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1
Ng, Jia Nian, and 黃嘉年. "RNF168 expression in breast cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/206551.
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Background: Breast cancer is the commonest female cancer. DNA double-strand breaks (DSBs) associated proteins such as BRCA1 have been shown to be involved in tumourigenesis of breast tissue. One of the key regulators of DSBs, the RING Finger Protein 168 (RNF168), controls DNA damage responses (including the manipulation of homologous recombinant and non-homologous end-joining repair) which are responsible for correction of errors that occur during DSBs in order to maintain genomic stability. The nature of this protein suggests that RNF168 may play an important role in development of breast cancer.
Material and methods: This study investigated the relationship of RNF168 expression in breast cancer by immunohistochemistry staining of 118 breast cancer samples in tissue microarray. The nuclear stain and cytoplasmic stain of the sections were assessed. Nuclear localization score was obtained and correlated with clinico-pathological features of the patients.
Results: Immunohistological staining of RNF168 was successful in 99 cases of the tested breast cancer specimens. The expression of RNF168 was found to be significantly correlated with the occurrence of breast cancer metastasis (p=0.032). Strong expression of the protein was also found to be significantly associated with poorer breast cancer prognosis (p=0.033). In addition, correlation analysis also showed marginal correlation between nuclear localization of RNF168 with the age of patients at their first disease diagnosis (p=0.061).
Conclusion: RNF168 might play a critical role in promoting breast cancer metastasis during the advanced stage of breast cancer, which results in poor disease prognosis. Detailed mechanism involved in metastasis promotion remained to be revealed in further study.published_or_final_version
Pathology
Master
Master of Medical Sciences
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Elshafae, Said Mohammed Abbas. "Pathogenesis and Treatment of Canine Prostate Cancer." The Ohio State University, 2017. http://rave.ohiolink.edu/etdc/view?acc_num=osu1492081831172341.
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Lau, Yuen-ting, and 劉婉婷. "Functional characterization of cancer-associated fibroblasts in the regulation of cancer stem cell-like properties in hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2015. http://hdl.handle.net/10722/209516.
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Thairu, Ngayu Munga. "Mechanisms of colorectal cancer pathogenesis : role of hypoxia." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/14361.
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Colorectal cancer (CRC) is the third most common cancer worldwide Hypoxia plays a pivotal role in cancer, regulating cellular processes such as angiogenesis via the Hypoxia Inducible Factor (HIF) pathway. HIF-1α and HIF-2α, isoforms of the α-subunit, were previously thought to be functionally redundant, but mounting evidence supports their divergent roles in many cancers. In CRC their relative roles remain unclear. This study aimed to elucidate their relative contribution to hypoxic regulation of CRC using the Caco-2 cell-line. Ex vivo cultures of primary cells isolated from CRC tissue were used to validate the Caco-2 data. Caco-2 cells were stimulated with hypoxia (1% O2) or the hypoxia-mimetic dimethyloxaloylglycine (DMOG), with normoxia (21% O2) controls. Expression of known hypoxia-induced genes was quantified by polymerase chain reaction (PCR) and a PCR-based array was used to further characterise angiogenic genes. Protein expression was determined using Western Blotting and ELISA. The effect of selective HIF-isoform knockdown on gene expression was evaluated. Tumour-derived cultures (TDCs) were established using tissue obtained from surgically resected CRC specimens. mRNA expression of epithelial cell markers (Ep-CAM, VE-Cadherin) was quantified by Q-PCR, and protein expression of the CRC tumour marker carcinoembryonic antigen (CEA) measured by ELISA. TDCs were exposed to hypoxia, and gene expression relative to normoxia was quantified by Q-PCR and PCR-based array. In Caco-2 cells, hypoxia upregulated both HIF isoform proteins, inducing genes involved in angiogenesis (VEGF, ANGPTL-4, EFNA-3, TGF-β1), metabolism (CA-IX, GLUT-1) and apoptosis (BNIP-3), with mRNA changes reflected at protein level. Three novel hypoxia-induced angiogenesis genes (ANGPTL-4, EFNA-3, TGF-β1) were identified. Hypoxia-induced ANGPTL-4, BNIP-3 and TGF-β1 expression was reduced by siHIF-1α only, while EFNA-3 and VEGF expression was reduced by both siHIF-1α and siHIF-2α. TDCs expressed epithelial CRC cell markers, and showed similar hypoxia-induced angiogenesis gene expression to Caco-2 cells, although there was significant inter-donor variability.
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Taraseviciute, Agne. "Tenascin-C in the pathogenesis of breast cancer /." Connect to full text via ProQuest. Limited to UCD Anschutz Medical Campus, 2008.
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Thesis (Ph.D. in Cell Biology, Stem Cells, and Development) -- University of Colorado Denver, 2008.Typescript. Includes bibliographical references (leaves 102-114). Free to UCD Anschutz Medical Campus. Online version available via ProQuest Digital Dissertations;
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Cartón, García Fernando. "Myosin VB in intestinal pathogenesis." Doctoral thesis, Universitat Autònoma de Barcelona, 2017. http://hdl.handle.net/10803/458251.
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Miosina VB es una proteína que actúa como un motor molecular usando la energía del ATP para moverse a lo largo de filamentos de actina. Participa en el trafico intracelular de endosomas de reciclaje en la parte subapical de células polarizadas y no polarizadas. Su expresión es muy abundante en el intestino donde participa en el establecimiento y mantenimiento de la polaridad de los enterocitos. Mutaciones en MYO5B causan la enfermedad de inclusión de microvellosidades, in raro trastorno congénito que afecta a las células epiteliales del intestino cursando con diarrea acuosa persistente que suele ser fatal. Esta enfermedad se caracteriza por la presencia de alteraciones morfológicas en los enterocitos, atrofia de las vellosidades y deslocalización de proteínas del polo apical y basolateral del enterocito. Su patología molecular no se conoce, principalmente por la falta de modelos animales. En el presente estudio, describimos un versátil modelo murino con inactivación constitutiva de Myo5b e inactivación condicional en las células epiteliales intestinales inducida por tamoxifeno. En ambos casos, los animales muestras un cuadro clínico muy semejantes al de los pacientes con enfermedad de inclusión de microvellosidades, presentado diarrea y deshidratación que causan la muerte del animal. A nivel histológico, el intestino muestra las mismas alteraciones en los enterocitos que las presentes en pacientes humanos, incluyendo atrofia de vellosidades y deslocalización de marcadores proteicos. Además, la inactivación de Myo5b también provocó hiperproliferación de las criptas intestinales. Por lo tanto, el modelo animal presentado constituye una herramienta muy útil para investigar las causas moleculares de la enfermedad y ensayar de manera preclínica fármacos u otras opciones terapéuticas. Por otro lado, la pérdida de polaridad y diferenciación es también una de las señas de identidad de los carcinomas metastásicos avanzados y correlaciona con un mal pronóstico de los pacientes. En concreto, para el cáncer colorrectal, investigaciones previas llevadas a cabo en nuestro laboratorio ya han demostrado que la pérdida de miosina IA promueve la progresión la enfermedad y tiene actividad supresora de tumores. Dicha proteína es abundante en el borde en cepillo de los enterocitos, y participa en el mantenimiento de la estructura polarizada. Otros estudios han señalado la relación entre la inactivación de MYO5B con un incremento en la motilidad e invasión de células de cáncer gástrico, aunque todavía no se conoce nada de su relación con en el cáncer colorrectal. Para resolver esta cuestión, hemos diseñado modelos in vitro inducibles por doxiciclina para sobre expresar y reducir la expresión de dicha proteína en líneas celulares de cáncer de colon. Además, se ha empleado la tecnología CRISPR/Cas9 para inactivar la expresión de MYO5B en la línea de cáncer de colon Caco2-BBE. Los resultados muestran cambios en la polarización y diferenciación de dichas líneas celulares, de acuerdo con observaciones previas. También se ha observado una posible relación entre MYO5B y la capacidad de movilidad e invasión de las líneas de cáncer de colon. Sin embargo, la hiperproliferación observada en el intestino de los ratones no se reproduce en las líneas de cáncer de colon empleadas tras reducir o sobre expresar MYO5B, o en modelos xenograft subcutáneos in vivo de dichas líneas. Por otro lado, usando un microarray de tejidos con 155 muestras de tumores primarios de pacientes con cáncer colorrectal en estadio Dukes C se ha comprobado que una reducción en la expresión de MYO5B se asocia con una disminución en el tiempo de recaída y en la supervivencia total de los pacientes de cáncer de colon. Además, tumores con un grado de diferenciación bajo también expresan niveles de MYO5B significativamente reducidos. Finalmente, todos estos resultados indican que MYO5B juega un papel importante en la diferenciación del intestino normal y de las líneas de cáncer de colon. De la misma manera, MYO5B también podría desempeñar un papel en la progresión del cáncer colorrectal promoviendo movilidad e invasión de las células tumorales.Myosin VB is a molecular motor protein that uses the energy of ATP to move along actin filaments. It participates in the recycling endosomes trafficking in the subapical cytoplasmic region of non-polarized and polarized cells. It is highly expressed in the small and large intestine, where its role in the establishment of polarized function in enterocytes is also well known. Inactivating mutations of MYO5B have been associated with microvillus inclusion disease (MVID), a rare congenital disorder of the intestinal epithelial cells that presents with persistent life-threatening watery diarrhea. It is characterized by morphological enterocyte abnormalities such as microvillus atrophy and mislocalization of apical and basolateral protein transporters. The molecular pathology of the disease is not well known mainly due to the lack of animal models. In the present study, we report a versatile murine model with targeted inactivation of Myo5b. This model allowed us to generate and characterized a constitutive Myo5b knockout mice and a tamoxifen-inducible intestinal-epithelium-specific Myo5b knockout. In both cases, the mice closely resemble the phenotype of MVID patients, developing watery diarrhea and dehydration causing the death of the animal. Histological study of the intestine showed all the characteristic enterocyte defects observed in MVID patients, including microvillus atrophy and mislocalization of protein markers. Moreover, the inactivation of MYO5B also originated hyperproliferation of the intestinal crypts. Therefore, our mice constitute a useful model to further investigate the underlying molecular mechanism of this disease and to preclinically assess the efficacy of novel therapeutic approaches. In addition, hyperproliferation as well as loss of cell polarity, differentiation, and tissue architecture are hallmarks of advanced metastatic carcinomas and strongly correlate with poor patient prognosis. Specifically, for colorectal cancer, the third most common type of cancer worldwide, we have previously demonstrated that the loss of brush border MYO1A, also involved in cell polarity, promotes cancer progression and has tumor suppressor activity. Other studies have indicated a relationship between MYO5B inactivation and gastric cancer, promoting invasion and motility, but little is known regarding its role in colorectal cancer. To address this question, we have developed novel doxycycline-inducible in vitro models of MYO5B overexpression and downregulation. Moreover, we have generated MYO5B knockout Caco2-BBE cells using CRISPR/Cas9 technology. Our results showed changes in the polarization and differentiation of colon cancer cells, in agreement with previous observations in the normal intestine. Moreover, we have observed a relationship between MYO5B and the motility and invasion capacity of colon cancer cells, indicating a possible role of MYO5B in colon cancer progression. However, the effect of MYO5B loss in cell proliferation observed in our Myo5b knockout mice could not be confirmed in our models in vitro and in vivo, employing cell line-derived xenografts. In addition, using a tissue microarray containing triplicate samples from 155 primary Dukes C colorectal tumors, reduced MYO5B expression was found to be associated with shorter disease-free and overall survival of the patients. Moreover, poorly differentiated tumors showed significantly reduced expression of MYO5B. Collectively, our results indicate that MYO5B plays an important role in the differentiation of the normal intestinal epithelium and colon cancer cells, as well as a possible role in cancer progression promoting cell motility and invasion.
