyroid cancers are unusual because the majority are slow-growing yet potentially fatal despite continued p16 expression. Further work is needed to elucidate the nature of the additional pathways controlling tumour growth, which will improve our understanding of thyroid tumorigenesis, and may potentially lead to the development of novel treatment strategies.
11
Faluyi, Olusola Olusesan. "Cyclooxygenase 2 expression in intestinal tumorigenesis". Thesis, University of Leeds, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275680.
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Kumar, Madhu S. (Madhu Sudham). "MicroRNAs in cellular transformation and tumorigenesis". Thesis, Massachusetts Institute of Technology, 2009. http://hdl.handle.net/1721.1/47879.
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Thesis (Ph. D.)--Massachusetts Institute of Technology, Dept. of Biology, 2009.Vita.
Includes bibliographical references.
MicroRNAs (miRNAs) are a novel class of small (approximately 23 nucleotides long), highly conserved, non-coding RNAs that function by broadly regulating gene expression. In animals, this regulation is achieved via interaction with target messenger RNAs (mRNAs), largely through their imperfect base pairing with the 3' untranslated regions (3' UTRs) of these target transcripts. Through this imperfect base pairing, miRNAs induce a repression of mRNA translation that is frequently coupled to enhanced turnover of the targeted transcript. This miRNA-mediated repression is highly related to that of RNA interference (RNAi), in which small non-coding RNAs exhibit perfect base pairing with target mRNA transcripts, leading to the endonucleolytic cleavage and degradation of these targeted mRNAs. Computational algorithms have been designed to predict putative miRNA binding sites within mRNAs. Using these predictions, it has been suggested that more than half of all mRNAs within mammals are under the control of miRNAs. Some of the earliest discovered miRNAs (characterized by genetic studies in the nematode Caenorhabditis elegans) were found to control the proliferation and differentiation of the cells in which they were expressed. As altered control of proliferation and differentiation frequently manifest in cancer in mammals, it was suggested that miRNAs might contribute to the development of tumorigenesis.
(cont.) In fact, several miRNAs are frequently deleted or amplified in human cancer and miRNA expression profiling studies have shown widespread reductions in steady-state miRNA levels in human cancers relative to normal tissue. These observations have implied a role for miRNAs in tumorigenesis. However, there is a paucity of functional studies demonstrating a role for miRNAs in oncogenic transformation. In the studies described below, we first provide strong evidence for the global loss of miRNAs in human cancers functionally enhancing cellular transformation and tumorigenesis. This enhanced transformation only occurred within tumor cells, suggesting that inhibiting miRNA biogenesis would not be sufficient to induce tumor formation. Moreover, we demonstrate that inhibition of miRNA processing in cancer must be incomplete, as Dicerl, a component of the miRNA processing pathway, suppresses tumorigenesis via haploinsufficiency. Finally, we examine the role of a specific miRNA family, the let-7 family, in the development of non-small cell lung cancer by showing that let-7 can suppress tumorigenesis via inhibition of its targets K-Ras and HMGA2. Taken together, these findings offer promise, not just for understanding the relationship of miRNAs and cancer, but for developing therapeutic agents against the disease.
by Madhu S. Kumar.
Ph.D.
13
Waters, Catherine. "Insights into Fhit loss-induced tumorigenesis". The Ohio State University, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=osu1438185414.
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Riley, Timothy E. W. "Post-transcriptional regulation of the c-myc proto-oncogene". Thesis, University of Cambridge, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.257194.
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Hipp, Nora [Verfasser]. "Mechanisms of MYC-induced tumorigenesis / Nora Hipp". Ulm : Universität Ulm. Fakultät für Naturwissenschaften, 2014. http://d-nb.info/1052062393/34.
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Tahkola, J. (Jenni). "Collagen XIII in cardiovascular development and tumorigenesis". Doctoral thesis, University of Oulu, 2008. http://urn.fi/urn:isbn:9789514289569.
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Abstract
Collagen XIII is a type II transmembrane protein, which has a short intracellular domain and a large, mainly collagenous ectodomain. It is located at many cell-matrix junctions and in focal adhesions in cultured cells and it has a function in cell adhesive processes.
Overexpression of collagen XIII molecules with an 83 amino acid deletion in part of the ectodomain leads to fetal lethality in Col13a1del transgenic mice. Doppler ultrasonography was performed at 12.5 days of gestation on fetuses resulting from heterozygous matings and matings between heterozygous and wild-type mice. Some fetuses had atrioventricular valve regurgitation (AVVR) and all of them were transgene positive. In addition, fetuses had pathological changes in functional parameters. Histological analysis showed the trabeculation of the ventricles to be reduced and the myocardium to be thinner in the fetuses with AVVR. Based on in situ hybridization (ISH), collagen XIII mRNA are normal constituents of these structures. Overexpression of mutant collagen XIII results in mid-gestation cardiac dysfunction in fetuses, and these disturbances in cardiac function may lead to death in utero. The heterozygous mice that were initially of normal appearance had an increased susceptibility to develop B cell lymphomas, which originated in the mesenteric lymph node. Collagen XIII protein was not detected in normal lymph nodes or in the lymphomas. The incidence of lymphomas was higher in conventional conditions than in a specific pathogen-free facility. In addition, the expression of collagen XIII was localized in the intestine and the basement membrane was highly abnormal. These findings suggest that collagen XIII is a critical determinant of lymphanogenesis.
