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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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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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3
Bryant, Jennifer. "Neuroendocrine and epithelial markers of small cell lung cancer." Thesis, University of Manchester, 2015. https://www.research.manchester.ac.uk/portal/en/theses/neuroendocrine-and-epithelial-markers-of-small-cell-lung-cancer(c7c51e2c-6443-4021-b2ff-469966cd10b6).html.
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Small cell lung cancer (SCLC) is an extremely aggressive disease characterized by early metastasis and acquired resistance to therapy. SCLC is distinguished by its neuroendocrine (NE) component; the role of which is not fully understood in metastasis and response to therapy. Patients respond exceptionally well to first round chemotherapy; however, relapse with therapy-resistant tumours is virtually inevitable. Hypoxic regions within tumours can contribute towards metastasis and therapy resistance, highlighting hypoxia-targeted therapy as a novel approach for improving treatment for SCLC patients. Tumours are highly phenotypically heterogeneous, raising debate over the roles played by each cell type. Analysis of NE and epithelial markers in SCLC cell lines highlighted this inter-tumour heterogeneity. Further heterogeneity is displayed in SCLC xenograft tumours that show areas of dual epithelial and NE marker expression as well as regions negative for both markers. Irradiating xenograft tumours enhanced heterogeneity of the NE marker, pro-opiomelanocortin (POMC), which is ectopically secreted by a subset of SCLC tumours. Examining changes in marker expression post-therapy could provide vital information regarding transitions that can serve to guide therapy. SCLC is a highly metastatic disease. The role of the NE phenotype in human SCLC is not fully understood, but is considered essential for metastasis in murine models. Sub-cutaneous, intravenous and intra-splenic injection were carried out and resulted in no metastasis, spontaneous tumour generation and peripheral liver tumour growth, respectively. POMC expression was present and extremely heterogeneous within the liver, suggesting that NE properties are maintained in metastases; however, further work is necessary to develop a more consistent metastatic model that can be used to assess responses to therapy in a more clinically relevant setting. SCLC tumours proliferate rapidly and outgrow their nutrient and oxygen supplies, resulting in hypoxic conditions. Here, carbonic anhydrase IX (CA IX) becomes up-regulated in order to maintain pH levels suitable for survival. The specific CA IX inhibitor, S4, induces hypoxia-specific cell death in vitro and impairs tumour growth in vivo. This response is further accentuated by combining S4 with single or repeated cisplatin doses. Combination treatment reduced gene expression of S-phase kinase-associated protein (Skp2), associated with cisplatin resistance. CA IX inhibition combined with cisplatin chemotherapy therefore presents a novel treatment for SCLC tumours that could reduce therapy resistance. In summary, heterogeneity is extremely important when choosing treatment options for SCLC and must be considered when basing treatment on single biopsies. NE and epithelial markers are present within sub-cutaneous and liver tumours; however, a reliable multi-organ metastatic model is necessary to fully appreciate the role of these markers in the spread of SCLC. Hypoxic regions within sub-cutaneous xenograft tumours upregulate CA IX. Inhibition of this enzyme resulted in impaired tumour growth, particularly when used together with cisplatin. Combining CA IX inhibition with cisplatin presents a much-needed novel therapy for SCLC.
4
Poiraudeau, Loïc. "Identification de nouvelles cibles thérapeutiques dans le cancer neuroendocrine de la prostate." Electronic Thesis or Diss., université Paris-Saclay, 2023. http://www.theses.fr/2023UPASL143.