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Li, Bin, and 李斌. "ID1-induced activation of PI3K/AKT/NFkB pathway: mechanisms and significance in esophageal cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2009. http://hub.hku.hk/bib/B43783880.
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Chan, Yuk Kit. "The role of exosomes in nasopharyngeal carcinoma." HKBU Institutional Repository, 2013. http://repository.hkbu.edu.hk/etd_ra/1509.
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Ralston, Stuart H. "The pathogenesis and management of malignancy-associated hypercalcaemia." Thesis, University of Glasgow, 1987. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.304658.
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Banh, Taylor. "Exploration of Adipose in the Pathogenesis of Cancer Cachexia." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1532520752821935.
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容振威 and Chun-wai Yung. "A molecular study of NPC pathogenesis." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1994. http://hub.hku.hk/bib/B31212748.
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Jones, Amy Victoria. "The molecular pathogenesis of myeloproliferative neoplasms." Thesis, University of Southampton, 2010. https://eprints.soton.ac.uk/162665/.
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Myeloproliferative neoplasms (MPNs) are a heterogeneous group of haematological stem cell malignancies characterised by proliferation of one or more cells of the myeloid lineage. The molecular investigation of MPN was revolutionized in 2005 by the finding that approximately 95% of cases with polycythaemia vera (PV) and 50-60% of cases of essential thrombocythaemia (ET) and primary myelofibrosis (PMF) are characterised by a single acquired mutation, JAK2 V617F. My study has focused on four principal areas: (i) Involvement of V617F in other myeloid disorders. After developing sensitive methods to detect and quantify V617F, this mutation was identified in 17% of cases of atypical chronic myeloid leukaemia (17/99) as well as other atypical MPN, thus demonstrating that it was more widely involved in myeloid disorders that initially thought. Homozygosity of V617F was shown to have arisen by acquired uniparental disomy (UPD) and examination of two cases with V617F plus either KIT D816V or BCR-ABL demonstrated that the mutations had arisen in independent clones. (ii) In vitro assays to predict imatinib sensitivity. Haemopoietic colony and liquid cultures were used to determine if peripheral blood or bone marrow cells from atypical MPN cases (n=200) were sensitive to imatinib. Of those that responded in one or both cultures (n=185) some had known abnormalities of PDGFRA or PDGFRB, but a significant minority proved negative for all molecular tests suggesting the presence of uncharacterised imatinib-sensitive mutations. (iii) V617F as a marker of response to therapy. JAK2 V617F was used as a molecular marker to monitor the response of PV patients (n=21) to therapy with imatinib and interferon-α. Neither therapy eradicated V617F but there was a modest reduction in %V617F which correlated with haematological response. By contrast, in those patients that did not respond (n=13) the %V617F marginally increased. (iv) Genetic predisposition to MPN. Whilst investigating the possible contribution of JAK2 single nucleotide polymorphisms to the phenotypic diversity associated with V617F, marked skewing of alleles associated with the mutation was observed. Further investigation revealed that V617Fassociated disease is strongly associated with a specific constitutional JAK2 haplotype, designated 46/1, in all three disease entities compared to healthy controls (PV, n=192, P=2.9x10-16; ET, n=78, P=8.2x10-9 and MF, n=41, P=8.0x10-5). Furthermore, allele-specific PCR demonstrated that V617F specifically arises on the 46/1 allele in most cases. The 46/1 JAK2 haplotype thus predisposes to the development of V617F associated MPNs (OR=3.7; 95% CI 3.1-4.3) and provides a model whereby a constitutional genetic factor is associated with an increased risk of acquiring a specific somatic mutation.
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Pylväs-Eerola, M. (Marjo). "Oxidative stress in the pathogenesis and prognosis of ovarian cancer." Doctoral thesis, Oulun yliopisto, 2015. http://urn.fi/urn:isbn:9789526209982.
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Abstract Ovarian cancer is the fifth leading cause of cancer-associated death in women in Finland. Although ovarian cancer is relatively common, the precise mechanism of its development is still unknown. Additionally, it appears that the modes of pathogenesis differ depending on histotype. Although the initial response to platinum-based chemotherapy is usually good, the majority of ovarian cancer patients relapse and develop platinum resistance. This is a major problem in the treatment of ovarian cancer. Reactive oxygen species (ROS) are metabolites of oxygen. They are continuously formed in normal cells as a by-product of aerobic respiration and they play an important role in normal cell functions. Oxidative stress occurs when ROS formation overrides the antioxidative defence system. Oxidative stress is associated with carcinogenesis. A small proportion of cancer cells are stem cells that survive initial chemotherapy. These cells are suspected of being associated with the development of platinum resistance. To evaluate the significance of oxidative stress in ovarian cancer we examined ROS-derived damage and antioxidant regulators in benign and borderline ovarian tumours and ovarian cancer samples by immunohistochemistry and analysis of serum samples. The existence of cancer stem cell markers was also assessed in ovarian cancer samples. The expression levels of various markers were compared with clinicopathological parameters. Our results confirm that oxidative stress (8-hydroxydeoxyguanosine) exists in benign tumours and antioxidant enzymes, such as peroxiredoxins and thioredoxin are widely expressed in benign and borderline tumours. Oxidative stress was associated with poor survival, higher stage and platinum resistance in ovarian cancer. Oxidative stress markers were more strongly expressed in certain histotypes of ovarian cancer, such as serous and endometrioid type. Cancer stem cell markers were found in ovarian cancer and they were associated with the development of platinum resistance. These observations are beneficial in understanding the pathobiology of ovarian cancer and help in the design of new treatment optionsTiivistelmä Munasarjasyöpä on yksi merkittävistä syöpäkuolleisuuden aiheuttajista naisilla Suomessa. Se on kohtalaisen yleinen, mutta sen perimmäinen syntymismekanismi on vielä epäselvä. Lisäksi näyttää siltä, että eri histologioilla syntymekanismit poikkeavat toisistaan. Vaikka yleensä platinapohjaisella solunsalpaajahoidolla saadaan hyvä vaste, suurimmalla osalla hoidetuista potilaista tauti uusii ja kehittyy vastustuskyky platinapohjaisille solunsalpaajille. Tämä on suuri ongelma munasarjasyövän hoidossa. Vapaat radikaalit ovat hapen johdannaisia. Niitä muodostuu jatkuvasti soluissa soluhengityksen sivutuotteena, ja niillä on tärkeä merkitys normaaleissa solun toiminnoissa. Jos vapaiden radikaalien tuotanto ylittää antioksidatiivisen puolustusjärjestelmän, syntyy oksidatiivinen stressitilanne. Oksidatiivisen stressin on todettu olevan yhteydessä useiden syöpien syntymiseen. Osaa syövän soluista kutsutaan kantasoluiksi. Nämä solut voivat selvitä solunsalpaajahoidoista ja niiden epäillään olevan yhteydessä vastustuskyvyn kehittymisessä platinapohjaisia sytostaatteja kohtaan. Tutkimuksessamme arvioimme oksidatiivisen stressin merkitystä munasarjakasvaimissa. Tutkimme vapaiden radikaalien aiheuttamia vaurioita ja antioksidatiivisia säätelijöitä hyvänlaatuisissa, rajalaatuisissa sekä munasarjasyöpä kasvaimissa immunohistokemiallisesti ja seeruminäytteistä. Lisäksi selvitimme syövän kantasolumerkkiaineiden esiintymistä munasarjasyövässä. Tutkittujen merkkiaineiden pitoisuuksia verrattiin kliinisiin potilastietoihin. Tutkimustuloksemme mukaan oksidatiivista stressiä (8-hydroxydeoxyguanosine) esiintyi jo hyvänlaatuisissa kasvaimissa. Myös antioksidatiiviset entsyymit, kuten peroksiredoksiinit ja tioredoksiini, esiintyivät jo hyvänlaatuisissa ja rajalaatuisissa kasvaimissa. Oksidatiivinen stressi oli yhteydessä huonompaan tautiennusteeseen ja platinakohtaisen vastustuskyvyn kehittymiseen. Oksidatiivista stressiä oli enemmän seroosissa ja endometrioidissa munasarjasyöpätyypissä. Syövän kantasolumerkkiaineita esiintyi munasarjasyövässä, ja ne olivat yhteydessä huonontuneeseen hoitovasteeseen platinapohjaisille solunsalpaajille. Tulokset auttavat ymmärtämään munasarjasyövän syntymekanismeja ja suunnittelemaan uusia hoitovaihtoehtoja erityyppisissä munasarjasyövissä
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Houben, G. M. P. "The aetio-pathogenesis of gastric cancer clinical and experimental studies /." [Maastricht : Maastricht : Universiteit Maastricht] ; University Library, Maastricht University [Host], 1997. http://arno.unimaas.nl/show.cgi?fid=5826.
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Bohula, Erin. "The type 1 insulin-like growth factor receptor (IGF1R) as a target for anti-cancer therapy of malignant melanoma." Thesis, University of Oxford, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.275360.