Using ISH, antibody staining and RT-PCR techniques collagen XIII expression was analyzed during carcinogenesis in mice and in man. Collagen XIII expression increased during carcinogenesis in mice and in man. In the malignant process collagen XIII mRNA localized in the basal epithelium and in the invasive cells. According to antibody staining malignant invasive cells were positive. Results may reflect the disturbed adhesion of epithelial cells and ECM and that may affect the behaviour of the malignant cells, suggesting that collagen XIII has a significant role in the initiation of the invasion.
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Yadollahi, Beta. "The Role of Gas3 in Skin Tumorigenesis". Thesis, University of Ottawa (Canada), 2010. http://hdl.handle.net/10393/28670.
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Retinoic acid (RA) plays an integral role during embryonic development, in addition to being a potential chemotherapeutic and chemopreventative agent in various cancer models due to its growth inhibitory and pro-differentiation properties. RA signaling occurs in a ligand-dependent manner through a family of nuclear receptors consisting of the RARs and RXRs. RA elicits growth inhibitory effects in transformed wild type keratinocytes, however the target genes that mediate this outcome remain largely unidentified. In order to isolate genes that could mediate the latter effects, a suppressive subtractive hybridization experiment was conducted by our lab and revealed growth arrest specific 3 (gas3) as a candidate gene. Gas3 is expressed in the skin and is induced by RA as early as two hours post-treatment in tissue culture models. We investigated a possible relationship between gas3 and epidermal tumorigenesis and found that this gene behaves in a context dependent, strain-specific manner as both an RA-mediated tumor suppressor and an oncogene. To further investigate this, I first demonstrated that RA-induced growth arrest in keratinocytes is mediated in part by gas3. Additionally, previous work from our lab demonstrated that gas3-null mice from an FVB/NJ background evaded tumor formation following the two-stage carcinogenesis protocol. I demonstrate that this occurs as a result of an increase in apoptotic response following chemical mutagenesis in gas3 mutants. Conversely, I found that Gas3 mutants on a C57Bl/6 background behave as wild type animals with respect to carcinogenesis, suggesting that genetic modifiers between these two strains impact on Gas3 function with respect to tumorigenesis. Finally, I found that p21 activity is affected by the loss of gas3, which may begin to elucidate how gas3 impacts on carcinogenesis.
18
Majounie, Elisa. "Molecular dissection of neurofibromatosis type 1 tumorigenesis". Thesis, Cardiff University, 2009. http://orca.cf.ac.uk/54088/.
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The present study investigated the possible involvement of nine candidate genes in NF1 tumours by assessing loss of heterozygosity, promoter hypermethylation, and expression in NF1-related tumours. The CDKN2A/p16INK4a , RB1, TP53 and MGMT genes have previously been found to be altered in NF1 tumours, and this was confirmed in this study. However, new candidate genes were also found to be involved in NF1 MPNSTs and rare malignancies (RARB, MLH1 and RASSF1A).
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Kaidi, Abderrahmane. "The role of hypoxia in colorectal tumorigenesis". Thesis, University of Bristol, 2007. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.439670.
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Graham, T. A. "The expansion of mutant clones in tumorigenesis". Thesis, University College London (University of London), 2009. http://discovery.ucl.ac.uk/18761/.
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The formation of a cancer is an evolutionary process. A somatic cell may acquire an (epi)-mutation that gives it a growth advantage relative to its neighbours. Progression to cancer occurs as cells in the resulting mutant clone acquire additional mutations, which may also confer a selective advantage. This thesis investigated the expansion of mutant clones both prior to, and during, tumour growth. First, the clonal expansion of a mutant lineage within a stem cell niche was considered. The behaviour of mutant germline stem cells in the Drosophila testis, a remarkably well-characterised niche, was investigated. A model was developed which identified stem cell phenotypes that were selectively advantageous in the niche. Crypt fission is thought to be the primary mechanism of clonal expansion in the gut. A model of crypt fission was developed, which was used to estimate the frequency of fission events in the normal human colon. Crypts were found to divide infrequently, and fission was predicted to decrease the likelihood that a mutant clone would be lost from the gut. Next, the expansion of mutant clones during the initial growth of colorectal adenomas was considered. Individual crypts were micro-dissected from small adenomas, and the mutation status of the APC and K-ras genes in each crypt was determined. Combining this information revealed how the adenoma had formed. It was found that K-ras mutations may have occurred earlier in tumorigenesis than had been previously established. Last, the effect of clonal expansion on the genetic heterogeneity in a cancer was examined. A model of microsatellite slippage during cancer growth was developed. The model showed that clonal expansion during cancer growth, coupled with a low rate of somatic mutation, can generate non-negligible amounts of genetic diversity. This suggested that there was little evidence for a low-level microsatellite mutator phenotype in colorectal cancers.
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Dickinson, Adam. "The role of mitochondrial DNA in tumorigenesis". Thesis, University of Warwick, 2013. http://wrap.warwick.ac.uk/58415/.
