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Dissertations / Theses on the topic 'Cancer de la prostate neuroendocrine'
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1
Vias, Maria. "Neuroendocrine differentiation in hormone resistant prostate cancer cells." Thesis, University of Cambridge, 2008. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.612330.
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Yeung, Jake. "Identification of RNA binding proteins associated with differential splicing in neuroendocrine prostate cancer." Thesis, University of British Columbia, 2014. http://hdl.handle.net/2429/46688.
Full textAbstract:
Alternative splicing is a tightly regulated process that
can be disrupted in cancer. Established cancer genes
express splice isoforms with distinct properties and
their differential expression is associated with tumour
progression. Although prostate adenocarcinoma (PCa) is
effectively managed at early stage by therapies targeting
the androgen receptor signaling axis, up to 30% of late
stage prostate cancers progress to a treatment-resistant
form of the disease called neuroendocrine prostate cancer
(NEPC), for which there are few therapeutic options. It is
histologically distinct from PCa, expresses a neuronal gene
signature and is associated with poor survival (<1 year).
We hypothesize that alternative splicing has an important role
in driving transformation of PCa tumours towards the NEPC
phenotype and we seek to identify regulators of aberrant
alternative splicing. We integrated a number of bioinformatics
tools to investigate alternative splicing in NEPC. Analyzing
RNA-Seq data from a patient-derived xenograft model of
neuroendocrine transdifferentiation, we compared splicing
profiles between NEPC and PCa and identified a set of
differentially spliced cassette
exons. We found these cassette exons to code for protein
segments containing DNA-binding domains, protein-binding
regions and posttranslational modification sites. We discovered
evolutionarily conserved motifs around intronic regions of
the cassette exons and implicated them with RNA recognition
motifs of tissue-specific RNA binding proteins. We corroborated
our findings by analyzing RNA-Seq data from a patient-tumour
cohort and found recurrent RNA binding proteins associated
with cassette exon inclusion. Our integrated analysis suggests
that splicing changes between PCa and NEPC are mediated by
tissue-specific RNA binding proteins, which may be of
therapeutic or diagnostic value.
3
Chen, Ruiqi. "Implications of PI3K/AKT inhibition on REST protein stability and neuroendocrine prostate cancer." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/62099.
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Treatment-induced neuroendocrine (NE) prostate cancer (t-NEPC) is an aggressive subtype of prostate cancer (PCa) that can arise as a consequence of rigorous androgen receptor pathway inhibition (ARPI) therapies now used to treat castration resistant disease (CRPC). While the PI3K/AKT pathway has been investigated as a co-therapeutic target with ARPI for advanced prostate adenocarcinoma, whether this strategy has implications on t-NEPC progression
remains unknown. Findings from this work indicate that PI3K/AKT inhibition alone reduces protein expression of the RE-1 silencing transcription factor (REST) and induces multiple NE markers in PCa cells. The loss of REST by PI3K/AKT inhibition is through protein degradation mediated by the E3-ubiquitin ligase β-TRCP and REST phosphorylations at the S1024, S1027, and S1030 sites. Since AR inhibition was previously reported to deplete REST, results from this project reveal that the combined inhibition of PI3K/AKT and AR further aggravates REST protein reduction. Upon profiling the transcriptomes of AKT inhibition, AR inhibition, and AKT/AR co-inhibition in the LNCaP cell model, Gene Set Enrichment Analysis (GSEA) shows that these transcriptomes are highly correlated with the REST-regulated gene signature. Co-targeting AKT and AR resulted in an even higher correlation comparing to those of single treatment. Comparing these transcriptomes to the RNA-seq gene signature of t-NEPC patients by GSEA, it was observed that adding AKT inhibition to AR blockade enhanced the expression of neurogenesis-related genes and resulted in a stronger and broader upregulation of REST-regulated genes specific to t-NEPC. Collectively, these results indicate that AKT pathway inhibition can induce NE transdifferentiation in PCa cells via REST protein degradation. It delineates a potential risk for the AR and PI3K/AKT co-targeting strategy as it may further facilitate t-NEPC development.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
4
Goodin, Jeremy Lee. "Characterization of Gene Expression During Adenosine 3':5'-Cyclic Monophosphate Induced Neuroendocrine Differentiation in Human Prostatic Adenocarcinoma." Diss., Virginia Tech, 2002. http://hdl.handle.net/10919/26791.
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The LNCaP cell line is a versatile and useful model that is suitable for the study of human prostate cancer in vitro. The elevation of LNCaP intracellular cAMP levels through the addition of membrane permeable cAMP analogues, phosphodiesterase inhibitors, adenylate cyclase activators, or components of the cAMP signal transduction pathway can induce reversible neuroendocrine differentiation. Elucidation of those genes that are differentially expressed between undifferentiated prostate cancer cells and prostate cancer cells that have been induced to differentiate may present new insights for the molecular mechanisms governing neuroendocrine differentiation, early detection of prostate cancer, and/or potential targets for gene therapy. In this study, differential display PCR was used to identify 226 differentially expressed PCR products. Twelve of the differential display PCR products were confirmed by Northern blot analysis and cloned. DNA sequencing and database comparisons were performed. Among the differentially expressed genes, the human ribosomal S3a gene was identified as down regulated in response to LNCaP differentiation. In order to better ascertain the mechanism by which HRS3a gene expression is decreased during differentiation, the promoter region for this gene was analyzed. Electrophoretic mobility shift assay, antibody supershift assays, site-directed mutagenesis, and luciferase reporter gene analysis were employed to authenticate the roles of several transcription factors in the regulation of the HRS3a gene. Two cyclic AMP response elements, a Sp1 element and a GA-binding protein element, were involved in the regulation of HRS3a gene expression. In order to ascertain the effect of HRS3a down regulation in LNCaP cells, antisense phosphorothioate oligonucleotides were designed to inhibit HRS3a gene expression. Treatment of LNCaP cells with antisense HRS3a oligonucleotides did not influence cAMP induced neuroendocrine differentiation but antisense treatment did result in a decrease in LNCaP cell growth. In addition, it was determined that morphological changes associated with cAMP induced differentiation of LNCaP cells from the epithelial to the neuroendocrine state may not require alterations in gene expression nor the expression of novel proteins.Ph. D.
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Hirth, Carlos Gustavo. "The prognostic value of neuroendocrine differentiation and stem cells markers for localized prostate cancer." Universidade Federal do CearÃ, 2016. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=18238.
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This study aimed to evaluate the new immunohistochemical markers related to neuroendocrine differentiation induction and stem cells with prognostic factors and biochemical recurrence in patients submitted to radical prostatectomy. Therefore, patients operated at the Hospital Walter CantÃdio, Federal University of CearÃ, in the period of 2008-2013, underwent clinical and outpatient follow-up, between the years 2008-2016. Biochemical recurrence was evaluated and was correlated with pathological characteristics and immunohistochemical reactions. Chromogranin (neuroendocrine differentiation), Aurora Kinase A (AURKA), N-MYC, C-MYC and CD44s were performad in paraffined material. From 74 patients underwent surgery was obtained the followup of 69, in a median period of 41 (2-89) months. Neoplastic neuroendocrine differentiation was associated with seminal vesicles infiltration (p = 0.032) and stage (p = 0.030). C-MYC was associated with Gleason score (p = 0.001) and seminal vesicles infiltration (p = 0.014). AURKA was expressed in rare cases. N-MYC protein was negative in all patients. CD44s was associated with lower preoperative PSA levels and lower Gleason scores. Biochemical recurrence was observed in 27.0% of patients. Recurrence was associated with serum preoperative PSA, Gleason score, seminal vesicle invasion and staging at least in one form of analysis. There was no significant association between recurrence and neuroendocrine differentiation, C-MYC and CD44s expression. Therefore, immunohistochemical detection of neuroendocrine differentiation, expression of C-MYC and loss of CD44s were related to more aggressive carcinomas (PSA, Gleason, seminal vesical invasion and/or stage), but no association with biochemical recurrence. Classic prognostic factors were affirmed like biochemical recurrence predictores.Este estudo objetivou avaliar novos marcadores imuno-histoquÃmicos relacionados à induÃÃo da diferenciaÃÃo neuroendÃcrina e cÃlulas-tronco com fatores de prognÃstico e recorrÃncia bioquÃmica, em pacientes submetidos à prostatectomia radical. Para tanto, pacientes operados no Hospital Walter CantÃdio, Universidade Federal do CearÃ, no perÃodo de 2008 a 2013, foram submetidos a acompanhamento clÃnico-ambulatorial, entre os anos de 2008 a 2016. Avaliou-se a proporÃÃo daqueles que apresentaram recorrÃncia bioquÃmica, bem como as caracterÃsticas clÃnico-patolÃgicas e a marcaÃÃo em reaÃÃes de imuno-histoquÃmica para cromogranina (diferenciaÃÃo neuroendÃcrina), Aurora quinase A (AURKA), N-MYC, C-MYC e CD44s, em material parafinado. De 74 pacientes submetidos à cirurgia, obteve-se acompanhamento de 69, com tempo de seguimento de 41 (2-89) meses; diferenciaÃÃo neuroendÃcrina na neoplasia se associou com infiltraÃÃo de vesÃculas seminais (p=0,032) e estadiamento (p=0,030). C-MYC associou-se com escore de Gleason (p=0,001) e infiltraÃÃo de vesÃculas seminais (p=0,014). AURKA expressou-se em raros casos. N-MYC foi negativo em todos os pacientes. CD44s se associou com menores nÃveis de PSA prÃ-operatÃrio e menores escores de Gleason. Observou-se recorrÃncia bioquÃmica em 27,0% dos pacientes. RecorrÃncia se associou, em pelo menos uma das formas de anÃlise, com nÃveis sÃricos de PSA prÃ-operatÃrio, escore de Gleason, invasÃo de vesÃculas seminais e estadiamento. NÃo houve associaÃÃo significativa entre recorrÃncia e diferenciaÃÃo neuroendÃcrina, C-MYC e CD44s. Dessa forma, nesse estudo, a detecÃÃo imuno-histoquÃmica da diferenciaÃÃo neuroendÃcrina; a expressÃo de C-MYC e a perda da expressÃo de CD44s relacionaram-se com carcinomas mais agressivos (PSA, Gleason, infiltraÃÃo de vesÃcula seminal e/ou estadiamento), porÃm sem associaÃÃo com a recorrÃncia bioquÃmica; bem como confirma a importÃncia de fatores prognÃsticos considerados como clÃssicos em sÃrie regional de pacientes com cÃncer de prÃstata.