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Liu, Ming, and 劉銘. "Identification and characterization of novel genetic alterations in the progression of hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2013. http://hdl.handle.net/10722/196441.
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Hepatocellular carcinoma (HCC) is one of the most frequent human malignancies worldwide with very poor prognosis. It is generally believed that accumulation of irreversible alterations in critical oncogenes and tumor suppressor genes during the long-term inflammation finally leads to the hepatocellular pathogenesis. Although under intensive investigation, the molecular pathogenesis of HCC still remains to be further elucidated.
In this study, we aimed to identify novel genetic alterations critical to the pathogenesis of HCC, especially in hot regions with recurrent chromosomal instability. Amplification of broad regions of 8q is one of the most frequent genetic alterations in HCC, suggesting the existence of oncogenes in addition to MYC at 8q24. By screening the publicly available microarray database and clinical samples, we found frequent amplification and overexpression of Serum and Glucocorticoid Kinase 3 (SGK3) in clinical HCC specimens, and SGK3 genomic activation was significantly associated with poor outcome of HCC patients. Functional assays revealed that SGK3 could increase G1/S cell cycle progression, cell survival, clonogenicity, anchorage-independent growth, and tumor formation in nude mice. We provided evidences that SGK3 could promote HCC growth and survival through inactivating GSK3-β and BAD respectively. We also found that expression of SGK3, which like AKT is activated by PI3K/PDK1, has more significance than overexpression of AKT in predicting poor outcome of HCC patients. Our findings suggested the existence of an AKT-independent SGK3 pathway, which may function in parallel with AKT pathway in the pathogenesis of HCC. In addition to large chromosomal alterations, small changes in nucleotides may also make substantial contributions to carcinogenesis. Recent advances in high-throughput deep sequencing technology have provided a powerful tool to understand the whole cancer transcriptome and identify novel genetic alterations related to cancer progression. In this study, we identified a high proportion of allele imbalance in genes related to cellular stress response by sequencing the whole transcriptome of 3 paired HCC tissues. A novel nucleotide variation which resulted in a R438H amino acid change was identified in the coding region of the gene Oxidative Stress Induced Growth Inhibitor 1 (OSGIN1), and the variant 438H form of OSGIN1 was found to be specifically retained in the tumor tissues in a cohort of HCC patients. OSGIN1 was found to be closely associated with chemotherapeutic reagents and exhibited strong tumor suppressive function in HCC by directly inducing cell apoptosis. The wild type OSGIN1 was found to have stronger tumor suppressive function than the variant allele, and this might be due to their different ability to localize to mitochondria. The significantly decreased basal apoptotic index in HCC patients carrying OSGIN1 variant allele and their poor prognosis further suggested that the specific retention of 438H OSGIN1 might be important in HCC progression.
In summary, we found a frequently amplified oncogenic SGK3 signaling pathway, as well as the allele-specific imbalance of tumor suppressive OSGIN1 in the pathogenesis of HCC. Further characterization of their mechanisms in hepatocarcinogenesis may help provide novel prognostic biomarkers and therapeutic targets in HCC treatment.published_or_final_version
Clinical Oncology
Doctoral
Doctor of Philosophy
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Hu, Yingchuan, and 胡穎川. "Molecular pathogenesis of oesophageal squamous cell carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2000. http://hub.hku.hk/bib/B31241797.
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Thudi, Nanda Kumar. "Pathogenesis of Osteoblastic metastasis in Prostate Cancer: Role of Animal Models." Columbus, Ohio : Ohio State University, 2009. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1244042766.
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Koornstra, Jan Jacob. "Apoptosis and colorectal cancer studies on pathogenesis and potential therapeutic targets /." [S.l. : [Groningen : s.n.] ; University Library Groningen] [Host], 2006. http://irs.ub.rug.nl/ppn/291230539.
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Rughooputh, Sanjiv. "Role of sexually transmitted organisms in the pathogenesis of cervical cancer." Thesis, University of Westminster, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.433897.
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Maxwell, Fraser. "The influence of biological ageing in the pathogenesis of colorectal cancer." Thesis, University of Glasgow, 2013. http://theses.gla.ac.uk/4264/.
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Despite improvements in risk factor awareness, diagnosis and enhanced management strategies, the incidence and five year survival of colorectal cancer, has remained largely unchanged over the last twenty years. As with many epithelial cancers, a preponderance of new colorectal cancer diagnoses occur in the over sixty five age group, making chronological age a strong risk factor. Given this indelible link between ageing and cancer in general, genetic pathways which are implicated in one process could influence the other. Thus, an understanding of the biology of ageing and factors which regulate it may provide insight into cancer pathogenesis. Telomeres are nucleo-protein complexes sited at the ends of all chromosomes and have a critical function in the protection of the genome. Telomeres are implicated in the ageing process as a result of the inadequacies of the DNA replication machinery in somatic cells meaning that a section of telomeric DNA sequence is lost during each round of cell division, thus telomere length reduces with age and is a putative marker of biological ageing. Control of telomere length is complex and involves interplay between a number of genetic and environmental factors, of which oxidative stress is particularly important. However, critically short and hence dysfunctional telomeres have been implicated in cancer development through an inability to maintain genomic intergrity and an effect on senescence. Telomeres play an integral role in the sensing and repair of DNA damage, however, cells must possess a finely tuned mechanism through which they can sense DNA damage and initiate a response. This usually involves the activation of cell cycle checkpoints, either temporarily to allow repair, or on an irreversible basis to prevent the clonal expansion of cells with deleterious mutations. If the damage is deemed irrepairable apoptotic pathways are initiated. The sirtuins are a group of genes first discovered and shown to control longevity in saccharomyces cerevisiae. Intense work has defined seven mammalian homologs termed SIRT1-7 which vary in their sub-cellular localisation, and have critical cellular functions ranging from the control of apoptosis, mitochondrial biogenesis, glucose and lipid metabolism, maintenance of genomic integrity and cell cycle control. Given these functions it is therefore no surprise that aberrancy of sirtuin expression is implicated in ageing and its commonly related diseases, particularly cancer. The aim of this study was therefore, to determine if patients with colorectal cancer display aberrancy of ageing related factors, namely telomere biology and sirtuin expression. This study was undertaken using two sources of material for investigation. Quantitative-PCR was utilised to measure telomere length in the peripheral blood leucocytes of 64 colorectal cancer patients and 1348 controls. In addition, telomere length was similarly measured in colorectal cancer tumour and normal adjacent tissue. Telomere length was then correlated with a number of clinical and pathological parameters to determine diagnostic or prognostic utility. Furthermore, an attempt was made to establish whether telomere lengths were reflected in circulating mediators of inflammation and redox control factors, including fetuin-A a circulating modulator of calcium homeostasis. Sirtuin relative transcriptional expression (SIRT1-7) was then measured in the tumour and normal tissue samples. Clinically relevant information was derived by analysing the SIRT1-7 transcriptional data in terms of clinico-pathological, inflammatory and outcome variables. Finally, sirtuin expression was correlated with other factors known to be involved with biological ageing to determine any potential association. Colorectal cancer patients had significantly shorter telomeres in their peripheral blood leucocytes (adjusted mean RelT/S=0.61) compared with chronologically older controls (mean age 75, adjusted mean RelT/S=0.70) (ANCOVA, p=0.004), indicating colorectal cancer patients were biologically older than their control counterparts. In addition, telomere length in tumour tissue (median=0.43, IQR=0.40) was significantly shorter than adjacent normal tissue (median=0.65, IQR=0.28) (p=0.004). Patients with low plasma fetuin-A levels were shown to have significantly shorter telomeres (p=0.041) and patients with rectal tumours had significantly higher levels of fetuin-A than those with colonic tumours (p=0.045). There was no correlation between telomere length and other redox factors, namely anti-oxidant vitamins, micronutrients and divalent cations. There was, however, a significant association between telomere length and systemic inflammation as determined by the neutrophil to lymphocyte ratio. SIRT 1-7 were differentially expressed between tumour and normal tissue, with significant attenuation evident in tumour samples when compared with normal tissue (p<0.0001 except SIRT2 p=0.003). SIRT2 (p=0.021) and SIRT4 (p=0.027) expression in tumour samples, was significantly associated with anatomical tumour site and pathologically determined nodal status respectively. Whilst, SIRT3 expression in normal tissue correlated with pro-inflammatory status, indicated by higher serum CRP levels. Finally, there was a significant inverse relationship with colorectal cancer tissue telomere length and SIRT3. When overall survival was considered, Kaplan-Maier analysis revealed a significant difference in survival in relation to SIRT4 expression levels. We have observed that patients with colorectal cancer display clear evidence of telomere attrition compared with controls. This is congruent with accelerated biological ageing in the pathogenesis of colorectal cancer and indicates cancer patients have ‘more miles on the clock’. An imbalance in redox control mechanisms and calcium homeostasis may be a contributing factor to telomere dynamics in these patients. The demonstration of attenuated sirtuin expression in colorectal cancer suggests a role as potential tumour suppressors and provides further evidence implicating biological ageing in the oncogenic process. Furthermore, plasma fetuin-A and tissue SIRT2 expression levels can be used to distinguish between colon and rectal cancers, providing further information regarding the molecular characteristics of these tumours. Telomere biology and the sirtuins could both play a pivotal role in the MTR (Mitochondria Telomere Ribosome biogenesis) paradigm, aberrancy of which could explain the apparent link between biological ageing and cancer. Enhancement of the understanding of the determinants of telomere length could mean that manipulation could lead to reduced colorectal cancer risk at the population level. In addition, the data provided in this thesis strengthens the evidence base which suggests that targeting individual sirtuins could be a future chemotherapeutic strategy, or indeed prove useful as markers of prognosis.
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zhang, qifang. "Role of Jak/Stat pathway in the pathogenesis of breast cancer." VCU Scholars Compass, 2010. http://scholarscompass.vcu.edu/etd/41.