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Mitochondria are cytoplasmic organelles that are found in almost all mammalian cells. Mitochondria contain their own genome, mitochondrial DNA (mtDNA) that encodes 13 subunits of the electron transfer chain, which is the primary generator of cellular energy. Precise regulation of mtDNA copy number is essential for normal cell function and also the differentiation of stem cells into specialized cell types. Abnormal regulation of mtDNA copy number is associated with cellular dysfunction, mitochondrial disease and more recently cancer. Glioblastoma multiforme (GBM) is a highly malignant subgroup of brain tumors that exhibit similar characteristics to human neural stem cells (hNSCs) including multipotency and the expression of the stem cell factors. It is unknown how GBM cells regulate their mtDNA copy number during differentiation and whether this differs to hNSCs. Furthermore, it is unknown what role mtDNA plays in the gene expression profiles and the tumorigenicity of GBM. To address these issues, GBM cells and hNSCs were differentiated for 28 days and their mtDNA copy number and gene expression were analyzed. In addition, GBM cells were progressively depleted of their mtDNA using the depletion agent, 2'-3'-dideoxycytidine, and their in vivo tumorigenicity assessed. hNSCs and GBM cell lines regulated their copy number in a differential manner during differentiation. hNSCs progressively expanded their mtDNA copy number and adopted a differentiated phenotype whilst GBM cells failed to mimic these processes and their differentiation was incomplete. In addition, progressive depletion of mtDNA copy number in GBM cells resulted in reduced proliferation rates and the down regulation of stem cell factors. In vivo, mtDNA depleted GBM cells formed tumors at a reduced rate and frequency relative to nondepleted cells. These outcomes demonstrate that mtDNA copy number is abnormally regulated in GBM cells and hinders their ability to complete differentiation. The failure of mtDNA-depleted GBM cells to consistently generate tumors strongly suggests that maintenance of mtDNA copy number is essential for GBM cells to be tumorigenic.
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Kawano(Akitake), Reiko. "Inhibitory role of Gas6 in intestinal tumorigenesis". Kyoto University, 2013. http://hdl.handle.net/2433/180339.
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Bonner, Allison E. "Organ development and tumorigenesis: a molecular link". The Ohio State University, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=osu1073936508.
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CLARK, ADAM MICHAEL. "THE ROLE OF MAP3K8 IN LUNG TUMORIGENESIS". University of Cincinnati / OhioLINK, 2004. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1077225470.
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Silberman, Rebecca Estelle. "Defining the role of aneuploidy throughout tumorigenesis". Thesis, Massachusetts Institute of Technology, 2021. https://hdl.handle.net/1721.1/130665.
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Thesis: Ph. D., Massachusetts Institute of Technology, Department of Biology, February, 2021Cataloged from the official PDF of thesis.
Includes bibliographical references.
Aneuploidy is a state of genome imbalance which alters the copy number of whole chromosomes. While aneuploidy is rare in healthy tissues, it is one of the most common features of cancerous tumors. Studies of aneuploid yeast and aneuploid mammalian cells growing in culture revealed that aneuploidy induces cellular stress and slows proliferation. So it is surprising that aneuploidy is a hallmark of cancer, a disease of cellular over-proliferation and inappropriate cell survival. We sought to elucidate aneuploidy's role in tumorigenesis by defining the factors that affect the prevalence of aneuploid cells in normal, pre-cancerous, and cancerous tissues. First, we investigated whether aneuploid mammalian cells experience fitness defects in vivo. We found that aneuploidy decreases hematopoietic stem cells' fitness and that aneuploid cells are selected against in normal, regenerating tissues in vivo.
However, we also found that aneuploid cells can accumulate in the hematopoietic system when purifying selection is relaxed following bone marrow reconstitution. We then sought to extend our observations to the context of pre-cancerous tissues. We analyzed the prevalence of aneuploidy in the highly tumorigenic, but histologically normal tissues of women harboring heterozygous germline BRCA2 mutations. Using single-cell sequencing, we revealed that breast cells from BRCA2 mutation carriers lack aneuploidy but feature a distinct form of genome imbalance called sub-chromosomal copy number variants (CNVs), even before the initiation of tumorigenesis. We then analyzed the timing with which these two forms of genome imbalance--whole-chromosomal aneuploidy and sub-chromosomal CNVs--arise during tumorigenesis. We found that CNVs are present in the cells of early precursors of multiple cancers, but that whole-chromosomal aneuploidy arises late in tumorigenesis.
Our findings propose that whole-chromosomal aneuploidy reduces cells' fitness in both normal and pre-cancerous tissues, and that aneuploidy is selected against throughout tumorigenesis. This has implications for the role of aneuploidy in cancer, suggesting that aneuploidy does not contribute to early tumorigenesis.
by Rebecca Estelle Silberman.
Ph. D.
Ph.D. Massachusetts Institute of Technology, Department of Biology
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Choi, Jinkuk. "Telomerase function in epithelial development and tumorigenesis /". May be available electronically:, 2009. http://proquest.umi.com/login?COPT=REJTPTU1MTUmSU5UPTAmVkVSPTI=&clientId=12498.
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Bonner, Allison E. "Organ development and tumorigenesis a molecular link /". Columbus, Ohio : Ohio State University, 2003. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1073936508.
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Thesis (Ph.D.)--Ohio State University, 2003.Title from first page of PDF file. Document formatted into pages; contains xviii, 183 p.; also includes graphics (some col.). Includes abstract and vita. Co-advisors: , Ming You and Christoph Plass, Dept. of Medical Microbiology and Immunology. Includes bibliographical references (p. 172-183).
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Capristo, Mariantonietta <1981>. "Respiratory chain complex I dysfunction in tumorigenesis". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4798/1/Capristo_Mariantonietta_Tesi.pdf.
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Diseases due to mutations in mitochondrial DNA probably represent the most common form of metabolic disorders, including cancer, as highlighted in the last years. Approximately 300 mtDNA alterations have been identified as the genetic cause of mitochondrial diseases and one-third of these alterations are located in the coding genes for OXPHOS proteins. Despite progress in identification of their molecular mechanisms, little has been done with regard to the therapy. Recently, a particular gene therapy approach, namely allotopic expression, has been proposed and optimized, although the results obtained are rather controversial. In fact, this approach consists in synthesis of a wild-type version of mutated OXPHOS protein in the cytosolic compartment and in its import into mitochondria, but the available evidence is based only on the partial phenotype rescue and not on the demonstration of effective incorporation of the functional protein into respiratory complexes. In the present study, we took advantage of a previously analyzed cell model bearing the m.3571insC mutation in MTND1 gene for the ND1 subunit of respiratory chain complex I. This frame-shift mutation induces in fact translation of a truncated ND1 protein then degraded, causing complex I disassembly, and for this reason not in competition with that allotopically expressed. We show here that allotopic ND1 protein is correctly imported into mitochondria and incorporated in complex I, promoting its proper assembly and rescue of its function. This result allowed us to further confirm what we have previously demonstrated about the role of complex I in tumorigenesis process. Injection of the allotopic clone in nude mice showed indeed that the rescue of complex I assembly and function increases tumor growth, inducing stabilization of HIF1α, the master regulator of tumoral progression, and consequently its downstream gene expression activation.