6
Nip, Ka Mun. "TNIK, a novel androgen receptor-repressed gene, is a potential biomarker for neuroendocrine prostate cancer." Thesis, University of British Columbia, 2017. http://hdl.handle.net/2429/64148.
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Traf2- and Nck-interacting kinase (TNIK) is a serine/threonine kinase upregulated and amplified in pancreatic and gastric cancer respectively. TNIK has also been identified as a potential therapeutic target of colorectal cancer. However, the role of TNIK in prostate cancer (PCa) has not been investigated. Interrogating public human PCa patient data, we found that TNIK expression is associated with an aggressive form of PCa termed neuroendocrine prostate cancer (NEPC). Treatment-induced NEPC can arise as a consequence of strong selective pressure from androgen receptor (AR) pathway inhibition. Clinically, TNIK expression is positively correlated with neuroendocrine (NE) markers and inversely correlated with androgen regulated genes. In agreement, our in vitro studies reveal that TNIK expression is increased under AR pathway inhibition. We found that TNIK is transcriptionally repressed by androgen via direct binding of the AR at the TNIK locus. Through gain of function studies, we demonstrated that TNIK is not required for NE differentiation. Likewise, loss of function studies using siRNA or small molecule inhibitors targeting TNIK did not have significant effect on the growth of Enzalutamide-resistant cells with NE phenotype in vitro. Overall, our results indicate that TNIK may serve as a possible biomarker for NEPC.Medicine, Faculty of
Experimental Medicine, Division of
Medicine, Department of
Graduate
7
Blanc, Charly. "La Neuropiline-1, un nouveau biomarqueur de résistance thérapeutique du cancer de la prostate." Thesis, Paris Est, 2016. http://www.theses.fr/2016PESC0072.
Full textAbstract:
Le cancer de la prostate représente actuellement un problème majeur de santé publique. L’hormonothérapie, par privation de l’axe androgénique, constitue aujourd’hui la seule arme thérapeutique efficace pour les formes avancées. Malgré un taux important de réponse initiale, une forme de résistance survient inéluctablement, conduisant pour la plupart au décès du patient. La progression tumorale vers la résistance à la castration est un processus multifactoriel. Elle peut être associée à une dérégulation de l’axe du récepteur des androgènes, l’activation de voies de survie cellulaire, et favoriser une différenciation cellulaire vers l’acquisition d’un phénotype neuroendocrine androgéno-indépendant. L’objectif de la recherche actuelle repose donc sur l’identification de nouveaux biomarqueurs de résistance thérapeutique afin de proposer de nouvelles cibles permettant de contrecarrer la résistance à la castration. La caractérisation d’une signature moléculaire associée à l’émergence d’une différenciation neuroendocrine du cancer de la prostate résistant à la castration a permis d’identifier la Neuropiline-1, une glycoprotéine transmembranaire impliquée dans le développement neuronal et vasculaire. La répression de la voie du récepteur des androgènes au cours de l’hormonothérapie régule dynamiquement l’expression de la Neuropiline-1 et favorise la résistance à la castration associée à une différenciation neuroendocrine. La Neuropiline-1 joue donc un rôle important dans la résistance thérapeutique puisqu’elle favorise la neuro-transdifférenciation, l’activation de voie de survie cellulaire et altère la sensibilité des cellules cancéreuses à la chimiothérapie. L’étude des voies de signalisation associées à la Neuropiline-1 a permis d’identifier la voie des PKCs, impliquée dans la régulation de la différenciation neuroendocrine du cancer de la prostate. Par conséquent, nous montrons pour la première fois que le ciblage de cette voie activée par la Neuropiline-1 bloque l’évolution tumorale vers la résistance à la castration et augmente l’efficacité d’une chimiothérapie à base de docétaxel sur des modèles précliniques in vivo. Parallèlement, la caractérisation des ligands de la Neuropiline a permis d’identifier de nouveaux partenaires dont la Pléiotrophine, comme nouveau ligand associé aux activités biologiques de la Neuropiline-1 dans la carcinogenèse prostatique. L’ensemble de ces travaux apporte de nouvelles connaissances sur la caractérisation de la résistance thérapeutique du cancer de la prostate, et fournit un réel intérêt clinique porteur d’espoir dans la prise en charge de la maladie neuroendocrine résistante à la castrationProstate cancer currently represents a major public health problem. Hormone therapy, by deprivation of androgen signaling axis represents the only efficient treatment for advanced forms. Despite effective initial response, a form of resistance inevitably occurs, leading mostly to patient's death. Tumor progression to castration resistance is a multifactorial process. It can be associated to dysregulation of the androgen receptor axis and activation of cell survival pathways, and thus promotes cell differentiation towards the acquisition of an androgen-independent neuroendocrine phenotype. Therefore, the goal of current research is based on the identification of new biomarkers of therapeutic resistance to propose new targets to counteract the castration resistance. The characterization of a molecular signature associated with the emergence of a neuroendocrine castration-resistant prostate cancer identified Neuropilin-1, a transmembrane glycoprotein involved in vascular and neuronal development. Down-regulation of androgen receptor axis during hormone therapy dynamically regulates the expression of Neuropilin-1 and promotes resistance to castration associated with neuroendocrine differentiation. Thus, Neuropilin-1 plays an important role in the therapeutic resistance since it favors the neuro-transdifferentiation, activation of cell survival pathway and alters the sensitivity of cancer cells to chemotherapy. Moreover, the study of signaling pathways associated with Neuropilin-1 and involved in the regulation of the neuroendocrine differentiation of prostate cancer has identified the PKCs pathway. We show for the first time that targeting this pathway activated by Neuropilin-1 blocks tumor evolution towards resistance to castration and increases the efficacy of docetaxel-based chemotherapy in preclinical models in vivo. In parallel, the characterization of Neuropilin’s ligands identified new partners, including Pleiotrophin, as a new ligand associated with Neuropilin-1 biological activities in prostate carcinogenesis. All this work provides new knowledge in the characterization of therapeutic resistance in prostate cancer, and supports a real promising clinical value in the treatment of neuroendocrine castration-resistant form of the disease
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Soori, Mehrnoosh. "Neuroendocrine differentiation of prostate cancer cells a survival mechanism during early stages of metastatic colonization of bone /." Access to citation, abstract and download form provided by ProQuest Information and Learning Company; downloadable PDF file, 105 p, 2009. http://proquest.umi.com/pqdweb?did=1654490661&sid=6&Fmt=2&clientId=8331&RQT=309&VName=PQD.
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Berenguer, Caroline. "Rôle de l'adrénomédulline dans le cancer de la prostate : implication dans la différenciation neuroendocrine et dans la progression tumorale." Aix-Marseille 2, 2006. http://www.theses.fr/2006AIX20691.
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Les cancers prostatiques (CaP) sont des pathologies des plus fréquentes et représentent donc un problème de santé publique. Ils constituent actuellement un enjeu thérapeutique puisque 25% des patients traités par hormonothérapie sont victimes à plus ou moins longue échéance d’une baisse de l’efficacité du traitement : « échappement hormonal ou androgéno-indépendance ». Une meilleure compréhension des mécanismes impliqués dans ce phénomène est donc indispensable. Plusieurs études suggèrent un rôle des cellules neuroendocrines dans l’émergence de l’hormonoindépendance des CaP. Ces cellules neuroendocrines présentent dans la prostate ne sont pas dépendantes des androgènes pour leur croissance et leur survie. Elles synthétisent une variété de neuropeptides spécifiques des cellules neuronales (ChgA, NSE, 5-HT) et des peptides bioactifs (somatostatine, bombésine, CGRP…). Parmi les différents facteurs de régulation, nous nous sommes intéressés aux peptides bioactifs, amidés en C-terminal par l’enzyme bifonctionnelle : Peptidylglycine-α-Amitating Monooxygénase (PAM), et décrits comme étant capables d’induire et de stimuler la croissance tumorale. Parmi les peptides amidés criblés, nous avons retenu comme candidat l’Adrénomédulline (AM), peptide mitogénique et angiogénique. Dans cette étude, nous avons émis l’hypothèse selon laquelle l’AM peut jouer un rôle dans l’évolution du CaP vers l’androgéno-indépendance et plus spécifiquement dans la composante neuroendocrine associée à cette phase de résistance thérapeutique. Nous avons également mis en évidence une augmentation de l’expression et de la synthèse de l’AM dans les cellules hormonodépendantes LNCaP en absence d’androgènes. L’analyse morphologique, histologique et moléculaire des cellules privées d’hormones, a mis en évidence une relation directe entre le phénotype neuroendocrine (prolongements cytoplasmiques, marqueurs neuroendocrines : NSE et ChgA) et le sysytème AM/Récepteur de l’AM. Confortant notre l’hypothèse sur le rôle de l’AM dans la composante neuroendocrine observée et décrite dans le CaP évoluant vers l’hormonorésistance. La deuxième partie de ce travail est dédiée à l’étude de l’AM au cours de l’hormonoindépendance. Nous avons ainsi mis en évidence un rôle de l’AM sur la croissance tumorale, sur la vascularisation intratumorale, chez des souris xénogreffées avec des cellules hormonoindépendantes DU145. Dans les tumeurs traitées par l’anticorps anti-AM, outre la diminution du volume tumoral, les structures vasculaires sont profondément modifiées. Ces résultats montre l’implication de l’AM dans les interactions entre les différents compartiments cellulaires (stroma/épithélium) et le microenvironnement tumoral. En conséquence, l'AM constitue une voie de recherche stimulante visant à améliorer la thérapie anti-cancéreuse au niveau de la prostate mais aussi au niveau d'autres types de tumeurs présentant une forte expression de ce peptide amidé.