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The Jak/Stat signaling cascade mediates cell proliferation, differentiation, survival, apoptosis and immune responses. Aberrant activation of this pathway mediates neoplastic transformation and abnormal growth of many malignancies including breast cancer, the most common cancer among women, and the second leading cause of cancer deaths in women in United States. The mechanism by which the Jak/Stat pathway modulates the pathogenesis of breast cancer is unclear. This dissertation elucidates roles of Jak/Stat members that mediate the pathogenesis of breast cancer. For these studies, we used 4T1 mouse mammary tumor cells as a model which mimics human breast cancer. First, we investigated the role of Tyk2 tyrosine kinase in the pathogenesis of breast cancer. Here we show for the first time that compared with wild type mice, Tyk2 -/- mice show increased tumor growth rate as well as metastatic disease and splenomegaly when inoculated with 4T1 breast cancer cells. Such increased tumorigenicity was associated with a significant decrease of IFNg production in 4T1 tumor-bearing Tyk2 deficient mice T cells compared with wild type (WT) mice. We demonstrated that NK cells or CD8+ T cells control tumor growth in both Tyk2-/- and WT mice, but neither Tyk2-/- NK cells alone nor Tyk2-/- CD8+ T cells alone do not contribute to enhanced tumor growth and metastatic disease of Tyk2-/- mice. Tumor-bearing Tyk2-/- mice have increased level of myeloid-derived suppression cells than tumor-bearing mice. Tyk2-/- MDSCs have a slight increase in suppression of T cell proliferation. Since elevated phosphorylation of Stat3 has been seen in human and murine breast cancer, and expression of Stat3 in the mitochondria (mitoStat3) appears to have important affects on cell growth, we studied the ability of Stat3 targeted to the mitochondria (MLS Stat3) to influence growth and metastasis of 4T1 cells. We show that a serine mutant of Stat3 expressed in the mitochondria (Stat3 S727A) inhibits the ability of 4T1 tumor cells to grow and metastasize. In contrast, a serine to aspartic acid mutant of Stat3 (S727D) enhances tumorigenesis. We found that expression of mitochondrial-targeted Stat3 does not affect cell growth rate in cell culture under normal conditions, however in low glucose, the serine to alanine mutant shows reduced growth rate and ability to invade. Moreover, we found that expression of mitochondrial-targeted Stat3 protects cells from hypoxia. Our data indicate that serine phosphorylation of mitochondrial-localized Stat3 is required for cell transformation. In summary, our studies provided new insights into the role of Stat3 in breast cancer and suggest new therapeutic targets for the treatment of this disease.
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Pang, Wen-chi Roberta, and 彭詠枝. "The role of Pin1 in the pathogenesis of human hepatocellularcarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36905847.
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The Best PhD Thesis in the Faculties of Dentistry, Engineering, Medicine and Science (University of Hong Kong), Li Ka Shing Prize,2005-2006published_or_final_version
abstract
Medicine
Doctoral
Doctor of Philosophy
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Done, Susan Jane. "Characterization of molecular events in the pathogenesis and development of breast cancer." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 2000. http://www.collectionscanada.ca/obj/s4/f2/dsk1/tape4/PQDD_0021/NQ53776.pdf.
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McLean, Mairi Hall. "The role of chronic inflammation in the pathogenesis of sporadic colorectal cancer." Thesis, University of Aberdeen, 2008. http://digitool.abdn.ac.uk/R?func=search-advanced-go&find_code1=WSN&request1=AAIU506376.
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The adenoma-carcinoma sequence is well established and describes the sequential change from normal colonic mucosa to pre-malignant benign adenoma to overt adenocarcinoma. Each stage is associated with well defined genetic mutations. Adenomas are subjected to persistent traumatic influences, including physical, chemical and microbial insults. We hypothesise that this creates a focus of chronic inflammatory activity within the polyp and that this is a key to carcinogenesis. The concept that development of sporadic colorectal cancer is an inflammatory linked process is novel. This thesis explores this hypothesis by investigating inflammatory activity within adenomatous polyps compared to adjacent normal mucosa. We have shown that inflammatory cell infiltrate is a key feature of adenomas, with a predominant neutrophil and Thelper cell infiltrate within the stroma of small polyps less than or equal to 1 cm in size, and a predominant macrophage and CD25+ T cell infiltration in larger lesions. This inflammatory infiltrate increases along with increasing degree of cell dysplasia towards malignancy and furthermore, our data suggests that macrophage function with the adenomas is predominantly pro-inflammatory in nature. Expression of cyclo-oxygenase 2, a key inflammatory mediator, is increased in adenomas and is linked to adenoma characteristics associated with malignant potential. We have also shown that inflammatory cytokine gene expression is dysregulated in polyps.
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何丹 and Dan He. "Clinical and pathological significance of HPV infection and p53 mutation in human esophageal cancer." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 1997. http://hub.hku.hk/bib/B31236959.
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Moorehead, Robert John. "A study of some aspects of the pathogenesis of colorectal neoplasia." Thesis, Queen's University Belfast, 1986. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.328030.
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Hendricks, Roshan. "Genetic analysis of the role of androgen metabolism in the pathogenesis of prostate cancer." Thesis, Stellenbosch : Stellenbosch University, 2004. http://hdl.handle.net/10019.1/49973.
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Thesis (MSc)--Stellenbosch University, 2004.ENGLISH ABSTRACT: Prostate cancer (CaP) has the highest incidence of any malignancy affecting South African males. The aetiology of prostate carcinoma indicate that ethnicity is one of the most important risk factors. The causes of these ethnic differences are unknown but presumably involve both environmental and genetic factors. Carcinoma of the prostate is androgen dependent, and it has been suggested that variations in androgen metabolism and synthesis may affect an individuals' risk. Therefore, genes involved in these pathways are candidates for determining CaP susceptibility. In this study two candidate genes in the androgen biosynthetic and metabolic pathway were analysed, viz., the androgen receptor gene (AR), involved in androgen transport and transcriptional activation, and the cytochrome p450c17a gene (CYP17), important for testosterone biosynthesis. Comprehensive mutation detection assays were designed (appropriate for analysis of archival paraffin-embedded material) for almost the entire coding region (excluding polymorphic repeat sequences), and including all splice site junctions of the AR gene, as well as the entire coding region of CYP17. The aim of this study was thus to determine the type and frequencies of genetic variants of these androgen metabolism genes within the diverse South African population, and to determine if the observed ethnic variation in the incidence and progression of CaP can be explained by ethnic-based genetic differences. For high sensitivity mutation detection, the most powerful of the pre-screening methods was used, namely denaturing gradient gel electrophoresis (DGGE). 20 CaP and 25 control benign prostatic hyperplasia (BPH) tissue samples were screened in order to identify possible mutations. Blood samples from the same patients were analysed in order to determine whether mutations are germline and therefore present in all cells of the body. Additional blood samples from the Western Province Blood Transfusion Service (WPBTS) (Refer to section 2.1.2, Table) were also analysed in order to determine the frequency of identified polymorphisms within the general population. Certain polymorphisms were further analysed in paraffin-embedded wax material (exclusively from Blacks) to determine the distribution of these polymorphisms in the Black population. Direct sequencing of mutant-containing DNA fragments was performed to determine the exact location and nature of mutation. Using the AR- DGGE assay 4 novel mutations were identified as well as a previously reported codon 211 (E211) polymorphism. With the CYP17- DGGE assay, 3 novel single nucleotide polymorphisms (SNPs) were detected. Three base variants occured, in codons 36 (L36), 46 (H46) and 65 (S65), as well as intronic substitutions in intron 4 (IVS+58G4C) and intron 6 (IVS-25C7A). Frequencies of SNPs were measured in the CaP and BPH samples. In conclusion, the identified polymorphisms could be used as markers in determining CaP susceptibility and may thus facilitate the identification of individuals with a high- or low-risk of developing carcinoma of the prostate.
AFRIKAANSE OPSOMMING: Prostaatkanker vertoon die hoogste voorkoms van enige kwaardaardigheid wat Suid-Afrikaanse mans aantas. Die etiologie van prostaatkarsinoom dui aan dat etnisiteit een van die mees belangrike risikofaktore is. Oorsake van hierdie etniese verskille is onbekend, maar vermoedelik is omgewing en genetiese faktore albei betrokke. Karsinoom van die prostaat is androgeenafhanklik en daar is voorgestel dat variasies in androgeenmetabolisme en androgeensintese 'n persoon se risiko mag affekteer. Gevolglik, is gene betrokke in hierdie paaie kandidate vir die bepaling van prostaatkanker vatbaarheid. In hierdie studie het ons twee kandidaat gene in die androgeen biosintetiese en metaboliese pad geanaliseer, naamlik, die androgeen reseptor geen (AR), betrokke in androgeen vervoer en aktivering van transkripsie, en die sitokroom p450c17a geen (CYP17), belangrik vir testosteroon biosintese. Ons het omvattende mutasie-bespeurings-essai-sisteme ontwikkel (ook uitvoerbaar op argivale paraffien-bewaarde materiaal), wat amper vir die hele koderende streek van die AR geen gebruik kan word (uitsluitend herhalende polimorfiese reekse) en wat alle splytpunt-aansluitings van die AR geen insluit, asook vir die hele koderende streek van CYP17. Die doel van hierdie studie was dus om die tipe en frekwensies van genetiese variante van androgeen metabolisme gene in ons diverse Suid-Afrikaanse bevolking te bepaal, en om vas te stel of die waarneembare etniese wisseling in die insidensie en vordering van prostaatkanker verstaan kan word deur etnies gebaseerde genetiese verskille. Die mees sensitiewe tegniek wat tans beskikbaar is vir vooraf-sifting vir onbekende mutasies is gekies, naamlik denaturerende gradiënt gel elektroforese (DGGE). Om moontlike mutasies op te spoor, het ons 20 prostaatkanker en 25 benijne prostaathiperplasie (BPH) monsters geanaliseer. Analise was gedoen op bloedmonsters van dieselfde pasiënte om vas te stel of kiemlyn mutasies (in alle liggaamselle) teenwoordig is. Bykomstige bloedmonsters (van die Westelike Provinsie Bloedoortappingsdiens) is ook geanaliseer om die frekwensie van bespeurde polimorfismes in die algemene bevolking te bepaal. Argivale paraffien-bewaarde materiaal (eksklusief van Swartes) is ook geanaliseer om die verspreiding van sekere polimorfismes in die Swart bevolking te bepaal. Direkte DNA volgorde bepaling van mutante DNA fragmente is uitgevoer om die ligging en tipe van mutasies te bepaal. Met die toepassing van ons AR-DGGE mutasiesisteem het ons 4 nuwe mutasies ontdek asook 'n kodon 211 (E211) polimorfisme wat voorheen gevind is. Vyf enkel nukleotied polimorfismes is met die CYP17-DGGE mutasiesisteem opgespoor. Die polimorfismes sluit in: drie basis veranderinge wat voorkom in kodons 36 (L36), 46 (H46) en 65 (S65), asook introniese substitutisies in intron 4 (IVS+58G4C) en intron 6 (IVS-25C7 A). Frekwensies van die polimorfismes was bereken in die prostaatkanker en BPH monsters. Die resultate aangebied in hierdie tesis dui aan dat die gevonde polimorfismes as merkers gebruik kan word om prostaatkanker vatbaarheid te bepaal en daardeur individue te identifiseer met 'n hoë of lae risiko vir prostaatkarsinoom ontwikkeling.