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Capristo, Mariantonietta <1981>. "Respiratory chain complex I dysfunction in tumorigenesis". Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2012. http://amsdottorato.unibo.it/4798/.
Pełny tekst źródłaStreszczenie:
Diseases due to mutations in mitochondrial DNA probably represent the most common form of metabolic disorders, including cancer, as highlighted in the last years. Approximately 300 mtDNA alterations have been identified as the genetic cause of mitochondrial diseases and one-third of these alterations are located in the coding genes for OXPHOS proteins. Despite progress in identification of their molecular mechanisms, little has been done with regard to the therapy. Recently, a particular gene therapy approach, namely allotopic expression, has been proposed and optimized, although the results obtained are rather controversial. In fact, this approach consists in synthesis of a wild-type version of mutated OXPHOS protein in the cytosolic compartment and in its import into mitochondria, but the available evidence is based only on the partial phenotype rescue and not on the demonstration of effective incorporation of the functional protein into respiratory complexes. In the present study, we took advantage of a previously analyzed cell model bearing the m.3571insC mutation in MTND1 gene for the ND1 subunit of respiratory chain complex I. This frame-shift mutation induces in fact translation of a truncated ND1 protein then degraded, causing complex I disassembly, and for this reason not in competition with that allotopically expressed. We show here that allotopic ND1 protein is correctly imported into mitochondria and incorporated in complex I, promoting its proper assembly and rescue of its function. This result allowed us to further confirm what we have previously demonstrated about the role of complex I in tumorigenesis process. Injection of the allotopic clone in nude mice showed indeed that the rescue of complex I assembly and function increases tumor growth, inducing stabilization of HIF1α, the master regulator of tumoral progression, and consequently its downstream gene expression activation.
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Taylor, Clare Petronella Florence. "The use of fluorescence in situ hybridisation techniques in the diagnosis and prognosis of malignancy". Thesis, University College London (University of London), 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.297282.
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Sandros, Jens. "Salivary gland tumorigenesis a cytogenetic and molecular study /". Göteborg : Faculty of Odontology, University of Göteborg, University of Göteborg, 1989. http://catalog.hathitrust.org/api/volumes/oclc/20361247.html.
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Hitchcock, Tamara. "The biological role of psoriasin in breast tumorigenesis". Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2001. http://www.collectionscanada.ca/obj/s4/f2/dsk3/ftp05/MQ62753.pdf.
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Woo, Yong. "Characterizing the Dynamics of Genome Evolution in Tumorigenesis". Fogler Library, University of Maine, 2009. http://www.library.umaine.edu/theses/pdf/WooY2009.pdf.
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Segditsas, Stefania. "Mechanisms of intestinal tumorigenesis resulting from APC mutations". Thesis, University College London (University of London), 2008. http://discovery.ucl.ac.uk/15923/.
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Colorectal cancer typically arises through the sequential accumulation of mutations in different genes. Mutations in the adenomatous polyposis coli (APC) gene are thought to be the initiating step in this sequence of events and are found in the majority of early colorectal tumours. Investigation of these lesions has revealed that selection of 'optimal' combinations of mutations at the APC locus is in place, but the roles of such selected combinations have never been clarified. In the work presented in this thesis, I have demonstrated that similar constraints on APC mutations are active in tumours from attenuated FAP (AFAP) patients and that given the sub-optimal location of the germline APC mutation in these patients, additional somatic mutations are often required, especially in patients with germline mutations in the alternatively spliced region of exon 9. I have also shown that APC promoter hypermethylation does not appear to play a fundamental role in the selection of optimal APC genotypes. I have shown that the optimum combinations of mutations at APC are those that allow retention of some APC activity with respect to β-catenin degradation and that this has effects on the resulting activation of the Wnt signalling pathway. Optimal combinations of APC mutations result in intermediate nuclear β-catenin levels, which surprisingly highly activate a selection of Wnt targets. In an attempt to identify novel Wnt targets that are important for tumorigenesis and could serve as therapeutic targets, I have validated results from a cross-species comparison that identified a set of genes showing consistent differential expression between early tumour samples carrying APC mutations and normal tissue. In addition, I have investigated the biological function of one such-identified molecule, the serum/glucocorticoid-regulated kinase (SGK1), and I have revealed its potential role as a key regulator of intestinal cell differentiation and apoptosis.
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Cromer, Michael Kyle. "Exome sequencing uncovers somatic drivers of endocrine tumorigenesis". Thesis, Yale University, 2014. http://pqdtopen.proquest.com/#viewpdf?dispub=3580657.
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Tumorigenesis of relatively late onset occurring in patients with no family history of cancer syndromes is assumed to be driven by somatic mutations. The advent of high-throughput sequencing allows unbiased probing for genomic aberrations on an unprecedented scale. Somatic mutations, insertions and deletions, and copy number variations are able to be identified by parallel sequencing of tumor DNA and normal DNA from an individual patient. Somatic aberrations identified are classified as either passenger mutations that do not contribute to tumorigenesis or pathogenic driver mutations. Driver mutations are able to be identified due to their recurrence across multiple affected patients at a frequency greater than would be expected by chance.