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Maina, Peterson Kariuki. "Novel oncogenic roles and regulations of histone demethylase PHF8 in prostate cancer." Diss., University of Iowa, 2017. https://ir.uiowa.edu/etd/5562.
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Prostate cancer (PCa) is the most common cancer in American men. Although initial androgen deprivation therapy (ADT) confers a five year survival rate of 99%, the relapse of metastatic and drug resistant PCa (CRPC- Castration-Resistant PCa) continues to account for most deaths. How certain PCa cells develop into CRPC is the key question in the field. In addressing it, attention has focused on epigenetic factors that contribute to CRPC development. Herein we investigated the role and regulation of histone demethylase PHF8 during PCa neuroendocrine differentiation (NED) and progression into CRPC. We utilized bioinformatic analyses and biochemical approaches in PCa/CRPC cell line and mouse models to unravel the following results:
First, we discovered that PHF8 post-transcriptionally clusters with cell cycle genes during NED and into CRPC via an AR/MYC/miR-22 regulatory axis. We showed that this axis is dysregulated in CRPC cells to allow enhanced cell proliferation and resistance to the clinical AR antagonist drug Xtandi® (enzalutamide). Second, we revealed that PHF8 is necessary for hypoxia induced NED by demethylating repressive H3K9me2 and H3K27me2, above maintaining active H3K4me3 on select NED genes. Importantly, we unveiled that PHF8 sustains HIF1α expression in CRPC cells via a regulatory role associated with full length AR. Third, we recapitulated the role of PHF8 in vivo by excising its floxed allele in the prostate of TRAMP mice -Transgenic Adenocarcinoma of the Mouse Prostate. We observed that KO of Phf8 lowered tumor burden in part by sustaining Ezh2 expression during NED transition into CRPC.
In conclusion, our data implicates PHF8 in multiple oncogenic roles and regulations during PCa NED into CRPC. Our results lay a foundation for understanding the dynamics of histone modifying enzymes during PCa progression and hint at designing small molecule inhibitors against PHF8 as a novel CRPC therapeutic target.
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Rossi, Gina. "Regulation of the physiological consequences of neuroendocrine differentiation in prostate cancer by kinase and phosphatase cross talk." Thesis, University of British Columbia, 2011. http://hdl.handle.net/2429/34186.
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Prostate cancer is a leading health concern among Canadian males, with one in seven Canadian men developing the disease in their lifetime and one in 27 dying from it. Localized prostatic disease can be treated with surgery, but once metastasis occurs, clinicians rely on the hormone dependent nature of the tumor for treatment. Androgen withdrawal therapy is very effective at limiting tumor growth; however, progression of the tumor to an androgen independent state is inevitable, and at the present time there is no effective therapy for this form of the disease.
Neuroendocrine (NE) cells are post-mitotic, secretory cells found distributed throughout both normal and malignant prostate tissue. Increased NE cell content is associated with hormone refractory disease, and it is suspected that these NE cells play a role in the adaptation of surrounding cells to androgen withdrawal conditions through the secretion of paracrine factors. The research in this thesis was aimed towards understanding the biochemical mechanisms by which trans-differentiation of an adenocarcinoma cell to a NE cell occurs. By understanding the nature of this process, rationally designed therapeutic reagents can be developed that either block transdifferentiation of adenocarcinoma cells and inhibit the increase in NE cell content following androgen withdrawal or block the actions of NE cells that promote tumor progression.
I used the Kinetworks™ Phospho-Site Screen KPSS 1.1 as well as the Human Operon Version 3.0 microarray to broadly profile changes in protein kinase regulation and mRNA expression levels occurring during NE differentiation of the human prostate cancer cell line model, LNCaP. I found that agents that induce NE differentiation in LNCaP cells cause a perturbation in the phospho-state of two downstream targets of the mammalian target of rapamycin (mTORC1), the ribosomal S6 kinase S6K1 and Rb, as well as increasing vascular endothelial growth factor (VEGF) mRNA expression. Both of these phenomena appear to involve the cAMP-dependent protein kinase PKA and a protein phosphatase PP2A family member. Since mTORC1 is considered to be a critical component in the control of tumourigenicity, and since increased VEGF is associated with advanced tumor progression, these findings appear to address some of the processes by which transdifferentiation of adenocarcinoma cells to NE cells may regulate prostate cancer progression.
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Cyrta, Joanna. "A Pleiotropic Role of the SWI/SNF Complex in Cancer – Insights From Two Tumor Types : Small Cell Carcinoma of the Ovary, Hypercalcemic Type and Prostatic Carcinoma Role of Specialized Composition of SWI/SNF Complexes in Prostate Cancer Lineage Genomic Correlates of Clinical Outcome in Advanced Prostate Cancer." Thesis, université Paris-Saclay, 2020. http://www.theses.fr/2020UPASL045.
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Le complexe de remodelage de la chromatine SWI/SNF est un régulateur épigénétique majeur impliqué dans le développement embryonnaire et dans la différentiation cellulaire. De plus, les gènes qui encodent les sous-unités de SWI/SNF sont altérés dans au moins 20% de cancers. Bien que le complexe SWI/SNF soit le plus souvent considéré comme suppresseur des tumeurs, il existe des preuves croissantes que le rôle de SWI/SNF dans le cancer peut dépendre du type de tissu et du contexte.Dans la première partie de cette dissertation, nous présentons la caractérisation moléculaire d’une cohorte indépendante de carcinomes à petites cellules de l’ovaire de type hypercalcémiant (SCCOHT), comme exemple d’un cancer sous-tendu par des altérations perte-de-fonction de la sous unité catalytique de SWI/SNF, SMARCA4. Dans la deuxième partie, nous explorons le rôle du SWI/SNF dans le cancer de la prostate (CP), y compris ses formes les plus agressives : le CP résistant à la castration et le carcinome neuroendocrine. Alors que les mutations des gènes de SWI/SNF sont très rares dans le CP, nous montrons que l’expression de certaines sous-unités peut être dérégulée et qu’une haute expression de SMARCA4 est associée à des CP agressifs. De plus, nous montrons que plusieurs lignées cellulaires de CP dépendent de SWI/SNF pour leur croissance.Au total, ces deux exemples supportent l’hypothèse que SWI/SNF peut jouer des rôles différents dans le cancer en fonction du type tumoralThe SWI/SNF chromatin remodeling complex is a major epigenetic regulator involved in embryonic development and in cell differentiation. In addition, genes encoding components of SWI/SNF are altered in at least 20% of cancers. Even though the SWI/SNF complex is usually regarded as a tumor suppressor, there is increasing evidence that the role of SWI/SNF in cancer may be tissue type- and context-dependent.In the first part of this dissertation, we present the molecular characterization of an independent cohort of small cell carcinomas of the ovary, hypercalcemic type (SCCOHT), as an example of a malignancy driven by loss-of-function alterations of the catalytic subunit of SWI/SNF, SMARCA4. In the second part, we explore the role of SWI/SNF in prostate cancer (PCa), including its most aggressive forms: castration-resistant prostate cancer and neuroendocrine prostate cancer. We show that while SWI/SNF mutations are exceedingly rare in PCa, the expression of several SWI/SNF subunits can be deregulated and that high SMARCA4 expression is associated with aggressive PCa. In addition, we show that many PCa cell lines are dependent on SWI/SNF for their growth.Taken together, these two examples further support the hypothesis that SWI/SNF can play different roles in cancer, depending on the tumor type
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Vanoverberghe, Karine. "Étude de l'altération de l'homéostasie calcique dans l'arrêt de croissance et la différenciation neuroendocrine des cellules cancéreuses prostatiques humaines." Lille 1, 2003. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2003/50376-2003-49.pdf.
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Le cancer prostatique évolue vers un stade androgéno-indépendant où aucun traitement hormonal ne peut provoquer un arrêt de la croissance cellulaire. Ce stade de la maladie est également caractérisé par la présence de cellules cancéreuses neuroendocrines, résistantes à l'apoptose. Le calcium joue un rôle primordial dans le contrôle de la croissance cellulaire. Aucune caractérisation des mécanismes calciques responsables d'un arrêt de croissance des cellules prostatiques cancéreuses androgéno-indépendantes et de la différentiation neuroendocrine, n'a été préalablement publié. Notre objectif fut donc de caractériser ces mécanismes. Nous montrons qu'une diminution de la concentration en calcium libre du réticulum endosplasmique ([Ca2+]RE) provoque l'arrêt de prolifération des cellules androgéno-indépendantes et que la différentiation neuroendocrine induit une réorganisation du cytosquelette, responsable d'une diminution de l'influx calcique et de la [Ca2+]RE que nous suggérons impliquée dans la résistance à l'apoptose des cellules neuroendocrines.
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Turpin, Anthony. "Étude des gènes réprimés par le récepteur aux androgènes dans les cancers de la prostate résistants à la castration et leur évolution neuroendocrine." Thesis, Lille, 2021. http://www.theses.fr/2021LILUS012.