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Dorkin, Trevor John. "The role of fibroblast growth factors in the pathogenesis of human prostate cancer." Thesis, University of Newcastle Upon Tyne, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.366585.
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Pellegrino, Loredana. "Distinct functional roles of microRNA-23b and microRNA-26a in breast cancer pathogenesis." Thesis, Imperial College London, 2013. http://hdl.handle.net/10044/1/24827.
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Tumour formation and metastasis are distinct processes that arise from cumulative alterations of genomic and epigenetic regulation. Uncontrolled modulation of cell cycle-related genes is crucial to tumour growth and additional genetic modifications provide cancer cells with motile and invasive phenotypes, leading to metastatic dissemination. The cytoskeleton constitutes the structural support to cell motility, invasion and adhesion. Among the best-characterised cytoskeletal modulators are the p21-activated kinases (PAKs). In breast cancer (BC), the HER2 pathway controls the cytoskeletal dynamics and cell motility via PAK activation, through distinct downstream signaling mechanisms. MicroRNAs (miRNAs) are small, non-coding RNAs that modulate gene expression post-transcriptionally. MiRNAs dysregulation can contribute to tumorigenicity, cell motility and metastasis by affecting relevant signaling pathways. We identified PAK2 as target of both miR-23b and miR-26a, implicating a direct role for these miRNAs in cytoskeletal remodeling. Experimentally, expression of miR-23b and miR-26a in BC cells promotes focal adhesions and cell spreading on substrates, but miR-23b alone controls cell-cell junctions and lamellipodia formation. Despite sharing the same target, the two miRNAs show additional distinct functions. MiR-26a overexpression in BC leads to formation of aneuploid cells associated with higher tumorigenicity. On the other hand, miR-23b inhibition enhances BC cell migration, invasion and metastasis in vivo. Clinically, low miR-23b levels correlate with metastatic development in BC patients. Mechanistically, growth factor-mediated signal transductions activate the transcription factor AP-1 and we show that this transcriptionally reduces miR-23b expression thus releasing PAK2 from its translational inhibition. The distinct cellular phenotypes described by the two miRNAs indicate that their global functions depend upon all the genes they regulate. Using RNA-sequencing and luciferase reporter assays, we validated a subset of genes as direct targets of either the two miRNAs. These genes are crucial to distinct molecular pathways and contribute to elucidate the observed phenotypes induced by miR-23b and miR-26a modulation.
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Minton, Ollie. "An investigation into the biological pathogenesis and clinical correlates of cancer-related fatigue in disease-free breast cancer patients." Thesis, St George's, University of London, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.568717.
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Background: 30-40% of women successfully treated for breast cancer experience chronic fatigue for up to five years after the end of therapy. They experience a number of associated problems including reduced quality of life, lower mood and concentration difficulties. The causes of these problems and the underlying biological pathogenesis of these symptoms are unclear. The primary objective of this research was to identify whether there were differences in objective activity, cognitive function and inflammatory cytokines between fatigued and non-fatigued women post-treatment. Methods: This was a cross-sectional observational study. Women were recruited from a nurse-led follow-up clinic at St George's hospital over a two-and-a-half-year period. These women were categorised on the basis of a semi-structured interview as to whether they met the criteria to be a case of cancer-related fatigue syndrome (CRFS) or acted as a control. All participants completed a set of questionnaires, activity recording, cognitive testing and had blood taken for analysis. Samples were sent to a commercial company for analyte panel testing (88 markers) and were also analysed using proteomic techniques (including mass spectrometry) to identify any differences in plasma proteins between groups. Results: 114 women were recruited; 45 cases and 69 controls. A between group analysis demonstrated statistically significant differences in sleep quality (p=0.02) and daytime activity (p=0.03) on activity recording, and slower processing speed (p=0.009) and impaired verbal memory (p=0.03) on cognitive testing. Blood analysis demonstrated statistically significant differences (p<0.03) with raised inflammatory cytokines on commercial testing (interleukin 18, vascular endothelial growth factor and macrophage inflammatory protein 1) and increased non-specific inflammatory markers on an exploratory proteomic analysis (serum amyloid A and collectin). Conclusions: Statistically significant differences in subjective symptoms, e.g. difficulty concentrating, and linked objective data, e.g. reduced cognitive processing speed, were identified. These differences were associated with evidence of an underlying prolonged inflammatory response (indicated by raised cytokine levels) in the CRFS group. Future work should examine these observed differences prospectively before, during and after treatment.
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Siddiqui, Nadeem. "The role of cellular retinoid binding proteins and nuclear retinoic acid receptors in the pathogenesis of endometrial adenocarcinoma." Thesis, University of Newcastle Upon Tyne, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.283618.
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Villalobos, Hernandez Alberto. "Role of suppressor of cytokine signalling 1 (SOCS1) in the pathogenesis of prostate cancer." Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/11618.
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Le cancer de la prostate (PCa) est le deuxième cancer le plus courant chez les hommes au niveau mondial. Le suppresseur de la signalisation des cytokines 1 (SOCS1) est considéré comme un suppresseur de tumeur en raison de la fréquente répression épigénétique de ce gène dans de nombreux cancers. Il a été reporté que SOCS1 inhibait l’activation de STAT3 induite par l’IL-6, ainsi que les cyclines et les kinases dépendantes des cyclines dans les cellules malignes de la prostate. D’autre part, il a été montré que SOCS1 n’était pas essentiel lors du contrôle de la signalisation de l’IL-6 dans les hépatocytes dépourvus de cette protéine, cependant elle est essentielle pour atténuer la signalisation du facteur de croissance des hépatocytes (HGF) via son récepteur MET. MET est un récepteur de tyrosine kinases qui est surexprimé dans le PCa agressif et métastatique. Notre hypothèse de recherche propose que la répression de SOCS1 par méthylation du promoteur et la dérégulation de l’expression de MET et de sa signalisation, sont des mécanismes pathogéniques liés au développement et à la progression du PCa. Nous avons généré des lignées de cellules PC3 et DU145 stables exprimant SOCS1. Les cellules ont été stimulées avec HGF et l’activation des voies de signalisation a été évaluée par immunobuvardage. Des essais in vitro de migration, de prolifération et d’invasion ont été effectués en présence de HGF. Des gènes de transition épithélio-mésenchymateuse ont été évalués par PCR quantitatif en présence ou non du facteur de croissance. Les cellules du PCa transfectées ou pas avec SOCS1 ont été inoculées dans des souris NOD SCID gamma de façon sous-cutanée ou orthoptique afin d’évaluer respectivement la croissance tumorale et la formation de métastases. Les tumeurs reséquées ont été analysées histologiquement et biochimiquement. Nos résultats montrent que SOCS1 atténue l'activation de MET induite par HGF et la phosphorylation d’ERK dans les cellules PC3, ainsi que la phosphorylation d’ERK et d’AKT dans les cellules DU145. SOCS1 inhibe également la prolifération cellulaire induite par HGF, ainsi que la migration et l’invasion in vitro. De plus, SOCS1 réduit l’expression des gènes de transition épithélio-mésenchymateuse impliqués dans la dégradation des composants de la matrice extracellulaire dans les cellules DU145 mais pas dans les cellules PC3. La surexpression de SOCS1 a stimulé l’augmentation de déposition de collagène, in vivo. Les tumeurs formées par les cellules exprimant SOCS1 étaient de taille significativement plus petites avec une réduction de la prolifération comparé aux tumeurs provenant des cellules contrôles. En outre, SOCS1 a inhibé la formation de métastases à distance dans un modèle orthotopique. En conclusion, nous suggérons que SOCS1 est un suppresseur de tumeur indispensable de la prostate, et qu’au moins une partie de sa fonction a lieu via la régulation négative de la signalisation du récepteur MET.Abstract : Prostate cancer (PCa) is the second most common cancer among men worldwide. Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic repression of the SOCS1 gene in several human malignancies. Inactivation of SOCS1 also occurs in PCa by gene methylation and micro-RNA-mediated repression. SOCS1 has been reported to inhibit IL-6-induced STAT3 activation and down-regulates cyclins and cyclin-dependent kinases in PCa cells. It has been shown that SOCS1 is not required to control IL-6 signaling in SOCS1-deficient hepatocytes, but is essential to attenuate hepatocyte growth factor (HGF) signaling via its receptor MET. This protein is a receptor tyrosine kinase (RTK), overexpressed in aggressive and metastatic PCa. Thus we hypothesized that the repression of SOCS1 via promoter methylation and deregulated MET expression and signaling are inter-related pathogenic mechanisms in PCa development and progression. We generated stable SOCS1-expressing PCa cell lines (PC3 and DU145) using lentiviral transduction followed by clonal selection via limiting dilution. Cells were stimulated with HGF and downstream signaling events were assessed by Western blot. Proliferation, migration and invasion assays were also conducted in the presence of HGF in vitro. Epithelial mesenchymal transition genes were evaluated by qPCR in the presence or absence of the growth factor. The PCa cells transfected with SOCS1 and non-transfected controls were inoculated into NOD SCID gamma mice as xenografts or as orthotopic tumors to assess tumor growth and metastasis formation, respectively. Resected tumors were further analyzed histologically and biochemically. Our results showed that SOCS1 attenuates HGF-induced MET activation and ERK phosphorylation in PC3 and DU145 PCa cell lines. SOCS1 inhibited HGF induced cell proliferation, migration and invasion in vitro. Additionally, SOCS1 decreased epithelial mesenchymal transition genes involved in the degradation of extracellular matrix components in DU145 cells but not in PC3. In vivo, SOCS1 overexpression leads to an increase of collagen deposition. Tumors formed by SOCS1 expressing cells were significantly smaller in size with reduced cell proliferation compared to tumors arising from control cells. Furthermore, SOCS1 inhibited distant metastasis formation in the orthotopic model. Overall our results suggest that SOCS1 has a tumor suppressor role in PCa evolution and part of this function is mediated by the negative regulation of MET receptor signalling and down-regulation of genes supporting migration and invasion processes such as matrix metalloproteinases.