Tumors occurring in the same tissue and from the same cell type often display diverse phenotypes with distinct mutational signatures. Therefore I applied high-throughput sequencing to probe for somatic mutations in two very specific endocrine tumor types - parathyroid-producing adenomas and insulin-producing adenomas (insulinomas). Prior to this study, neither tumor type had been probed for somatic mutations in a large-scale, unbiased manner. Though a limited number of mutated genes had been identified to play a role in familial and sporadic tumorigenesis in these tumor types, the majority of pathogenesis remained unexplained.
In order to maximize detection of variation in coding regions of the genome, an exome capture array was applied to the DNA prior to sequencing. In both tumor types, exome sequencing was applied to a small number of tumor-normal tissue pairs. Additional targeted sequencing of candidate driver mutations was then performed using Sanger sequencing on larger validation cohorts of tumors.
Exome sequencing revealed few somatic, protein-altering mutations in each tumor type (average <4 per tumor), therefore any recurrent variation was highly probable to be tumorigenic. Exome sequencing of the parathyroid adenomas revealed that four of eight tumors harbored a frameshift deletion or nonsense mutation in MEN1, which was always accompanied by loss of heterozygosity (LOH) of the remaining wild-type allele. No other mutated genes were shared among the eight tumors. One tumor harbored a Y641N missense mutation of the histone methyltransferase EZH2 gene, previously linked to myeloid and lymphoid malignancy formation. Targeted sequencing in an additional 185 parathyroid adenomas revealed somatic MEN1 mutations in a large number of tumors (35%). Furthermore, this targeted sequencing identified an additional parathyroid adenoma that contained the identical, somatic EZH2 mutation that was found by exome sequencing. This confirms the frequent role of LOH of chromosome 11 and MEN1 gene alterations in sporadic parathyroid adenomas and implicates a previously unassociated methyltransferase gene, EZH2, in endocrine tumorigenesis.
Exome sequencing identified an identical somatic, heterozygous mutation in Yin Yang 1 transcription factor (YY1) in two of seven insulinomas. Targeted sequencing of an additional 36 insulinomas revealed twelve more insulinomas that harbored this identical T372R missense mutation in YY1. This mutation occurs at a highly-conserved residue in a highly-conserved zinc finger DNA-binding domain. ChIP-Seq demonstrated that this mutation changes the DNA motif bound by YY1. This altered binding likely drives pathogenesis due to aberrant regulation of genes not regulated by YY1WT. With the goal of identifying differentially-expressed genes in YY1T372R tumors, I performed gene expression analysis on eleven tumors; six that were YY1WT and five that were YY1T372R. This demonstrated that YY1T372R imparts a unique expression signature. Interestingly, several differentially-expressed genes were involved in key pathways regulating insulin secretion, including ADCY1 (an adenylyl cyclase) and CACNA2D2 (a Ca2+ channel pore-forming subunit), both of which were upregulated in YY1T372R-tumors. Importantly, in vitro studies using the INS-1 rat insulinoma cell line demonstrated that upregulation of each of gene is sufficient to markedly increase insulin secretion. Furthermore, both genes harbored specific YY1T372R binding sites that may account for their significantly altered expression.
Both studies identify novel driver mutations that shed light on the mechanisms of endocrine tumorigenesis. Furthermore, my findings reinforce the notion that common somatic mutations within the exome account for the majority of instances of sporadic tumorigenesis.
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O'Bryant, Deon. "Mechanisms of Age-Related Prostate Growth and Tumorigenesis". DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2018. http://digitalcommons.auctr.edu/cauetds/138.
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Prostate cancer is the most commonly diagnosed malignancy among men, but few genetic factors that drive prostate cancer initiation have been identified. The WD repeat domain 77 (Wdr77) protein is essential for cellular proliferation when it localizes in the cytoplasm of epithelial cells at the early stage of prostate development. In the adult prostate, it is transported into the nucleus and functions as a co-regulator of the androgen receptor to promote cellular differentiation and prostate function. This developmental process is reversed during prostate tumorigenesis i.e., Wdr77 is translocated from the nucleus into the cytoplasm to drive proliferation of prostate cancer cells. In this study, we used in vivo genetic studies to investigate the role of Wdr77 in prostate tumorigenesis. We found that prostate-specific deletion of Wdr77 abolished prostate tumor initiation induced by loss of the tumor suppressor Pten. Mechanistically, Wdr77 ablation inhibited E2F3 activation and enhanced TGFb signaling, leading to attenuated cellular proliferation induced by loss of Pten. These findings establish an essential role of Wdr77 for prostate tumor initiation.
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Coutermarsh-Ott, Sheryl Lynn. "Investigations into the role of inflammation in tumorigenesis". Diss., Virginia Tech, 2018. http://hdl.handle.net/10919/90788.