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Dans le cancer de la prostate, la présence de gènes de fusion, issus de remaniementschromosomiques TMPRSS2:ERG dans plus de 50% des cas, aboutit à une dérégulation dutranscriptome prostatique. Le récepteur aux androgènes (AR), membre de la famille desrécepteurs nucléaires, reste toutefois l’acteur majeur de l’évolution du cancer de la prostate.Notre objectif est d’identifier des gènes pouvant avoir un rôle dans l’évolution du cancerde la prostate, en lien avec la fusion TMPRSS2:ERG et AR.Par une analyse transcriptomique, à partir d’un modèle de surexpression de la fusionTMPRSS2:ERG dans une lignée de cellules tumorales prostatiques humaines (PC3c) capablesd'induire des lésions osseuses in vivo, nous avons identifié deux gènes régulés par la fusionparmi lesquels Plexine A2 (PLXNA2), déjà décrit par l’équipe (Tian et al. Oncogene.2014), etégalement Fascine-1 (FSCN1) codant pour une protéine qui permet de regrouper les filamentsd’actine et impliqué dans les phénomènes de migration et invasion tumorale grâce à laformation d’invadopodes. Nous avons recherché d’une part les partenaires fonctionnels dePLXNA2 en réalisant une étude in silico grâce au logiciel Ingenuity Pathway Analysis®, etavons identifié Neuropiline 1 (NRP1) comme potentiellement dérégulé par la fusion. D’autrepart nous avons évalué l’implication de FSCN1, associé à l’évolution de plusieurs cancers maisencore peu connu dans le cancer de la prostate.Pour chaque gène sélectionné nous avons déterminé, pour la validation clinique, leurexpression dans des échantillons humains de cancers de la prostate primitifs, également enanalysant des données de cohortes publiées et en suivant l’expression in vivo parimmunohistochimie dans des cancers avancés. D’autre part nous avons étudié leur rôlefonctionnel in vitro, dans des modèles cellulaires hormono-indépendants et neuroendocrines.Enfin, nous avons réalisé une analyse bioinformatique et recherché dans les données de ChIPseq-ERG et -AR publiées, l’existence de la fixation des facteurs ERG ou AR sur les 2 gènesNRP1 puis FSCN1. Une fois identifiée, nous avons réalisé des expériences de ChIP in vitro àpartir des modèles cellulaires dont nous disposons et nous avons mis en évidence la régulationdirecte de NRP1 puis de FSCN1 par AR.L’ensemble de nos résultats met en évidence NRP1 et FSCN1 comme gènes répriméspar AR, qui se ré-expriment en phase de résistance à la castration et acteurs potentiels de ladifférenciation neuroendocrine lorsque le niveau d’AR est bas ou inactif. Leur régulation par lafusion TMPRSS2:ERG et les mécanismes précis, en lien avec AR et ses cofacteurs restent àdémontrer. Ces deux gènes pourraient toutefois jouer un rôle dans les mécanismes derésistances aux hormonothérapies, et constituer à l’avenir des cibles thérapeutiquesThe presence of fusion genes, resulting from TMPRSS2:ERG chromosomalrearrangements in more than 50% of cases, leads to deregulation of the prostate cancertranscriptome. Androgen receptor (AR), a member of the nuclear receptor family, remains themajor actor in the development of prostate cancer.Our objective is to identify genes that may be involved in the evolution of prostate cancer, in relation to the TMPRSS2:ERG fusion and AR.Using a transcriptomic analysis, derived from a PC3c prostate tumour cells line model over expressing TMPRSS2:ERG fusion, we have identified two genes regulated by the fusion:Plexin A2 (PLXNA2), already described in the literature by the team (Tian et al. Oncogene.2014), and also Fascin-1 (FSCN1) coding for a protein that groups actin filaments together and isinvolved in migration and tumour invasion phenomena through invadopods formation. Wesearched for functional partners of PLXNA2, performing an in silico study with Ingenuity Pathway Analysis® software, and have identified Neuropilin-1 (NRP1) as a potentially deregulated gene by fusion. On the other hand, we have evaluated the involvement of FSCN1,associated with the evolution of several cancers but poorly known in prostate cancer.For each selected gene, we have determined, for clinical validation, their expression inhuman samples of primary prostate cancers, also by analyzing published cohort data andmonitoring their expression in vivo by immunohistochemistry in advanced cancers. We havealso studied their functional role in vitro, in hormone-independent and neuroendocrine cellmodels. Finally, we performed a bioinformatics analysis and searched in the published ChIPseq-ERG and -AR data, the existence of ERG or AR factor binding on the 2 genes NRP1 andFSCN1. Once identified, we have performed in vitro ChIP experiments using the availablecellular models and we have demonstrated the direct regulation of NRP1 and FSCN1 by AR.Together, our results highlight NRP1 and FSCN1 as genes repressed by AR, which arere-expressed in the phase of resistance to castration and are potential actors of neuroendocrinedifferentiation when the level of AR is low or inactive. Their regulation by the TMPRSS2:ERGfusion and its precise mechanisms, in relation to AR and co-factors, need to be furtherdemonstrated. However, these two genes could play a role in the mechanisms of resistance tohormone-based therapies such as androgenic deprivation or selective competitive silentantagonist of AR, and could constitute therapeutic targets in the future
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Dayon, Audrey. "Rôle de la sphingosine kinase-1 dans la survie et la progression des cellules tumorales prostatiques LNCaP vers l'androgéno-indépendance." Toulouse 3, 2008. http://thesesups.ups-tlse.fr/307/.
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Le traitement du cancer de la prostate est basé sur la privation androgénique dont l'efficacité n'est que temporaire jusqu'à l'acquisition de l'androgéno-indépendace tumorale. Notre équipe a montré que l'oncogène sphingosine kinase (SK) est surexprimé dans le tissu tumoral prostatique, et que son activité enzymatique augmente avec l'agressivité tumorale. Nous avons exploré le rôle potentiel de la SK dans la survie et la progression des cellules tumorales prostatiques LNCaP vers l'androgéno-indépendance. Premièrement, nous montrons in vitro et in vivo que la privation androgénique entraîne une inhibition de l'activité SK qui est corrélée à une diminution de la prolifération cellulaire. Cette perte des capacités prolifératives peut être surmonté par la surexpression du gène codant pour la SK. L'addition de dihydrotestostérone (DHT) stimule l'activité SK et permet de ré-induire la prolifération cellulaire. Par ailleurs, l'inhibition pharmacologique de la SK bloque les effets prolifératifs de la DHT. Deuxièmement, nous démontrons l'implication de la SK dans la progression des cellules LNCaP vers le statut androgéno-indépendant. Lors de la privation androgénique prolongée nous observons une augmentation de l'activité et de l'expression protéique de la SK associées à la transdifférenciation neuroendocrine des cellules. Ces travaux impliquant la SK dans la transition vers l'androgéno-indépendance suggèrent que l'inhibition pharmacologique de la SK pourrait représenter une stratégie viable pour prévenir ou retarder la progression vers l'androgéno-indépendanceAs prostate cancer cell proliferation is regulated by androgens, strategies aimed at reducing the production of androgens and/or effects are the standard of care in the management of patients with recurrent or advanced disease. Unfortunately all patients become resistant to hormonal manipulation and it is not clear how prostate cancer cells make the transition from being androgen-dependent to being androgen-independent after hormone ablation therapy. We have shown in the Lab that the oncogenic sphingosine kinase (SK) is overexpressed in tumor samples from prostate cancer patients (as compared with normal counterparts). We provide the first evidence that androgen privation induces a differential effect on SK activity in the hormono-sensitive LNCaP prostate cancer cell model. Short-term androgen removal induced a rapid and transient SK inhibition in vitro and in vivo in an orthotopically LNCaP model established in SCID mice. Conversely, long-term removal of androgen resulted in a progressive increase in SK expression and activity throughout the progression to androgen-independence state, which was characterized by the acquisition of a neuroendocrine (NE)-like cell phenotype. Fascinatingly, the reversability of the NE phenotype by exposure to normal medium was linked with a pronounced inhibition of SK activity. These results suggest that SK activation upon chronic androgen privation may serve as a compensatory mechanism allowing prostate cancer cells to survive in androgen-depleted environment, giving support to its inhibition as a potential therapeutic strategy to delay/prevent the transition to androgen-independent prostate cancer
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El, Bizri Rana. "Characterization of Pten and Trp53 deficient prostatic tumors in mice." Thesis, Strasbourg, 2018. http://www.theses.fr/2018STRAJ097.