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Maher, Louise Sameen. "Helicobacter pylori and the E-cadherin-catenin complex in the pathogenesis of gastric cancer." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.248047.
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Camacho, Moll Maria Elena. "Germ cell neoplasia in situ (GCNIS) and the pathogenesis of testicular germ cell cancer." Thesis, University of Edinburgh, 2017. http://hdl.handle.net/1842/28807.
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Testicular germ cell cancer (TGCC) has been increasing in incidence over recent decades, and is currently the most common malignancy amongst young men resulting in significant morbidity. These tumours are believed to arise from premalignant germ cell neoplasia in situ (GCNIS) cells, which originate from the aberrant germ cell differentiation from gonocyte to spermatogonia during fetal/early postnatal life. GCNIS cells remain dormant in the testis until puberty when they are activated to become tumours. Therefore, GCNIS cells remain in a pre-invasive stage during early childhood and early adulthood prior to the development of a seminoma or non-seminoma TGCC. GCNIS cells are phenotypically similar to gonocytes with expression of stem cell/early germ cell markers including OCT4, PLAP and LIN28. Furthermore, proteins which are expressed in more mature germ cells (spermatogonia) such as MAGE-A4 have also been shown to be expressed in GCNIS cells and these studies have indicated that GCNIS cells are a heterogeneous population in terms of protein expression profile. The relationship between the protein expression profile of individual GCNIS cells populations and their oncogenic potential has not been fully explored. GCNIS cells are located in the seminiferous tubules supported by somatic Sertoli cells. These cells have been previously reported to exhibit an immature protein expression profile in GCNIS tubules from patients with testis cancer, suggesting that the germ stem cell niche in GCNIS tubules resembles that of a fetal one. Associations between Sertoli cell maturation and GCNIS progression into tumour formation has not been fully investigated. Oncogenes are key players in the regulation of oncogenic potential of cancer cells. Gankyrin is an oncogene that has been shown to down-regulate OCT4, and interact with MAGE-A4 in hepatocellular carcinoma and colorectal cancer, where Gankyrin interaction with MAGE-A4 reduces the oncogenic potential of tumour cells. In this study I aimed to investigate the heterogeneity of GCNIS in relation to disease stage and Sertoli cell development. We also aimed to determine the role of Gankyrin in TGCC cell survival and invasion. The co-expression of early germ cells proteins such as OCT4, LIN28 and PLAP was characterized in GCNIS cells during childhood and adulthood pre-invasive TGCC and in invasive disease characterized by the presence of a testicular tumour. These results show that LIN28 was expressed in 95% of OCT4 GCNIS cells, whereas PLAP expression in GCNIS cells increased as the disease progressed from childhood pre-invasive disease to invasive seminoma (32.3% v 76%; p < 0.05). In contrast there was a reduction in the proportion of MAGE-A4 expressing GCNIS cells with disease progression. The MAGE-A4 expressing population was also less proliferative than the MAGE-A4 negative GCNIS population. The methylation status of GCNIS cells was then investigated. EZH2 a methyltransferase previously reported to be important for TGCC development, was expressed in GCNIS cells at all stages of disease, however the histone 3 modification H3K27me3 (mediated by EZH2) was expressed in a significantly higher percentage of the proliferative OCT4+/MAGE-A4- GCNIS cells compared with the OCT4+/MAGEA4+ population (11.7% v 1.1%; p < 0.01) which could indicate a repressive role for H3K27me3 over MAGE-A4 expression. Next, it was determined whether an association between Sertoli cell maturation status and progression of TGCC could be observed. The maturation status of Sertoli cells was studied using proteins indicative of immature (desmin, cytokeratin, fibronectin and AMH) and mature (vimentin and androgen receptor) Sertoli cells. These studies demonstrated heterogeneity of Sertoli cells maturation in GCNIS-containing tubules. Desmin, fibronectin, AMH and vimentin expression did not show any association with TGCC progression. Cytokeratin was expressed in Sertoli cells of human fetal testis up to second trimester of fetal life, absent in tubules with active spermatogenesis but heterogeneously present in GCNIS, demonstrating that cytokeratin expression is indicative of the presence of GCNIS. Androgen receptor was weakly present in Sertoli cells from human fetal testis and pre-pubertal pre-invasive TGCC testis whereas in GCNIS of adult pre-invasive testis and invasive samples, androgen receptor was abundantly expressed in Sertoli cells of GCNIS-containing tubules. These combined results for cytokeratin and androgen receptor suggest that Sertoli cells from GCNIS-containing tubules, in pre-invasive and invasive TGCC patients are partially differentiated. Gankyrin expression was characterised in fetal germ cells, GCNIS cells and TGCC tissue. In fetal testis nuclear Gankyrin was absent in OCT4+/MAGE-A4- (gonocyte) population whereas it was present in a subpopulation of OCT4-/MAGE-A4+ (spermatogonia) germ cells. In GCNIS cells from TGCC patients nuclear Gankyrin was expressed in 87%, 63.3%, 91.5% and 79% in childhood pre-invasive, adult pre-invasive, seminoma and non-seminoma GCNIS cells respectively. Finally, in seminoma cells, Gankyrin was expressed in the cytoplasm indicating a change in localisation as the GCNIS cells become invasive. We used siRNA to knockdown Gankyrin in NT2 (a TGCC cell line) cells in-vitro and demonstrated a decrease in cell number, suggesting that Gankyrin might play a role in TGCC progression and invasiveness. Gankyrin down-regulation also resulted in an increase in p53 and p21 mRNA level. Given the role of P53 and p21 in cisplatin cytotoxic effect in TGCC we went on to investigate the role of Gankyrin in cisplatin resistance using NT2 cells. We demonstrate that Gankyrin mediated cisplatin resistance through the p53/p21 pathway, upregulating apoptosis rates through BAX and FAS, whilst there was no effect on cell proliferation, cell cycle or cell migration. In conclusion, we have shown that GCNIS cells are heterogeneous and their phenotype can determine their oncogenic potential. We also show that Sertoli cells from GCNIS-containing tubules undergo partial differentiation displaying markers of immature and mature Sertoli cells, with a heterogeneous association of cytokeratin with GCNIS presence. We also demonstrate that the oncogene Gankyrin has a role in NT2 cells survival and cisplatin resistance indicating that manipulation of Gankyrin may have a role in the treatment of TGCC.
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Zhao, Wei, and 趙煒. "BRAF mutation and aberrant methylation of gene promoters in the pathogenesis of gastrointestinal tract adenocarcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2006. http://hub.hku.hk/bib/B36718464.
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Harwood, Catherine Anne. "Human papillomavirus and the molecular pathogenesis of non-melanoma skin cancer associated with organ transplantation." Thesis, Queen Mary, University of London, 2003. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.407957.
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Bryant, Richard John. "The role of the polycomb group protein EZH2 in the molecular pathogenesis of prostate cancer." Thesis, University of Sheffield, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.489711.
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Although prostate cancer causes morbidity and mortality many men have indolent disease with few health consequences. There is an urgent need to identify which patients with prostate cancer require clinical intervention, thereby preventing both under- and overtreatment. The Polyeomb Group (PeG) gene EZH2 is up-regulated in hormone-refractory metastatic prostate cancer, suggesting that EZH2 promotes progression to an advanced tumour phenotype. EZH2 is a transcriptional repressor during normal embryonic development by virtue of its histone methyltransferase activity. At the start of this work the role ofEZH2 during tumour progression was unclear. This thesis identifies EZH2 as a dual-function promoter of prostate cancer progression. EZH2 function promotes proliferation of both androgen-responsive and androgen-independent prostate cancer cells, suggesting that aberrant EZH2 function may occur earlier than originally thought during prostate cancer progression. It was discovered that EZH2 function promotes prostate cancer cellular invasiveness, demonstrating a mechanism which can account for the association between increased EZH2 expression and advanced disease. It was observed that androgen-induced expression of the TMPRSS2:ERG gene fusion in prostate cancer cells was associated with a trend towards increased expression of HDAC1 and the PeG genes EZH2 and SUZ12. It was also observed that EZH2 regulates actin polymerisation in prostate cancer cells, which may account for the abrogation of cellular invasiveness observed following EZH2 knock-down. Given that EZH2 is a transcriptional repressor, a search for candidate EZH2 target genes was performed. EZH2 may promote transcriptional repression ofp21 and MMP7. . Effects of overexpression of EZH2 and a dominant gain-of-function allele, EZH2R732K, were investigated in prostate cancer cells. No discernible phenotype was observed, suggesting additional factors are required to promote the progression to an aggressive prostate cancer phenotype. The results presented in this thesis suggest mechanisms that can account for the association between increased EZH2 expression and advanced prostate cancer.
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Shim, Tang Ngee. "Aetiological factors in the pathogenesis of male genital lichen sclerosus, penile precancer and penile cancer." Thesis, Imperial College London, 2016. http://hdl.handle.net/10044/1/45003.
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Male genital lichen sclerosus (MGLSc) results in sexual and urological dysfunction and predisposes to penile intraepithelial neoplasia (PeIN) and squamous cell carcinoma of the penis (PSCC). The pathogenesis of MGLSc is controversial. Evidence has accumulated that it is due to chronic, occluded exposure to urine caused by post-micturition microincontinence. Infection with hepatitis C (HCV) or human papillomavirus (HPV), autoimmunity and HLA immunogenotype have been incriminated. PeIN and PSCC are associated with HPV and MGLSc. Down-regulation of the gene Cables 1 (associated with squamous carcinogenesis) has been reported in MGLSc. The role of HLA in PeIN and PSCC is unknown. Urinary microincontinence, HPV, HLA, HCV and Cables 1 have been investigated in MGLSc (n=88), PeIN (n=72) and PSCC (n=37). Clinical charts were reviewed retrospectively for microincontinence. HCV antibody titres were assayed serologically. Cables 1 expression was assessed by immunohistochemistry of biopsies. DNA was extracted from blood and tissue for broad-spectrum HPV and comprehensive HLA typing by specific and sensitive PCR-based methodologies. Nearly 90% of men with GLSc (p = < 0.01) had post-micturition microincontinence. HPV was identified in 37.5% of cases of MGLSc (n=88), 90.2% PeIN and 54.1% PSCC. MGLSc was associated with 34.7% cases of PeIN. No significant HLA associations were found in MGLSc. Significant (p < 0.05) HLA associations were i) susceptibility to a) PeIN (C*15) - specifically HPV16 +ve PeIN (C*15, DQA1*02, DQA1*03) and b) HPV16 +ve PSCC (B*57), and ii) protection against PeIN (DQA1*01). No association between HCV and MGLSc was found. Cables 1 expression was normal. Microincontinence and urinary exposure are implicated in the pathogenesis of MGLSc. HPV is involved in the pathogenesis of PeIN and PSCC but associated with MGLSc only as a passenger phenomenon. Immunogenotype may play a role in the pathogenesis of PeIN and PSCC but not of MGLSc. HCV and Cables 1 are not important in MGLSc.