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Inflammation has been found to play a role in the development of many different tumors. However, a tumor's ability to evade immune cell recognition can be integral to its progression as well. The following works explore this complicated role with a focus on histiocytic sarcoma (HS) and breast cancer. Chapter 1 opens with a broad overview of inflammation in tumorigenesis while Chapter 2 focuses on a review and discussion of current HS literature. Our investigations into the role of inflammation specifically in HS are initiated in Chapter 3 where we explore the role of the regulatory NLR, NLRX1, in the development of HS in mice. NLRX1 is an intracellular patter recognition receptor that functions to regulate pro-inflammatory cell pathways. Our studies reveal that in carcinogen-induced HS in mice, NLRX1 acts as a tumor suppressor. Moreover, when NLRX1 is lost, tumors that develop are associated with increases in expression of genes in NF-κB and AKT pathways. Though uncommon, HS is a clinically relevant tumor in dogs. In Chapter 4, we further investigate the role of the pathways identified in Chapter 3 in canine patients. Not only were these pathways increased, but our results also revealed previously unreported differences in tumors diagnosed as HS versus those diagnosed as hemophagocytic HS. To improve the use of canine HS both as an experimental and translational model, we sought to create a murine xenograft model. In Chapter 5, we discuss the development of our model and the results of pilot studies using targeted drug therapy. The focus of Chapters 3-5 is to further explore the role of inflammation in the development of HS. However, as aforementioned, the role of inflammation in tumorigenesis is quite complicated. In Chapter 6, we aim to address the concept that the lack of inflammation through immune evasion, can also be important in tumors. Breast cancer in humans is traditionally recognized as being highly immunosuppressive. In this final chapter, we investigate the use of an attenuated strain of bacteria to treat these tumors by way of shifting the immunosuppressive tumor microenvironment to a more pro-inflammatory state.Ph. D.
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Mahoney, Emilia. "Molecular Alterations in Bone Development and Bone Tumorigenesis". The Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc_num=osu1243957525.
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Stengel, Kristy R. "Modifiers of Ras-driven Tumorigenesis and Therapeutic Response". University of Cincinnati / OhioLINK, 2011. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1318610225.
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Vasiliauskas, Juozas. "Hepatocyte Growth Factor-Like protein In prostate tumorigenesis". University of Cincinnati / OhioLINK, 2015. http://rave.ohiolink.edu/etdc/view?acc_num=ucin1428070127.
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Gonzalez, Rachel Marie. "Reduced BRCA1 expression in breast and ovarian tumorigenesis /". Thesis, Connect to this title online; UW restricted, 2004. http://hdl.handle.net/1773/6334.
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Bowen, Timothy J. "Tumor suppressor dysregulation in mouse models of tumorigenesis /". Diss., Connect to a 24 p. preview or request complete full text in PDF format. Access restricted to UC campuses, 2005. http://wwwlib.umi.com/cr/ucsd/fullcit?p3170247.
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Múnera, Jorge O. "Ets2 regulates colonic stem cells and sensitivity to tumorigenesis". Diss., [La Jolla] : University of California, San Diego, 2010. http://wwwlib.umi.com/cr/ucsd/fullcit?p3397225.
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Thesis (Ph. D.)--University of California, San Diego, 2010.Title from first page of PDF file (viewed March 30, 2010). Available via ProQuest Digital Dissertations. Vita. Includes bibliographical references (p. 101-108).
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Plym, Forshell Tacha Zi. "Examining the role of metabolism in Myc-driven tumorigenesis". Doctoral thesis, Umeå universitet, Institutionen för molekylärbiologi (Teknisk-naturvetenskaplig fakultet), 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-46564.
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Myc transcriptionally regulates genes involved in processes such as cell proliferation, metabolism, differentiation, and angiogenesis. MYC expression is deregulated in many types of human cancer; therefore discovering the mechanisms behind MYCs role in tumorigenesis is essential. In this dissertation, I have focused on several Myc target genes, Spermidine synthase (Srm); Lactate dehydrogenase (Ldh); 3-phosphoglycerate dehydrogenase (Phgdh); Serine hydroxymethyltransferase (SHMT) 1 and 2; and Pim-3 (a member of the Pim family of serine/threonine kinases). These enzymes play a role in various functions: Spermidine synthase (polyamine synthesis); Lactate dehydrogenase (glycolysis); Phgdh and Shmt (serine metabolism); and Pim-3 (cell signaling). In order to elucidate the impact Myc over-expression has on metabolism in tumorigenesis, we use human cell lines, and transgenic mice as well as cell lines and tissues derived from these mice. The impact of inhibition of these target genes on Myc-driven tumorigenesis was done by genetically inhibiting the target gene (using RNAi or mouse models) or inhibiting the protein with a chemical inhibitor. Investigating these Myc target genes will help determine if inhibition of Myc target genes is a viable approach for chemotherapeutics, and under what conditions this inhibition may be the most valuable. In paper I, we examine SRM; a highly expressed enzyme in the polyamine synthesis pathway that converts putrescine to spermidine, and is important for actively growing cells. Genetic inhibition via RNAi against Srm, or chemical inhibition of Srm, resulted in decreased proliferation of B-cell tumor lines from transgenic mice in vitro. In vivo treatment of λ-Myc transgenic mice with a chemical SRM inhibitor exhibited a significant chemopreventative effect on tumor formation. These results support previous findings that inhibition of polyamine synthesis pathway enzymes has a place in cancer therapy. Many Myc target genes have been suggested as attractive targets in battling Myc-driven tumorigenesis. Surprisingly in paper II, when we analyzed the inhibition of other Myc target genes, such as Ldh, Shmt, and Phgdh, we found that inhibition of these genes did not inhibit Myc-driven tumorigenesis to any significant degree. However, inhibition of Ldh, Phgdh and Shmt2 had a notable effect on in vitro Ras-driven transformation. These findings suggest that chemotherapeutic inhibition of metabolic genes such as Ldh, Phgdh and Shmt2 may be effective in genetically defined settings, keeping in mind the oncogenic lesion behind the tumor. The Pim kinase family consists of three serine/threonine kinases, Pim1-3. In paper III, we found that Pim-3 is a direct Myc target gene and that Pim-3 expression is high in Burkitt Lymphoma samples taken from human patients, as well as spontaneously arising lymphomas from Myc transgenic mice. We also found that inhibition of Pim-3 using a pan-Pim kinase inhibitor, Pimi, in these spontaneously arising Myc lymphomas resulted in caspase independent cell death. These results indicate that Pim kinase inhibition may be a potential chemotherapeutic strategy in human lymphomas that rely on Pim-3 kinase expression.