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Le cancer de la prostate est la forme de cancer la plus fréquente et la troisième cause de décès par cancer chez l’homme dans les sociétés occidentales. Alors que la plupart des cancers de la prostate localisés sont éradiqués chirurgicalement, la plupart des tumeurs métastatiques répondant initialement aux thérapies par privation d’androgènes deviennent résistantes au traitement, causant généralement le décès du patient. Les gènes suppresseurs de tumeur PTEN et p53 étant fréquemment mutés dans les cancers de la prostate métastatiques et résistants à la castration, le laboratoire d’accueil a généré des modèles murins dans lesquels Pten et/ou Trp53 sont sélectivement invalidés à l’âge adulte dans les cellules épithéliales prostatiques dans le but de déterminer les évènements clés conduisant à la progression du cancer de la prostate. Notre étude révèle que l’invalidation de PTEN stimule la prolifération des cellules épithéliales prostatiques et conduit à des néoplasmes prostatiques intraépithéliaux en quelques mois. Cette hyper-prolifération induit un stress réplicatif et une réponse aux dommages de l’ADN qui va conduire à un arrêt progressif de la croissance cellulaire et une entrée en sénescence. Les cellules sénescentes sécrètent de nombreuses cytokines et de chimiokines, et peuvent accumuler des mutations contribuant ainsi à la progression de la tumeur. Il est notable qu’en l’absence de Trp53, les épithéliums prostatiques dépourvus de Pten développent des néoplasmes prostatiques intraépithéliaux entrant en sénescence. Cependant, la formation d’adénocarcinomes est accélérée et des tumeurs sarcomatoïdes pouvant générer à long terme des métastases apparaissent. En l’absence de Pten, certaines cellules épithéliales prostatiques perdent leur identité moléculaire en exprimant des marqueurs caractéristiques de cellules souches et différenciation neuroendocrinienne. Nous avons également mis en évidence des cellules épithéliales prostatiques déficientes en PTEN et p53 résistantes à la castration exprimant à la fois des marqueurs de cellules basales et luminales. En conclusion, nos travaux ont permis une avancée dans la compréhension des mécanismes conduisant à des formes incurables de cancer de la prostate. Les traitements actuels ayant des effets secondaires importants et pouvant générer des résistances, le développement de nouvelles stratégies thérapeutiques permettant l’élimination des cellules sénescentes mais aussi des cellules épithéliales prostatiques exprimant des marqueurs de cellules basales et luminales dans les lésions précancéreuses représente des perspectives intéressantes pour traiter le cancer de la prostateProstate cancer (PCa) is a leading cause of male cancer death worldwide. While most locally PCa are curable, metastatic tumors initially respond to androgen deprivation therapy but ultimately relapse to castration-resistant prostate cancer (CRPC), which is a lethal disease. Since the tumor suppressor genes PTEN and p53 are frequently mutated in metastatic and CRPC, the host laboratory generated mouse models in which Pten and/or Trp53 are selectively ablated in adult prostatic epithelial cells (PECs) in order to unravel the key events leading to prostate cancer progression. Our study reveals that Pten ablation stimulates PECs proliferation forming prostatic intraepithelial neoplasia (PIN) within a few months. This hyper-proliferation induces replicative stress and a DNA damage response (DDR), which in turn leads to a progressive growth arrest with characteristics of cell senescence. As senescent cells secrete a large number of cytokines and chemokines, and can accumulate other mutations, they might contribute to tumor progression. Importantly, in the absence of Trp53, most Pten-null PECs develop PINs that enter senescence. However partial loss of PECs identity is detected as we show enhanced stemness and focal neuroendocrine differentiation of luminal Pten-null PECs. In some cases, adenocarcinoma and sarcomatoid tumors are formed, and more than one-third of the latter develop metastases. Strikingly, we also show formation of a castrate-resistant cell entity of both Pten and Pten/Trp53-null PECs sharing luminal and basal markers. Taken together, as current treaments lead to side effects and resistance, the development of therapeutic strategies to eliminate senescent cells/and or PECs expressing luminal and basal/stem progenitor in pre- cancerous lesions represents promising option for prostate cancer treatment
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Lallet-Daher, Hélène. "Implication du canal potassique calcium dépendant à conductance intermédiaire IKca1 dans la cancerogenèse humaine." Thesis, Lille 1, 2008. http://www.theses.fr/2008LIL10135/document.
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Des études récentes montrent que l'homéostasie calcique intracellulaire, ainsi que l'expression et l'activité de canaux ioniques jouent un rôle essentiel dans le contrôle de la prolifération cellulaire aussi bien dans un contexte physiologique que dans certains cancers. Cependant, aucune approche proposant les canaux ioniques comme cible thérapeutique n'est actuellement envisagée dans le cadre des traitements des cancers de la prostate. Dans ce travail nous avons mis en évidence l'expression, la fonctionnalité et l'implication des canaux potassiques calcium-activés (IKca1) dans la prolifération des lignées cellulaires cancéreuses de la prostate humaine. Ces études ont également montré que l'activation du canal lKca1 favorise l'entrée de calcium via un canal calcique de la famille des TRP, le canal TRPV6, impliqué dans l'entrée passive de calcium dans les cellules cancéreuses prostatiques. De plus, par des études de co-immunoprécipitations, nous avons montré que le canal IKca1 et le canal calcique TRPV6 sont associés formant ainsi un complexe moléculaire fonctionnel permettant l'entrée de calcium et la prolifération des cellules cancéreuses prostatiques humaines. Par ailleurs, une suppression du canal IKcat induit la différenciation neuroendocrine des cellules cancéreuses prostatiques humaines. Ceci suggère un rôle essentiel joué par le canal IKca1 pour favoriser la croissance ou induire la différenciation cellulaire. Nos études ont également mis en évidence une surexpression de l'ARNm et de la protéine d'IKca1 dans les tissus prostatiques atteints d'un cancer de la prostate humaine. Ces données permettraient de proposer ces canaux ioniques comme marqueurs de cancer et/ou comme cibles thérapeutiques potentielles dans le traitement des cancers de la prostate humaineRecent studies show that the intracellular calcium homeostasis, as well as expression and the activity of ionic channels play an essential role in the control of cell proliferation as weIl in a physiological context as in certain cancers. However, no approaches offering ionic channels as therapeutic target is nowadays envisaged as part of the treatments of the cancers of the prostate. ln the present work, we showed the expression, functionality and involvement of calcium-activated potassium channels (IKCa1) in the proliferation of the human prostate cancer cells. These studies also showed that the activation of the IKca1 channel favours the calcium entry via a member of the TRP family of calcium channels, TRPV6, in the prostate cancer cells. Besides, by studies of co-immunoprécipitations, we showed that the IKca1 potassium channel and the TRPV6 calcium channel form a functional molecular complex allowing the calcium entry and the proliferation of the prostate cancer cells. Moreover, a down-regulation of the 1Kca1 channel leads to the neuroendocrine differentiation of the human prostate cancer cells. This suggests an essential role played by the 1Kca1 channel to favour growth or lead to cell differentiation. Our immunohistotluorescence studies also showed an overexpression of IKca1 mRNA and protein in human prostate cancer compared to non-tumor tissues. These data would allow to propose these ion channels as markers and/or as potential therapeutic targets in the treatment of the human prostate cancers
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Monet, Michaël. "Mécanismes d'homéostasie calcique impliqués dans l'évolution du cancer de la prostate humaine : rôle des facteurs de croissance et du canal TRPV2." Lille 1, 2007. http://www.theses.fr/2007LIL10079.
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Le cancer de la prostate, seconde cause de mortalité par cancer chez l'homme, est une maladie fréquente dont le développement est sous contrôle androgénique. Les traitements actuels visant à réduire l'activité des androgènes ont une efficacité temporaire car, chez la majorité des patients, une résistance aux traitements émerge. Elle est le résultat (i) de l'évolution des cellules cancéreuses prostatiques vers l'androgéno-indépendance et (ii) de l'augmentation de la différenciation neuroendocrine, ce qui requière l'intervention de facteurs non androgéniques tels que les facteurs de croissance. Le calcium étant l'un des facteurs de régulation de la différenciation, de la prolifération et de l'apoptose, les modifications de l'homéostasie calcique pourraient participer à l'évolution du cancer de la prostate. Les canaux calciques de la superfamille des TRP (<< Transient Receptor Potential ») sont des candidats prometteurs de la régulation du calcium intracellulaire des cellules non excitables. Pour la première fois, nos résultats montrent que des variations du taux de calcium du réticulum modifient la croissance des cellules cancéreuses androgéno-dépendantes LNCaP et décrivent que les facteurs de croissance EGF, IGF, TNFalpha modulent la croissance cellulaire via des modifications de l'homéostasie calcique. D'autre part, nous démontrons que l'EGF, en plus d'induire la différenciation neuroendocrine des cellules cancéreuses androgéno-indépendantes DU145, permet de réduire la quantité de calcium libérable par le réticulum endoplasmique. Cette modification du calcium réticulaire permet de protéger les DU145 de l'apoptose induite par une élévation du taux de calcium cytoplasmique. Parmi les différents responsables de cette dérégulation, nous avons remarqué que le canal TRPV2 (TRP Vanilloid 2) était plus exprimé et impliqué dans les dérégulations de l'homéostasie calcique du cancer prostatique. Nous avons prouvé que PI3-kinase favorisait l'activité du canal TRPV2 de souris surexprimé indépendamment de la translocation du canal à la membrane plasmique. Nos travaux ont mis en évidence pour la première fois que les lysophospholipides étaient des agonistes physiologiques de TRPV2 en induisant la translocation et l'activation des canaux humains et de souris. Enfin nous avons démontré que l'expression du canal TRPV2 était détectée dans les cellules androgéno-indépendantes y compris les cellules neuroendocrines du cancer de la prostate ce qui est corrélé aux modifications de l'homéostasie calcique de ces cellules. Le canal TRPV2 pourrait donc représenté un nouveau marqueur des cellules cancéreuses prostatiques évoluant vers les phénotypes les plus agressifs.
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Lemonnier, Loïc. "Caractérisation moléculaire et fonctionnelle des canaux chlorure volume-dépendants : implication dans la cancerogenèse prostatique." Lille 1, 2004. http://www.theses.fr/2004LIL10012.
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Le cancer de la prostate est la seconde cause de mortalité par cancer chez l'homme. Ce cancer est dépendant des androgènes dans les premiers stades de la maladie,puis évolue vers un stade androgéno-indépendant caractérisé par l'apparition de cellules neuroendocrines, par la surexpression de l'oncoprotéine Bel-2, ainsi que par une plus forte résistance à l'apoptose. Nous avons montré que les canaux chlorure volume-dépendants (VRAC) sont présents dans les cellules cancéreuses de la prostate humaine. De plus, la surexpression de Bel-2, tout comme la différenciation neuroendocrine, provoquent d'après nos résultats une forte augmentation de l'activité des VRAC. Enfin, nous avons montré au cours de cette thèse qu'il existe un couplage fonctionnel entre les VRAC et des canaux intervenant dans l'apoptose prostatique (les SOC: storeoperated channels), et que ce couplage tend à disparaître dans les cellules surexprimant Bcl-2 ou. Différenciées.
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Thiébault, Stéphanie. "Caractérisation moléculaire et fonctionnelle des canaux cationiques chimio-dépendants de type TRP : implication dans la cancérisation prostatique." Lille 1, 2004. http://www.theses.fr/2004LIL10061.
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Seconde cause de mortalité par cancer chez l'homme, le cancer de la prostate évolue vers un stade androgéno-indépendant. Cette capacité à proliférer en l'absence d'androgènes implique notamment le calcium. Bien que ses mécanismes d'action demeurent méconnus dans la prostate, il jouerait un rôle essentiel via, en particulier, les canaux cationiques chimio-dépendants représentés par les canaux TRP "Transient Receptor Potential". Nous avons identifié et caractérisé les récepteurs alphal -adrénergiques et purinergiques dans les cellules épithéliales prostatiques humaines respectivement comme promoteur ou inhibiteur de la prolifération cellulaire. Nos résultats montrent l'implication des canaux TRPC3 et C6 dans la voie alpha-adrénergique alors que TRPC1, C3 et C4 seraient les sous-unités principales formant les canaux couplés à la voie purinergique. Nous avons par ailleurs caractérisé fonctionnellement le canal TRPM8 dont l'expression croît lors de la cancérisation prostatique.