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Fox, Christopher Paul. "Investigating the role of Epstein-Barr virus in the pathogenesis of NK and T cell lymphoproliferations." Thesis, University of Birmingham, 2011. http://etheses.bham.ac.uk//id/eprint/2847/.
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Epstein-Barr virus (EBV) is strongly associated with rare but aggressive lymphoproliferative diseases of NK and T cell origin. The finding of clonal and episomal forms of the virus in tumour cells from these clinically diverse diseases indicates involvement of EBV at an early stage of lymphomagenesis. However, many fundamental questions about EBV’s contribution to pathogenesis remain unanswered. In vivo analyses herein found that infection of tonsillar (but not peripheral blood) T cells occasionally occurred in primary and persistent infection, whilst infection of NK cells was a rare event. By contrast, a high EBV load was found in peripheral blood NK cells from 3 adult patients with EBV-associated haemophagocytic-lymphohistiocytosis, a disease previously associated with CD8+ T cell infection in children. Complementary studies examined EBV latent gene expression in EBV+ T/NK malignancies. Notwithstanding an apparent absence of latent membrane protein 2A and 2B (LMP2A/B), these tumour cells were recognised and killed by LMP2-specific cytotoxic T lymphocytes. This paradox was resolved by identifying a novel LMP2 mRNA, initiated from within the terminal repeat (TR) region of the viral genome and containing downstream epitope-encoding exons. Expression of LMP2-TR in T/NK cell lines and primary tissue implicates this truncated viral protein in T/NK lymphomagenesis.
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Oram, L. "The role of p53 gain-of-function mutations in the pathogenesis of basal-like breast cancer." Thesis, Queen's University Belfast, 2014. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.680241.
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Basal-like breast cancers (BLBC) are an aggressive sub-type of breast cancer which associates with high rates of proliferation and metastasis. However, the molecular mechanisms underlying these tumours are still largely unknown as most BLBC are also triple-receptor negative, which is defined by the lack of expression of oestrogen (ER) and progesterone (PR) receptors, with normal HER2 status. Consequently, there are currently no targeted therapies available for these tumours, which display the worst prognosis of all breast cancer subtypes. TP53 mutations occur within 20% of all breast tumours, however, this rate is observed to increase dramatically to approximately 85% within the basal-like subtype. Moreover, TP53 missense mutations can lead to the production of mutant proteins which possess novel oncogenic capabilities, known as Gain-of-Function (GOF) p53 mutants. These GOF mutants may display wild-type protein conformation (contact mutants) or exhibit conformational alterations to the tertiary protein structure (structural mutants). We have shown that siRNA-mediated knockdown of endogenous mutant p53, particularly contact GOF mutants significantly reduces survival of BLBC cells. We also demonstrate that contact, but not structural, p53 mutant proteins can directly bind to the transcription factor Etsl, and are also involved in upregulation of its expression. We show that mutant p53 interaction with Etsl is a critical event for both survival of these cells and co-regulation of downstream target genes. We have identified several novel mutant p53-specific transcriptional targets, some of which play important roles in the proliferation and survival of BLBC cells. Additionally, we have putatively detected an alternatively-spliced p53 protein isoform following over-expression of a structural GOF p53 mutant in non-tumourigenic and tumour-derived cell lines.
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Mahauad, Fernandez Wadie Daniel. "Role of bone marrow stromal antigen 2 (BST-2) in viral pathogenesis and breast cancer progression." Diss., University of Iowa, 2016. https://ir.uiowa.edu/etd/6191.
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Bone marrow stromal antigen 2 (BST-2/tetherin) is a type II transmembrane protein that plays various roles, including protective and detrimental roles in the host. Cellular responses to BST-2 expression or the lack thereof, may be cell type and context-dependent and may vary with time. When protective, BST-2 functions as an antiviral factor, renowned for its ability to tether budding enveloped viruses to the membrane of infected cells. Tethering of budding virions prevents their release into the extracellular milieu limiting infection of naïve cells. The antiviral role of BST-2 has been predominantly studied using cultured cells. Insight into the role of BST-2 in inhibition of viral infection in vivo came from our study of the alphavirus Chikungunya virus (CHIKV) and the retrovirus mouse mammary tumor virus, (MMTV). BST-2 prevents the release of CHIKV and MMTV virions from infected cells and limits the replication of both viruses in mice. In the context of CHIKV infection, BST-2 protects the host in a tissue-type dependent manner. In lymphoid and most non-lymphoid tissues, expression of BST-2 limits CHIKV replication. In addition, BST-2 regulates CHIKV-induced inflammatory responses in mice, an indication that BST-2 may function to initiate and amplify innate immune responses. Host response to MMTV infection depends on the stage of the infection and disease sequela. Acute infection of immune cells with MMTV results in an initial increase in BST-2 expression followed by a sharp decline. In contrast, in MMTV-induced mammary tumors, BST-2 mRNA and protein are elevated, so is the viral load. This is an indication that the antiviral role of BST-2 is not operative once mammary tumors have developed. These data provided the initial evidence that BST-2 may promote breast cancer progression. Indeed, data from two mouse models of breast cancer show that expression of BST-2 is necessary for cell to cell and cell to extracellular matrix interactions. Thus, BST-2 expression in breast cancer cells enhances cancer cell adhesion, anchorage-independency, migration, and invasion, culminating in increased tumor mass, increased metastases, and reduced host survival. Structurally, BST-2 homodimerization is important for its cancer-promoting role as dimers of BST-2 regulate anchorage-independency, resistance to anoikis, and enhanced adhesion between cancer cells and components (proteins and cells) of the tumor microenvironment. How BST-2 is enriched in breast cancer cells was elusive until our in silico analyses of a large human breast cancer dataset that revealed the involvement of epigenetic regulation of BST-2 in breast tumors. In highly aggressive breast cancers, specific CpG sites in and at close proximity to the BST-2 promoter are hypomethylated. This is in sharp contrast to non-aggressive luminal cancers and normal breast epithelial cells. These data suggest that a progressive loss of methylation on the BST-2 gene may contribute to constitutive overexpression of BST-2 in tumors. Overall, these findings show that 1) BST-2 contributes to the emergence and progression of breast malignancies and may be used as a therapeutic target or as a biomarker for aggressive breast cancers; and, 2) BST-2 acts as a viral sensor to initiate antiviral inflammatory responses and could be exploited therapeutically to treat viral infections. We highlight the need for additional research on the antiviral and cancer-promoting roles of BST-2 to reconcile both functions for the purpose of therapeutics.
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劉國培 and Kwok-pui Lau. "Clinicopathological roles of transforming growth factor alpha (TGFα) in papillary thyroid carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2007. http://hub.hku.hk/bib/B39558733.
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Liu, Wen. "Functional Analysis of the Tumor Metastasis Suppressor, NDRG1." OpenSIUC, 2011. https://opensiuc.lib.siu.edu/dissertations/347.
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Metastasis suppressors regulate multiple steps during the process of dissemination of tumor cells from primary sites to distant organs, while they do not affect the growth of the primary tumor. Previously, we identified NDRG1 (N-myc downstream regulated gene 1) as a tumor metastasis suppressor gene and found that it is negatively involved in metastatic progression of prostate and breast cancers. To elucidate the molecular mechanism of NDRG1 function, we used the yeast two-hybrid system to identify proteins interacting with NDRG1. In the first part of this project, we demonstrate that NDRG1, interacts with the Wnt receptor, LRP6, followed by blocking of the Wnt signaling, and therefore, orchestrates a cellular network that impairs the metastatic progression of tumor cells in vitro and in animal model. We also found that restoring NDRG1 expression by a small molecule compound significantly suppressed the capability of otherwise highly metastatic tumor cells to thrive in circulation and distant organs in animal models. In addition, our analysis of clinical cohorts data indicate that Wnt+/NDRG-/LRP+ signature has a strong predictable value for recurrence-free survival of cancer patients. Collectively, we have identified NDRG1 as a negative master regulator of Wnt signaling during the metastatic progression, and therefore revealed a novel control mechanism of Wnt signaling in tumor progression. Previously, we identified the metastasis promoting transcription factor, ATF3, as a downstream target of NDRG1. Further analysis revealed that the KAI1 promoter contained a consensus binding motif of ATF3, suggesting a possibility that NDRG1 suppresses metastasis through inhibition of ATF3 expression followed by activation of KAI1 gene. In the second part of this project, we examine a possible link between two metastasis suppressor genes, NDRG1 and KAI1, through ATF3. We demonstrated that ectopic expression of NDRG1 was able to augment endogenous KAI1gene expression in prostate cancer cell lines, while silencing NDRG1 accompanied with significant decrease in KAI1 expression in vitro and in vivo. In addition, our results of ChIP analysis indicate that ATF3 indeed bound to the promoter of KAI1 gene. Importantly, our promoter-based analysis revealed that ATF3 modulated KAI1 transcription through cooperation with other endogenous transcription factor as co-activator (ATF3-JunB) or co-repressor (ATF3-NFêB). Moreover, loss of KAI1 expression significantly abrogated NDRG1-mediated metastatic suppression in vitro as well as in a spontaneous metastasis animal model, indicating that KA11 is a functional down-stream target of NDRG1 pathway. Our result of immunohistochemical analysis showed that loss of NDRG1 and KAI1 occurs in parallel as prostate cancer progresses. We also found that a combined expression status of these two genes serves as a strong independent prognostic marker to predict metastasis-free survival of prostate cancer patients. Taken together, our result revealed a novel regulatory network of two metastasis suppressor genes, NDRG1 and KAI1, which together concerted metastasis-suppressive activities through intrinsic transcriptional cascade.