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Saxena, Swati. "Obesity associated colon tumorigenesis: An assessment of tumor phenotype". Thesis, University of Waterloo, 2006. http://hdl.handle.net/10012/2980.
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Colon cancer and obesity are two significant and related pathological states with multiple etiological factors. In this dissertation, it was hypothesized that tumor growth is accelerated in the altered state of obesity due to their resistance towards tumor necrosis factor-alpha (TNF-alpha) mediated cytotoxicity. Physiologically elevated TNF-alpha in an obese state induces increased nuclear transcription factor-kB (NF-kB) activity, known to transcribe genes crucial to cell survival. Insulin resistance, oxidative stress, and a pro-inflammatory environment are few of the biological consequences of TNF-alpha and NF-kB pathway activation, and further contribute to disease progression. Three major studies were conducted to investigate phenotypical changes in obesity associated tumors. Firstly, characteristics of the TNF-alpha resistant phenotype were preliminarily assessed by evaluating the effects of exogenous TNF-alpha treatment to HT-29 cells. Elevated levels of NF-kB in response to exogenous TNF-alpha gave an indication that this pathway is critical for cell survival. Furthermore, upregulation of TNF-alpha receptor 2 (TNFR2) suggested another strategy by which the cells were utilizing exogenous TNF-alpha for a survival advantage. Inhibition of NF-kB via St. John?s Wort treatment demonstrated that HT-29 cells may be sensitized towards TNF-alpha mediated cytotoxicity.
Zucker obese (Zk-Ob), Zucker lean (Zk-Ln), and Sprague Dawley (SD) animal models were used to assess tumor phenotype in vivo. Remarkable physiological differences between genotypes were observed. Zk-Ob rats had significantly higher body and organ weights as well as plasma TNF- alpha, insulin, leptin, and oxidative markers than Zk-Ln and SD animals. Tumor incidence and multiplicity were also notably higher in Zk-Ob rats. Protein analyses demonstrated increased levels of TNF-alpha, TNFR2, NF-kB, IkB kinase beta (IKKbeta), insulin receptor (IR), insulin like growth factor-I-receptor (IGF-IR), and mitogen activated protein kinase (MAPK) in Zk-Ob tumors than Zk-Ln counterparts. In all groups, tumors generally had higher protein expression than surrounding, normal appearing colonic mucosa. It is well known that these molecules are involved in signaling pathways that influence and co-operate with each other in rendering growth autonomy to tumor tissue.
A higher number of lesions in the distal than proximal colon in Zk-Ob rats was observed, supporting the emerging concept that genotype/physiological state of the host affects development and distribution of tumors. Thus, a third study was conducted to explore differences between distal and proximal tumor phenotype. Results demonstrated that expression of TNFR2, NF-kB, IR, IGF-IR, and MAPK p44 were significantly higher in distal than proximal tumors. This observation suggested that development of tumors in different regions of the colon varied under the same physiological conditions. Moreover, phenotype of distal tumors appeared to be upregulating survival pathways in comparison to proximal lesions, possibly explaining the higher tumor incidence in the distal colon.
Research documented in this thesis supported the hypothesis that the physiological status of the host intricately affects tumor phenotype. In particular, the TNF-alpha resistant phenotype was most prominent in Zk-Ob tumors, and appeared to be associated with upregulation of multiple signaling pathways cooperating towards tumorigenesis.
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Chen, Changfeng. "Retinoic acid receptors and mouse epidermal tumorigenesis and development". Thesis, McGill University, 2003. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=84492.
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Retinoic acid (RA), the major biologically active form of vitamin A, plays important roles in regulating a broad range of biological processes.Progressive loss of RARs is associated with skin carcinogenesis both in human and animals. Despite such observations, the biological significance of RAR loss in skin carcinogenesis has not yet been clarified. To this end, we established keratinocyte cell lines deficient in RARalpha, RARgamma, or both and employed a well-established tumorigenesis model to investigate whether loss of RARs is causally related to skin tumorigenesis. We found that RARgamma is the major RAR subtype mediating the growth and AP-1 inhibitory effects of RA on keratinocytes in vitro. Consistent with this observation, loss of RARgamma, but not RARalpha, predisposed keratinocytes to tumor formation, suggesting that RARgamma may act as a tumor suppressor. Reconstitution of RARs in the RARalphagamma-/- keratinocytes inhibited their tumorigenic potential, further proving that RARs have tumor suppressive effects.
As expected, expression of dnRARalpha resulted in profound epidermal defects. Intriguingly, dnRAalphaDBD caused a virtually identical skin phenotype, suggesting that dnRARalpha acts to affect epidermal development via a DNA-binding-independent mechanism. The epidermal phenotype of these transgenic mice is reminiscent of that seen in the p63-/- mice, and p63 expression was indeed significantly reduced in the epidermis expressing dnRARalpha or dnRARalphaDBD, suggesting that downregulation of p63 by dnRARalpha may be attributable to the epidermal phenotypes associated with the transgenic mice. These observations also suggest that DNA-binding is not required for dnRARalpha to attenuate p63 expression in the epidermis. Consistent with these observations, I also found that p63 is indeed not a RAR-target, as no overt changes in p63 expression were observed in the RARalphagamma-/- epidermis, which appeared normal. (Abstract shortened by UMI.)