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Vanden, Abeele Fabien. "Caractérisation moléculaire et fonctionnelle des canaux calciques de type SOC (Store Operated Channel) : implication dans la cancerogénese prostatique." Lille 1, 2003. https://pepite-depot.univ-lille.fr/RESTREINT/Th_Num/2003/50376-2003-221.pdf.
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Seconde cause de mortalité par cancer chez l'homme, le cancer de la prostate presente une incidence croissante liée à l'augmentation de l'espérance de vie dans les pays développés. Ce cancer est, à l'origine, dépendant des androgènes, puis évolue vers un stade androgéno-indépendant pour lequel aucun traitement curatif n'existe. Le cancer androgéno-indépendant de la prostate se caractérise par l'àpparition de cellules tumorales surexprimant l'oncoprotéine Bcl-2 et de cellules cancéreuses différenciées en cellules neuroendocrines. Ces deux types cellulaires présentent un défaut d'apoptose rendant inefficaces les chimiothérapies. Il est maintenant bien établi que le calcium est un des facteurs majeurs impliqués dans l'apoptose. Cependant, les mécanismes exacts par lesquels le calcium participe à ce processus sont encore mal connus. Les canaux calciques de type SOC (Store Operated Channel) de la membrane cellulaire, activés par la vidange des réserves calciques intra-réticulaires, seraient des éléments clés, intervenant dans le contrôle de l'apoptose des cellules cancéreuses. Or, ces canaux n'ont jamais été étudiés dans les cellules cancéreuses prostatiques. Malgré des efforts de recherche intenses durant ces dix dernières années, deux questions principales restent encore posées concernant les canaux de type SOC: qu'elle est la nature du signal permettant l'activation spécifique de ces canaux et en quoi consiste leur nature moléculaire ? L'identification et la caractérisation électrophysiologique du courant SOC dans les cellules cancéreuses prostatiques LNCaP nous ont ensuite permis de détenniner la nature moléculaire et le mécanisme de couplage de ces canaux. De nombreuses recherches ont été dévolues ces dernières années aux canaux de type TRP "Transient Receptor Potential" et à leur relation possible avec les SOCs. Nos résultats montrent l'implication de trois protéines TRP dans la constitution des canaux SOC des cellules LNCaP. TRPC1, TRPC4 et TRPV6 seraient les Sous unités principales à la base de complexes hétéromultimériques encore non caractérisés et formant les canaux SOC. TRPC1 serait préférentiellement couplée à la vidange des stocks par un couplage de type conformationnel tandis que TRPC4 serait préférentiellement couplée via un facteur diffusible encore inconnu à ce jour. La protéine TRPV6, quant à elle, présente à la fois un couplage par un facteur diffusible et de type conformationnel. Nous avons mis en évidence une perturbation importante des mécanismes d'homéostasie calcique dans les cellules LNCaP rendues androgéno-indépendantes par surexpression de l'oncoprotéine Bcl-2 ou par différenciation neuroendocrine. Dans les deux cas, il s'ensuit une diminution importante de la concentration en calcium réticulaire et une inhibition du fonctionnement des canaux SOC. De ce fait, la résistance à l'apoptose observée dans les cellules androgéno-indépendantes serait en partie due à des perturbations de l'homéostasie calcique impliquant notamment les canaux SOC. Au cours de ma thèse, nous avons donc obtenu de nouveaux résultats qui pennettent d'expliquer le rôle des canaux SOC et du calcium réticulaire dans la régulation de l'apoptose des cellules cancéreuses de la prostate humaine.
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Guy, Laurent. "LES Tumeurs neuro-endocrines de la prostate." Clermont-Ferrand 1, 1994. http://www.theses.fr/1994CLF1MS06.
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Holt, Jim. "Prostate Cancer." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/6456.
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Birtle, A. J. "Prostate specific antigen negative prostate cancer." Thesis, University College London (University of London), 2005. http://discovery.ucl.ac.uk/1444634/.
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Prostate specific antigen (PSA) has been used in the diagnosis and monitoring of prostate cancer for almost 20 years. Most men who present with metastatic prostate cancer have markedly elevated serum levels of PSA. However, approximately 1% of cases have serum PSA levels that are much lower than the tumour burden would suggest - so-called "PSA-Negative" tumours. Their diagnosis may be delayed, and management compromised. Little is known about this patient group. The aim of this study was to improve the understanding and management of "PSA-negative" prostate cancer. The clinical history and tissue from 33 patients who presented with treatment-naive metastatic prostate cancer and a serum PSA < 10 ng/ml were included in this study, the largest series so far reported. Clinical and immunohistochemical features were defined and alternative biomarkers investigated. Potential mechanisms underlying PSA-negativity were explored using prostate cancer cell lines and archival tissue. From the clinical case notes review, patients presenting with low serum PSA and metastatic prostate cancer have a similar pattern of disease to men with high PSA prostate cancer. However, response duration to first line hormonal treatment and overall survival were shorter. Immunohistochemistry performed on archival prostatic tissue has shown that the majority of the cancers are positive for PSA, despite low serum levels. The extent of PSA immunostaining is patchy and could be missed on biopsy. PSMA and AR are expressed, however, and represent alternative diagnostic aids. The study indicates that PSMA and PAP should be explored as potential serum biomarkers in this patient group. The androgen receptor (AR) remains expressed in over 90 % of these cases and therefore defects in this pathway are unlikely to explain the low serum PSA levels. Neither loss of heterozygosity nor gene methylation of AR or PSA appear to be mechanisms underlying low serum PSA levels.
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Holt, Jim, and Fereshteh Gerayli. "Prostate Cancer Screening." Digital Commons @ East Tennessee State University, 2019. https://dc.etsu.edu/etsu-works/6471.
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Whether to screen for prostate cancer in aging men is a topic that is fairly well researched, but recommendations are controversial, because the evidence supporting any recommendation is equivocal. The evidence clearly does not support routine screening of all average-risk men, but for men aged 55 to 69 years, either not routinely screening, or engaging each man in shared decision making for his individual preference on screening, is reasonable and consistent with the evidence. Many organizations, including the American Cancer Society, have not yet reassessed their guidelines, in response to the US Preventative Services Task Force revised guideline.
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Gackière, Florian. "Rôle du canal calcique de type T Cav3.2 dans les cellules cancéreuses prostatiques humaines." Thesis, Lille 1, 2008. http://www.theses.fr/2008LIL10066/document.
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Le cancer de la prostate évolue progressivement vers l'androgéno-indépendance, stade incurable pour lequel la recherche biomédicale tente de déterminer de nouvelles cibles thérapeutiques. Cette évolution est marquée par une différenciation neuroendocrine des cellules prostatiques qui s'accompagne d'une surexpression de canaux calciques voltage-dépendants de type T (Cav3.2) responsable d'une altération de l'homéostasie calcique intracellulaire. L'objectif de cette thèse était donc de déterminer l'implication des Cav3.2 dans les cellules cancéreuses prostatiques humaines, et notamment dans les cellules neuroendocrines. Nos résultats montrent que, dans ces cellules non-excitables, les Cav3.2 participent à l'homéostasie calcique en permettant une entrée basale de calcium au potentiel de repos sans contribuer à une entrée capacitive de calcium provoquée par la vidange des réserves intracellulaires de calcium. De plus, ces canaux interviennent dans la sécrétion de la Phosphatase Acide Prostatique, un marqueur des cellules épithéliales prostatiques, dans les cellules neuroendocrines. Par ailleurs, nous montrons l'existence d'un couplage fonctionnel entre les Cav3.2 et les canaux de type BK qui constituent les principales conductances potassiques voltage-dépendantes des cellules prostatiques. Enfin, nos travaux mettent en évidence que ce couplage entre ces deux canaux participe à la prolifération cellulaire des cellules cancéreuses prostatiques. En conclusion, ce travail de thèse contribue à élargir les connaissances sur les canaux calciques de type T, Cav3.2 en particulier, et leur rôle au sein des cellules prostatiques cancéreuses humainesProstate cancer inevitably evolves towards an incurable androgen-independent stage for which biomedical research attempts to identity new therapeutic targets. This progression is characterized by a neuroendocrine differentiation of prostate cells accompanied by an overexpression of voltage-dependent T-type calcium channels (Cav3.2), responsible for an alteration of intracellular calcium homeostasis. The aim of this PhD thesis was to determine the involvement of Cav3.2 in human prostate cancer cells, mainly in neuroendocrine cells. Our results show that, in these non-excitable cells, Cav3.2 channels participate to basal calcium homeostasis by promoting calcium entry at resting membrane potential without contributing to the capacitative calcium entry triggered by calcium depletion from endoplasmic reticulum stores. ln addition, these channels are involved in the secretion of Prostatic Acid Phosphatase, a marker of prostatic epithelial cells, in neuroendocrine cells. Furthermore, we show that Cav3.2 channels are functionaly coupled to BK channels which constitute the main voltage-dependent potassium conductances in prostate cells. Finally, our work demonstrates that this coupling between both channels regulates prostate cancer cell proliferation. As a conclusion, this work contributes to the understanding of the role of Cav3.2 T-type calcium channels in human prostate cancer cells
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Warnier, Marine. "Rôle du canal calcique de type T, Cav3.2 et de ses protéines partenaires dans la tumorogenèse prostatique." Thesis, Lille 1, 2013. http://www.theses.fr/2013LIL10158/document.