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Margielewska, Sandra Karolina. "The contribution of discoidin domain receptor 1 to the pathogenesis of diffuse large B cell lymphoma." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8421/.
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Collagen is the ligand for the discoidin domain receptor-1 (DDR1), a receptor tyrosine kinase that is over-expressed in Hodgkin lymphoma. However, the role of DDR1 in diffuse large B cell lymphoma (DLBCL) is not known. I showed that DDR1 is over-expressed in a subset of DLBCL where it positively correlates with expression of its collagen ligands, and negatively correlates with expression of mitotic spindle genes. DDR1 correlated genes also overlapped with three aneuploidy signatures and DDR1 expression correlated significantly with autosomal aneuploidy index. RNAseq analysis revealed that over-expression of DDR1 in primary germinal centre B cells down-regulated expression of CENPE, an essential component of the mitotic spindle checkpoint that when inactivated leads to chromosome mis-segregation and aneuploidy. CENPE expression was also significantly reduced in primary DLBCL. Moreover, I showed that the constitutive activation of DDR1 in an in vitro lymphoma model led to aneuploidy. Finally, I showed that DDR1 can be inhibited by three small molecules and established the basis for in vivo model to test these inhibitors in DLBCL xenograft. My data provide evidence that DDR1 can induce aneuploidy in B cells, and as such identify a mechanism to potentially explain the link between chronic inflammation and lymphomagenesis.
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Austen, Belinda. "A study of the role of ATM mutations in the pathogenesis of B-cell chronic lymphocytic leukaemia." Thesis, University of Birmingham, 2007. http://etheses.bham.ac.uk//id/eprint/23/.
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Mutations in the ATM gene have previously been identified in CLL tumours. In this project, I have demonstrated that their detection would have prognostic value. With a prevalence of 12%, ATM mutations represent the commonest single gene defect to be detected in CLL tumours and they identified a subgroup of CLL patients that had a significant reduction in both treatment free and overall survival. Furthermore, ATM mutations provided prognostic information that was independent of age, clinical stage, the mutation status of the IGVH genes and TP53 mutations. The temporal acquisition of the ATM mutations and their relationship with loss of an ATM allele via a chromosomal 11q deletion provides clues into their mechanism of action. There was only a partial correlation between CLL tumours with mutations in the ATM gene and those with a chromosome 11q deletion. In certain cases, the ATM mutations represented germ-line changes and in others were acquired very early in the disease course raising the possibility that they might contribute to the initial clonal transformation process. However, in some CLL tumours, the ATM mutations had been acquired after the development of the tumour clone during disease progression indicating that there may be a step-wise acquisition of ATM allelic defects during the ontogeny of CLL. The ATM protein is the key coordinator of the cellular response to DNA double strand breaks. In this study, I showed that bi-allelic defects in the ATM gene lead to deficient ATM dependent responses, including the up regulation of p53, following both ionising irradiation and also treatment with the chemotherapeutic drug, Fludarabine. Thus an important mechanism accounting for the poor outcome in CLL patients with ATM mutations is likely to relate to chemo-resistance. Interestingly, there were differential responses to DNA damage with both irradiation and fludarabine amongst the category of tumours with an 11q deletion according to the status of the remaining ATM allele. Therefore, ATM mutations can stratify tumours with a chromosome 11q deletion into two functional subgroups. The identification of CLL tumours with ATM mutations would therefore predict those patients that will have a poor clinical outcome and be both more likely to require early treatment for their disease. Patients whose tumours had bi-allelic ATM defects will be expected to have deficient responses to DNA damaging chemotherapeutic drugs, while those with mono-allelic ATM defects might identify a group in whom the use of DNA damaging agents could provide selective pressure for the emergence of sub-clones that have subsequently acquired bi-allelic ATM defects.
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Douis, Hassan. "The role of imaging in advancing the understanding of the pathogenesis, diagnosis and staging of central chondroid bone tumours." Thesis, University of Warwick, 2017. http://wrap.warwick.ac.uk/102063/.
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Central chondroid bone tumours are one of the most common primary bone tumours. Benign central chondroid tumours are termed enchondromas and its malignant counterpart are called chondrosarcomas. Enchondromas are frequently observed on routine imaging. Similarly, chondrosarcomas are the second most common primary bone tumour after osteosarcoma. Imaging is crucial in the diagnosis of central chondroid tumours and in the differentiation of enchondromas from chondrosarcomas. Furthermore, imaging plays a vital role in the staging of chondrosarcomas. In this thesis, the published scientific literature on the role of imaging in the diagnosis of benign chondroid tumours and chondrosarcomas and the role of imaging in the staging of chondrosarcomas is reviewed and summarised. Furthermore, the contribution of the authors’ published work is highlighted in the thesis. The first two articles are review articles which discuss the clinical and imaging features of benign and malignant chondrogenic tumours and the significance of imaging in the diagnosis of these tumours. The third article is an original article which investigates the theory of the pathogenesis of enchondromas. It is widely believed that enchondromas arise from cartilage islands which are displaced from the growth plate during the process of skeletal maturation. However, this theory is unproven, and the origin of this theory was forgotten prior to the authors’ study. Based on the incidental prevalence of enchondromas of the knee in the adult population of 2.9%, the study assesses the prevalence of cartilage islands/enchondromas in skeletally immature patients. In this study, no cartilage islands/enchondromas in skeletally immature patients were identified. The study therefore shows the rarity of enchondromas in skeletally immature individuals which is in contrast to the adult population. Furthermore, in view of the absence of cartilage islands in this study, the study raises doubts about the validity of the unproven theory. Lastly, the very origin of this theory is rediscovered in this thesis which has been forgotten in modern medicine. The fourth article is an original article which evaluates the role of diffusion-weighted MRI (DWI) in the diagnosis of central cartilage tumours. Prior to the authors’ study the role of DWI in the diagnosis of central cartilage tumours was uncertain. The authors’ study demonstrates that DWI cannot be used to differentiate between enchondromas and chondrosarcomas and that DWI does not aid in the distinction of low-grade chondroid tumours from high-grade chondrosarcomas. This is a finding which was not known prior to the study. The fifth article is an original article which assesses the utility of conventional MRI in the differentiation of low-grade from high-grade chondrosarcomas of long bone. Prior to the authors’ study the role of conventional MRI in the differentiation of low- grade from high-grade chondrosarcomas of long bone was unknown. The authors’ study shows that bone expansion, active periostitis, soft tissue mass and tumour length can be used to differentiate high-grade from low-grade chondral lesions of long bone on conventional MRI. Furthermore, the presence of these four MRI features shows a diagnostic accuracy of 95.6%. These findings were not known prior to the study and have significantly furthered the knowledge about the role of conventional MRI in the grading of chondrosarcoma of long bone. The sixth article is an original article which evaluates the role of bone scintigraphy and Computed Tomography of the chest in the staging of chondrosarcoma of bone. Whilst guidelines regarding the staging of bone sarcomas state that bone scintigraphy should be performed to assess for the presence of skeletal metastases and that Computed Tomography (CT) of the chest should be performed to evaluate for possible pulmonary metastases, there has been no research on the utility of bone scintigraphy in chondrosarcoma of bone and on the role of CT-chest in the staging of chondrosarcomas. Furthermore, the prevalence of skeletal and pulmonary metastases of chondrosarcoma at presentation was unknown prior to this study. The authors’ study demonstrated no skeletal metastases on bone scintigraphy in chondrosarcoma of bone at presentation. In contrast, pulmonary metastases were observed in approximately 5% of all patients with chondrosarcoma at presentation on CT-chest. The finding therefore demonstrates the rarity of skeletal metastases in chondrosarcoma of bone at presentation which is in contrast to osteosarcoma and Ewing sarcoma. The study therefore concludes that there is little role for skeletal scintigraphy in the surgical staging of chondrosarcoma. In contrast, the study shows that there is a role for CT-chest in the staging of chondrosarcoma. These above described findings are important new findings and represent a significant contribution to the knowledge base regarding metastatic behaviour of chondrosarcomas at presentation and regarding the staging of chondrosarcoma of bone. In summary, the authors’ publications have significantly enhanced and furthered the understanding of the pathogenesis of enchondromas, the role of functional MRI in the differentiation of enchondromas from chondrosarcomas, the utility of MRI in the grading of chondrosarcomas and the role of skeletal scintigraphy in the staging of chondrosarcomas.
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Green, Clara Emily. "Understanding shared pathogenesis between chronic obstructive pulmonary disease (COPD) and lung cancer by means of cell specific genomics." Thesis, University of Birmingham, 2018. http://etheses.bham.ac.uk//id/eprint/8230/.
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Introduction: COPD (Chronic Obstructive Pulmonary Disease) and lung cancer are related conditions associated with inflammation. Relatively little focus has been given to the endothelium, through which inflammatory cells transmigrate to reach the lung. We sought to determine if coding and non-coding alterations in pulmonary endothelium exist in COPD and lung cancer. Methods: Patients with and without COPD undergoing thoracic surgery were recruited. Pulmonary Endothelial Cells were isolated from lung and tumour and extracted RNA (ribonucleic acid) used for miRNA (micro-RNA) and mRNA (messenger RNA) microarrays. Ingenuity pathway analysis (IPA) was also carried out. Results: 2071 genes and 43 miRNAs were significantly upregulated in COPD. 4 targets were validated by quantitative polymerase chain reaction, of which miR-181b-3p was chosen for functional validation. Another target, miR-429, was also increased in lung tumour. Several cancer-related pathways such as transforming growth factor- β were altered in the IPA. There was significantly reduced tube formation and endothelial sprouting in Human umbilical vein endothelial cells transfected with miR-181b-3p, consistent with an effect on angiogenesis. Conclusions: Upregulation of miR-181b-3p reduces tube formation and sprouting by endothelial cells. This might be significant in the development of emphysema as lung vasculature is important in the structural maintenance of alveoli.
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Koivisto, Christopher Steven. "Dissecting the Pathogenesis of Type I Endometrial Carcinoma through Mouse Models." The Ohio State University, 2018. http://rave.ohiolink.edu/etdc/view?acc_num=osu1531995361428894.
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Kim, Kyeok. "Differences in kimchi and glutathione intake in Koreans vs. Korean-Americans : possible role in pathogenesis of stomach cancer /." The Ohio State University, 1997. http://rave.ohiolink.edu/etdc/view?acc_num=osu1487948158629012.
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