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He, Zhiheng 1971. "Functional characterization of progranulin in wound healing and tumorigenesis". Thesis, McGill University, 2001. http://digitool.Library.McGill.CA:80/R/?func=dbin-jump-full&object_id=37898.
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The human progranulin gene encodes a 593 amino acid secreted glycoprotein, progranulin (also called PC cell-derived growth factor, acrogranin or granulin/epithelin precursor). The biological activities of this protein were poorly defined at the beginning of the project. Here, we determined that the progranulin gene is widely expressed in vivo and strongly associated with immune, neuronal and highly proliferative epithelial cells. It is not expressed in fibroblasts and endothelial cells in vivo unless these cells are stimulated by, for example, tissue damage and this expression correlates temporally with the healing process. Thus progranuhn is induclbly expressed in mesenchymal cells but is a constitutive product in proliferative epithelial cells. These studies defined a physiological context for investigating the roles of progranulin in the body. To correlate the expression studies with function, we assessed the ability of progranulin to regulate wound repair and epithelial growth. Progranulin enhances the growth and motility of fibroblasts and endothelial cells, and promotes the formation of tubule-like structures by endothelial cells on Matrigel, suggesting that progranulin may accelerate fibroplasia and serve as a pro-angiogenic factor in the proper environment. These effects are mediated through the activation of the p44/42 MAP kinase, PI-3 kinase and focal adhesion kinase (FAK) pathways, as inlubition of the MAP kinase and PI-3 kinase pathways by PD98059 and wortmannin blocked progranulin-induced cell migration, and progranulin was found to hyper-phosphorylate FAK in endothelial cells. The association of strong progranulin expression with highly proliferative epithelial cells suggests that progranulin may take part in epithelial homeostasis. To investigate this hypothesis, we either overexpressed or downregulated the progranulin gene in SW-13 and MDCK cells. SW-13 cells are derived from human adrenal cancer, but their growth resembles non-transformed epithel
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Moore, Amy Elizabeth. "The role of HGF/Met signalling in colorectal tumorigenesis". Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544331.
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Zhao, Fung, i 趙楓. "Role of FOXM1 in ovarian cancer tumorigenesis and chemoresistance". Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/211053.
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Ovarian carcinoma is the most lethal gynecological malignancy. The high relapse and mortality rates are attributable to late diagnosis and development of drug resistance. Identifying novel prognostic and therapeutic targets for ovarian carcinoma is crucial for improving patients' long-term survival rate.
Forkhead box protein M1 (FOXM1), which is a widely studied member of the FOX superfamily of proteins, participates in cell proliferation and apoptosis affecting the developmental function of many organs. Recently, there has been emerging evidence supporting the biological significance of FOXM1 in carcinogenesis. Overexpression of FOXM1 has been reported in multiple human malignancies including primary breast cancer, lung cancer, prostate cancer, etc. However, whether FOXM1 participates in the development of ovarian cancer, with emphasis on the association with clinicopathological parameters and chemoresistance, remains unknown. This study aims at elucidating the functional role of FOXM1 in the tumorigenesis of ovarian cancer.
Immunohistochemical study showed higher nuclear FOXM1 expression was significantly associated with advanced stages of ovarian cancer (P=0.035). Though not reaching statistical significance, FOXM1 overexpression displayed association with serous histologic subtype, high grade cancers (poor differentiation) and chemoresistance. Patients with a low FOXM1 level had a significantly longer overall (P=0.019) and disease-free survival (P=0.014) than those with high FOXM1 expression. Multivariate progression analysis established high expression of FOXM1, advanced cancer stages and poor histological differentiation (high grade) as independent prognostic factors for short overall and disease-free survival. Consistently, in vitro Transwell assays demonstrated transient knockdown of FOXM1 was capable of reducing SKOV-3 migration and invasion. Furthermore, paclitaxel treatment down-regulated FOXM1 expression in the sensitive cell line but not the resistant one. Immunofluorescence and flow cytometric analyses demonstrated FOXM1 knockdown could enhance paclitaxel-mediated mitotic catastrophe in ovarian cancer cells.
Recent attention has been drawn to the oncogenic roles of kinesin-like protein KIF2C and p21-activated kinase 4 (PAK4) in human cancers. Interestingly, the expressions of KIF2C and PAK4 altered in a similar pattern to FOXM1 expression upon paclitaxel treatment by displaying down-regulation only in the paclitaxel sensitive cell line but not the resistant one. FOXM1 silencing, qPCR, luciferase reporter assay and chromatin immunoprecipitation confirmed KIF2C and PAK4 to be novel transcriptional targets of FOXM1. Clonogenic assay showed KIF2C knockdown could re-sensitize resistant cell line to paclitaxel treatment. Flow cytometry demonstrated KIF2C silencing was able to increase the number of cells blocked at G2/M cell cycle phase in sensitive cell line and raise the number of apoptotic cells in resistant cell line. Up-regulations of miR-590 and miR-370 were also observed in a panel of drug resistant ovarian and breast cancer cell lines. While ectopic expression of miR-590 reduced FOXM1 expression, FOXM1 also seemed to be able to regulate the expression of miR-590.
In summary, this study showed overexpression of FOXM1 in ovarian cancer correlated with poor survival of patients and paclitaxel resistance. KIF2C and PAK4 were identified as novel transcriptional targets of FOXM1 implicated in chemoresistance.published_or_final_version
Pathology
Doctoral
Doctor of Philosophy
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Mao, Jian-Hua. "Stochastic modelling of tumorigenesis in p53 deficient transgenic mice". Thesis, University of Glasgow, 1997. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.286124.
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