Full textAbstract:
La progression du cancer de la prostate s’accompagne d’une augmentation du nombre de cellules neuroendocrines, cellules qui expriment fortement les canaux calciques voltage-dépendants de type T Cav3.2. Ces canaux favorisent la sécrétion de phosphatase acide prostatique, marqueur des cellules épithéliales prostatiques, et d’autres facteurs mitogènes potentiellement responsables de la prolifération des cellules avoisinantes. L'objectif de cette thèse était de déterminer les protéines partenaires du canal Cav3.2 et leur(s) rôle(s) dans la tumorogenèse prostatique. Nous montrons que les canaux Cav3.2 sont couplés aux canaux potassiques BK dans les cellules cancéreuses prostatiques. Ces 2 types de canaux interviennent dans la prolifération cellulaire. De plus, nous montrons que la sous-unité accessoire α2δ2 des canaux calciques voltage-dépendants est exprimée plus fréquemment dans les tissus cancéreux prostatiques par rapport aux tissus sains, et que son expression augmente avec le grade du cancer. Par des études in vitro et in vivo, nous mettons en évidence son rôle promoteur de la croissance tumorale et de l’angiogenèse. Par ailleurs, nous montrons que Cav3.2 et α2δ2 peuvent s’associer dans un même complexe protéique et qu’α2δ2 est capable de moduler l’activité de ce canal. Cependant, nos travaux suggèrent également que le rôle de cette sous-unité dans la prolifération prostatique pourrait être indépendant de son association avec Cav3.2. En conclusion, ce travail amène à une meilleure compréhension de l’implication des canaux calciques de type T et de ses protéines associées dans le cancer de la prostateProstate cancer progression leads to an androgen-refractory aggressive stage. This is associated with an increased number of neuroendocrine cells overexpressing Cav3.2 T-type calcium channels. Cav3.2 channels promote the secretion of prostatic acid phosphatase and other mitogenic factors responsible for the proliferation of epithelial cells. In order to determine the role of T-type channels and to understand their regulation during cancer progression, the aim of this work was to identify proteins that interact with Cav3.2 channels and their role in physiopathology. First, we demonstrate that Cav3.2 channels are coupled with BK channels in prostate cancer cells. We show that both channels are involved in proliferation. Moreover, we show that accessory α2δ2, γ4 and β4 subunits, putative partners of voltage-gated calcium channels, are expressed in prostate cancer cell lines and prostatic tissues. We show that the α2δ2 subunit is more frequently expressed in cancerous tissues than in healthy ones, and that its expression increases with cancer grade. We propose that the α2δ2 subunit may be used as a biomarker for prostate cancer diagnosis. Furthermore, using in vitro and in vivo studies, we highlight the promoting role of α2δ2 on tumor growth and angiogenesis. In addition, we show that Cav3.2 and α2δ2 can associate in a protein complex and that α2δ2 can modulate the activity of Cav3.2 channels. However, our study also suggests that the role of the α2δ2 subunit in prostate cell proliferation could be independent of its association with Cav3.2. In conclusion, this work leads to a better understanding of the role of T-type calcium channel and its partners in prostate cancer
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Wirth, Manfred P., and Michael Fröhner. "Adjuvant Hormonal Treatment for Prostate Cancer: The Bicalutamide Early Prostate Cancer Program." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133551.
Full textAbstract:
Adjuvant hormonal therapy has been demonstrated to be able to delay disease progression in nonmetastatic prostate cancer. To date, however, a favorable impact on survival has only been demonstrated in lymph-node-positive disease and in external-beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors. The Bicalutamide Early Prostate Cancer Program is the largest study under way to define the role of adjuvant treatment in early prostate cancer and identify subgroups of patients likely to benefit from immediate hormonal therapy. At the time of the most recently published analysis, the risk of objective clinical progression was significantly reduced in the bicalutamide arm (hazards ratio 0.58, 95% confidence interval 0.51–0.66, p < 0.0001). However, further maturation of data is needed to see whether this difference will lead to a survival advantageDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Wirth, Manfred P., and Michael Fröhner. "Adjuvant Hormonal Treatment for Prostate Cancer: The Bicalutamide Early Prostate Cancer Program." Karger, 2003. https://tud.qucosa.de/id/qucosa%3A27515.
Full textAbstract:
Adjuvant hormonal therapy has been demonstrated to be able to delay disease progression in nonmetastatic prostate cancer. To date, however, a favorable impact on survival has only been demonstrated in lymph-node-positive disease and in external-beam radiotherapy series with locally advanced and probably mainly micrometastatic tumors. The Bicalutamide Early Prostate Cancer Program is the largest study under way to define the role of adjuvant treatment in early prostate cancer and identify subgroups of patients likely to benefit from immediate hormonal therapy. At the time of the most recently published analysis, the risk of objective clinical progression was significantly reduced in the bicalutamide arm (hazards ratio 0.58, 95% confidence interval 0.51–0.66, p < 0.0001). However, further maturation of data is needed to see whether this difference will lead to a survival advantage.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.
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Hendrickx, Wouter R. L. "Selenium and prostate cancer." Thesis, University of East Anglia, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.588614.
Full textAbstract:
Prostate cancer is the second most common diagnosed cancer and the third most common cause of death related to cancer among men in developed countries. Several epidemiological studies, prospective cohort studies and animal tumour models state an inverse relationship between selenium status and cancer incidence. Se- methylselenocysteine (SeMSC), present in garlic, onions, leeks and broccoli, has been shown to be the most effective anti-carcinogenic selenium form in animal models. The aim of the work presented in this thesis was to investigate the influence of selenium compounds (Se-methylselenocysteine and selenomethionine) on prostate cancer progression and metastasis using various human cell lines (LNCaP, OU145 and PC3). Standard 20 gel and SILAC (stable isotope labelling with amino acids in cell culture) proteomics were used, in combination with mass spectrometry, to identify selenium- responsive proteins. IMPOH2, GPI, EZR and RGS10 were validated by western blot, while POIA3 and 00X5 showed a selenium response under serum depleted conditions. Some proteins require more scrutinizing (galectin-1, XRCC5, TAGLN2, 00X5 and FLT) as conflicting results were obtained during validation. Preliminary analysis using 20 gel proteomics revealed galectin-1 to be selenium-responsive in PNT1A cells, although this could not be confirmed by Western blot or an in-house ELlSA. Previously, it has been shown that SeMSC decreased the expression of collagen I and increased that of collagen IV and collagen VI. A LNCaP 3D gel suspension model was developed to allow further investigation of extracellular matrix components using fluorescence microscopy. In addition, the effect of selenium exposure on the migration and invasion of PC3 cells was investigated using a transwell kinetic assay and revealed a dose response increase, especially under low baseline selenium concentrations. In order to optimize future selenium in vitro projects the dynamics of several selenium biomarkers were investigated using different conditions, enabling better comparison between cell lines and/or selenium compounds.
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Grönberg, Henrik. "Prostate cancer : epidemiological studies." Doctoral thesis, Umeå universitet, Onkologi, 1995. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-96894.
Full textAbstract:
Prostate cancer is a large and increasing medical problem both in Sweden and in the rest of the developed world, with about 300.000 new cases diagnosed world wide annually. Despite the high incidence of this disease, little is known about the aetiology of prostate cancer. The aim of this study was to try to understand more about the natural history and to find possible a etiological risk factors for this tumour. In a population based study of prostate cancer cases in northern Sweden it was found that the large increase in prostate cancer during the last two decades was mainly caused by well (Gl) and moderately (G2) differentiated tumours. However, the incidence of poorly differentiated (G3) tumours remained unchanged. The introduction of new diagnostic methods is the most plausible explanation for the increase of these low grade tumours. The relative survival in prostate cancer was found to be independent of patient age at diagnosis, indicating that tumour proliferation and the aggressiveness of this disease is equal in all ages. However, due to the increasing occurrence of concurrent diseases with growing age the number of lost years caused by prostate cancer decreases dramatically in older age groups. The overall cause specific mortality for prostate cancer was found to be around 50%. In accordance with most other cancer tumours, the annual mortality rate decreased with longer survival also for prostate cancer patients. In a study from the Swedish Twin Register it was found that the proband concordance rates for prostate cancer were 4,5 time greater among monozygotic compared to dizygotic twins. In a large nation-wide cohort study of men who had a father with prostate cancer, the overall standardised incidence ratio (SIR) was 1.70 for prostate cancer. Younger age at diagnosis among the fathers were associated with an increased risk among sons. This cohort study and the twin study indicates that both inherited and familial factors are of importance in a subgroup of prostate cancer patients. In a prospective case-control study, both a high body mass index (BMI) and a high food intake were found to be independent risk factors for prostate cancer. Both BMI and a high food intake might be indicators of a high fat diet, which so far is the most consistent exogenous risk factor for prostate cancer. The use of tobacco or alcoholic beverages were not associated with prostate cancer risk.Härtill 5 uppsatser
digitalisering@umu
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Wirth, Manfred P., and Oliver W. Hakenberg. "Brachytherapy for Prostate Cancer." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133901.
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Wirth, Manfred P., and Oliver W. Hakenberg. "Brachytherapy for Prostate Cancer." Karger, 1999. https://tud.qucosa.de/id/qucosa%3A27547.
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Storey, Dawn J. "Fatigue and prostate cancer." Thesis, University of Edinburgh, 2008. http://hdl.handle.net/1842/29383.
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Methods: Four studies were conducted: Study A, was a pilot study which examined fatigue over 3 months after different treatments for localised prostate cancer (radiotherapy, brachytherapy and androgen deprivation, n=45). Study B focussed on fatigue over 12 months after brachytherapy (n=51). Two cross sectional postal surveys explored fatigue in recurrence free prostate cancer survivors (Study C, n=443) and hormone controlled prostate cancer (Study D, n=198). Throughout, fatigue was assessed using the Brief Fatigue Inventory and a case definition of clinically significant fatigue (CSF) was also constructed and applied in Studies A and B. Results: Study A found CSF increased after treatment but returned to baseline 3 months after radiotherapy, whereas it appeared to be prolonged after brachytherapy. CSF was not associated with C reactive protein or interleukin-6. Study B found CSF increased between baseline and 1 month after brachytherapy (6 vs.29%, p=0.001) and was higher than the non-cancer comparison group (29 vs. 4% p=0.001). CSF returned towards baseline levels of 6 months. There were no baseline predictors of developing CSF. Study C found 29% of recurrence free prostate cancer survivors had fatigue after radiotherapy or radical prostatectomy (33 vs. 22% p=0.024) but it was not independently associated with treatment received after controlling for other factors 43% of men with hormone controlled prostate cancer had fatigue in Study D. Conclusions: Fatigue is an important symptom in men treated for prostate cancer but resolves within months of brachytherapy. Almost one third of recurrence free survivors have fatigue but it does not appear to be related to the type of treatment received. Fatigue is most prevalent in men with hormone controlled prostate cancer.
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Harper, Curt E. "Prostate cancer chemoprevention with genistein and resveratrol in models of spontaneously developing prostate cancer." Thesis, Birmingham, Ala. : University of Alabama at Birmingham, 2007. https://www.mhsl.uab.edu/dt/2007p/harper.pdf.
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Downing, David G. "Cancer-related Masculine Threat, Body Compassion, and Prostate-specific Functioning in Prostate Cancer Patients." Xavier University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=xavier1557162136506447.
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Hanna, Fahmy William Fahmy. "Calcitonin and related peptides in mammalian neuroendocrine tumours." Thesis, Queen's University Belfast, 1995. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.295357.
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Romanuik, Tammy Lee. "Gene expression in prostate cancer." Thesis, University of British Columbia, 2008. http://hdl.handle.net/2429/5313.
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Development and maintenance of the prostate is dependent on androgens and the androgen
receptor. The androgen pathway continues to be important in prostate cancer. Here, we evaluated
the transcriptome of prostate cancer cells in response to androgen using Long Serial Analysis of
Gene Expression (L0ngSAGE) libraries. We identified 35 genes with novel associations to
androgen signalling and validated 24 of these genes using quantitative real time-polymerase
chain reaction (qRT-PCR). These genes were: ARL6IF5, BL VRB, C]9orf48, C]orfJ22,
C6orf66, CAMK2NJ, CCNI, DERA, ERRFI], GLUL, GOLFH3, HMJ3, HSP9OB], MANEA,
NANS, NIPSNAP3A, SLC4JA], SOD], SVIF, TAOK3, TCP], TMEM66, USP33, and
VTAJ. The physiological relevance of these expression trends was evaluated in vivo using the
LNCaP Hollow Fibre model.
There is no cure for castration-recurrent prostate cancer (CRPC), and the mechanisms underlying
the disease are not known. To address this problem, we assayed the transcriptome of LNCaP
human prostate cancer cells as they progress to castration-recurrence in vivo using replicate
L0ngSAGE libraries. We identified 96 novel genes consistently differentially expressed in
CRPC. The expression profiles support a role for the transcriptional activity of the androgen
receptor genes (CCNH, CUEDC2, FLNA, and FSMA 7), steroid synthesis and metabolism genes
(DHCR24, DHRS7, ELOVL5, HSDJ 7B4, and OPRKJ), neuroendocrine cell genes (ENO2,
MAOA, OPRK], SJOOA]O, and TRPM8), and proliferation genes (GAS5, GNB2L], MT-ND3,
NKX3-], PCGEM], PTGFR, STEAFJ, and TMEM3OA) in castration-recurrence.
Screening for prostate cancer using serum levels of prostate-specific antigen has resulted in the
over-treatment of indolent disease. Novel diagnostic and prognostic markers for prostate cancer
are required. To address this need, the levels of 27 transcripts were investigated with qRT-PCR.
Expression of POP3 (100 kb from EST CF140309) was prostate-specific, with restricted
expression ofADAM2, POP1 (50 kb from AK000023), POP4 (truncated TMEFF2), POP 10
(intron ofADAM2), ELOVL5, RAMP], and SPON2. ELO VL5, NGFRAP1, POP5 (intron of
NCAM2), POP8 (intron of EFNA5), RAMP], SPON2, and TMEM66 were differentially
expressed between laser microdissected tumour and normal clinical samples of prostatic tissue.
These studies suggest that ADAM2, ELOVL5, POP 1, POP3, POP4, POP 10, RAMP], and SPON2
may be good candidates for biomarkers of prostate cancer.
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Thorn, Shirley A. "Prostate cancer, the screening conundrum." Thesis, National Library of Canada = Bibliothèque nationale du Canada, 1998. http://www.collectionscanada.ca/obj/s4/f2/dsk2/tape17/PQDD_0003/MQ32265.pdf.
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Lindmark, Fredrik. "Prostate cancer and inflammatory genes." Doctoral thesis, Umeå : Strålningsvetenskaper, 2005. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-667.
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Lexander, Helena. "Protein expression in prostate cancer /." Stockholm, 2006. http://diss.kib.ki.se/2006/91-7140-617-4/.
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Wiklund, Fredrik. "Genetic epidemiology of prostate cancer." Doctoral thesis, Umeå : Univ, 2004. http://urn.kb.se/resolve?urn=urn:nbn:se:umu:diva-281.
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Sorreta, Arianne G. "Docosahexaenoic acid and prostate cancer." abstract and full text PDF (free order & download UNR users only), 2007. http://0-gateway.proquest.com.innopac.library.unr.edu/openurl?url_ver=Z39.88-2004&rft_val_fmt=info:ofi/fmt:kev:mtx:dissertation&res_dat=xri:pqdiss&rft_dat=xri:pqdiss:1446441.
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Collin, Simon Michael. "Folate metabolism and prostate cancer." Thesis, University of Bristol, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.541606.
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Mavrou, Athina. "Targeting angiogenesis in prostate cancer." Thesis, University of Bristol, 2013. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.654119.
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Angiogenesis, primarily induced by vascular endothelial growth factor (VEGF). has been shown to be required for prostate cancer development and metastasis. Alternatively spliced isoforms associated with cancer progression have been described in all of the hallmarks of cancer, including angiogenesis. VEGF mRNA is alternatively spliced at the terminal exon, to produce two families of isoforms. The pro- angiogenic family, VEGFxxx. has been shown to be up-regulated in several cancer types including prostate cancer, whereas the antiangiogenic family is preferentially expressed in normal non-angiogenic tissues, but down-regulated in prostate cancer. One of the molecules shown to be involved in the regulation of VEGF alternative splicing is SRPK1. This is a protein kinase that phosphorylates the splicing factor SRSF1 and favours the production of the proangiogenic VEGF isoform. I therefore tested the hypothesis that SRPK1 regulates VEGF mRNA splicing in prostate cancer and that down-regulation of this kinase would increase the production of the anti-angiogenic isoform, preventing angiogenesis and tumour growth. I also tested the hypothesis that SRPK1 and SRSF1 are up-regulated in prostate cancer, given the extensive mis-regulation of splicing events in this malignancy. Studies on prostatectomy samples from patients with prostate cancer showed an up -regulation of SRPK1 and SRSF1 in malignant compared to benign tissues. In addition, a panel of prostate cancer cell lines showed increased expression of SRPK1 when compared with primary prostate epithelial cells. Stable SRPK1 knock-down in PC-3 and LnCap prostate cancer cells and inhibition of SRPK1 using small molecule inhibitors caused a reduction in the pro - angiogenic VEGF expression and splice factor phosphorylation . In vivo, inhibition of SRPK1 by lentiviral knockdown and a small molecule inhibitor resulted in a reduction of prostate tumour growth and decreased vascular density. This study identifies a molecular mechanism that regulates angiogenesis in prostate cancer and provides evidence for the potential use of an SRPK1 inhibitor in the treatment of prostate cancer.
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Wirth, Manfred P., and Oliver W. Hakenberg. "Curative Treatment of Prostate Cancer." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-133890.
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The guidelines for the curative treatment of prostate cancer presented by the German Society of Urology are discussed. They are based on the current knowledge of the outcomes of surgical and radiotherapeutic treatment for prostate cancer. Radical prostatectomy is recommended as the first-line treatment for organ-confined prostate cancer in patients with an individual life expectancy of at least 10 years. Radiotherapy can be considered as an alternative treatment modality, although current knowledge does not allow a definite assessment of the relative value of radiotherapy compared to radical prostatectomy. Locally advanced cT3 prostate cancer is overstaged in about 20% and curative treatment is possible in selected cases. Guidelines represent rules based on the available evidence. This implies that exceptions must be made whenever appropriate and that guidelines have to be reviewed regularly as new information becomes availableDieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich
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Adamson, Andrew Stephen. "Procoagulants, coagulopathy and prostate cancer." Thesis, University of Southampton, 1992. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.316445.
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Lundberg, Kajsa. "On immunotherapy against prostate cancer." Stockholm : Karolinska institutet, 2010. http://diss.kib.ki.se/2010/978-91-7409-805-1/.
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Oxley, Jonathan David. "Prognostic indicators in prostate cancer." Thesis, Queen Mary, University of London, 2001. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.394837.
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Wirth, Manfred P., and Oliver W. Hakenberg. "Curative Treatment of Prostate Cancer." Karger, 1999. https://tud.qucosa.de/id/qucosa%3A27546.
Full textAbstract:
The guidelines for the curative treatment of prostate cancer presented by the German Society of Urology are discussed. They are based on the current knowledge of the outcomes of surgical and radiotherapeutic treatment for prostate cancer. Radical prostatectomy is recommended as the first-line treatment for organ-confined prostate cancer in patients with an individual life expectancy of at least 10 years. Radiotherapy can be considered as an alternative treatment modality, although current knowledge does not allow a definite assessment of the relative value of radiotherapy compared to radical prostatectomy. Locally advanced cT3 prostate cancer is overstaged in about 20% and curative treatment is possible in selected cases. Guidelines represent rules based on the available evidence. This implies that exceptions must be made whenever appropriate and that guidelines have to be reviewed regularly as new information becomes available.Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.