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Le cancer de la prostate est le cancer le plus fréquent chez l'homme et il constitue la deuxième cause de mortalité par cancer chez l'homme dans les pays industrialisés. Le traitement systémique de ces cancers repose sur une déprivation androgénique par castration chirurgicale ou pharmacologique. Le cancer de la prostate métastatique résistant à la castration (mCRPC) est traité par des inhibiteurs de la voie des androgènes (ARPI). Cependant, environ un tiers des patients ne sont pas sensibles à ces médicaments et les autres, sensibles initialement, développent malheureusement une résistance secondaire, acquise dans un délai d'environ 1 à 2 ans. Les mécanismes qui expliquent la résistance primaire et secondaire ne sont pas bien connus. Une différenciation neuroendocrine (NE) des constitue l'un de ces mécanismes. En effet, entre 15 et 20% des tumeurs évoluent vers un phénotype neuroendocrine de la prostate (NEPC). Le pronostic de ces patients est très mauvais car les mécanismes moléculaires précis impliqués dans la différenciation neuroendocrine ne sont pas clairement élucidés et il n'existe pas de solution thérapeutique adaptée à ces tumeurs. L'objectif de cette thèse était d'étudier la différenciation neuroendocrine afin d'identifier des nouvelles cibles thérapeutiques. Nous nous sommes appuyés sur l'étude MATCH-R visant à étudier les mécanismes de résistance aux thérapies ciblées (enzalutamide, abiraterone) dans le cancer de la prostate métastatique. Les biopsies de patients ont été caractérisées par des méthodes de séquençage à haut débit et d'immunohistochimie. Dans le cadre de cette étude le laboratoire a aussi développé et caractérisé des modèles précliniques de xénogreffes dérivées de patients (PDX). Nous montrons à partir du WES et RNAseq de biopsies de patients que la différenciation neuroendocrine résulte probablement d'altérations transcriptomiques et épigénétiques. Par ailleurs, nos PDX NEPC maintiennent les caractéristiques génétiques, moléculaires et pharmacologiques par rapport à leurs biopsies d'origine. L'analyse du RNAseq a permis d'identifier une protéine membranaire spécifiquement exprimée par les NEPC. L'expression de cette protéine est corrélée à l'expression de marqueurs NE tels que synaptophysine (SYP) et chromogranine A (CHGA) ainsi qu'à un plus mauvais pronostic. Le traitement de nos PDX NEPC exprimant cette protéine avec une unique injection intraveineuse d' un anticorps conjugué ciblant la protéine résulte en une diminution significative du volume tumoral dans le groupe de souris traitées par rapport au groupe de souris non traitées. Enfin, nous avons identifié un récepteur nucléaire orphelin NR0B2 surexprimé dans les NEPC qui pourrait être impliqué dans la résistance aux inhibiteurs de la voie du RA. Au final, la thèse a permis de confirmer la différenciation neuroendocrine comme mécanisme important de résistance aux thérapies ciblant la voie du récepteur aux androgènes, de développer de nouveaux modèles pertinents (PDX et organoïdes), d'identifier et valider une nouvelle cible thérapeutique et enfin de suggérer le rôle d'un facteur nucléaire orphelin comme acteur moléculaire dans la résistance des cancers neuroendocrinesProstate cancer is the most common cancer in men and the second leading cause of cancer death in men in industrialized countries. The systemic treatment of these cancers is androgen deprivation therapy (ADT), which can be achieved through surgical or pharmacological castration. Metastatic castration-resistant prostate cancer (mCRPC) is treated with androgen receptor inhibitors (ARi). However, approximately one-third of patients are not responsive to these drugs and the others, who are initially responsive, unfortunately develop secondary resistance, which is acquired within approximately 1-2 years. The mechanisms that explain primary and secondary resistance are not well understood. Neuroendocrine differentiation (NE) of mCRPC is one of these mechanisms. In fact, between 15 and 20% of resistant tumors evolve into neuroendocrine prostate cancer (NEPC). The prognosis of these patients is very poor because the precise molecular mechanisms involved in neuroendocrine differentiation are not clearly elucidated and there is no therapeutic solution adapted to these tumors.The objective of this thesis was to study neuroendocrine differentiation in order to identify new therapeutic targets. We relied on the MATCH-R study, which aimed to study the mechanisms of resistance to targeted therapies (enzalutamide, abiraterone). Patient biopsies were characterized using high-throughput sequencing and immunohistochemistry methods. As part of this study, the laboratory also developed and characterized preclinical patient-derived xenograft (PDX) models. We show from WES and RNAseq performed on patient biopsies that neuroendocrine differentiation is likely the result of transcriptomic and epigenetic alterations. Moreover, our PDXs retain the genetic, molecular, and pharmacological characteristics of their original biopsies. RNAseq analysis identified a membrane protein, which is specifically expressed by NEPC. The expression of this protein is correlated with the expression of NE markers such as synaptophysin (SYP) and chromogranin A (CHGA), as well as a worse diagnosis. Treatment of our NEPC PDXs with a single intravenous injection of an antibody-drug conjugate targeting this protein, resulted in a significant decrease in tumor volume in the treated group compared to the untreated group. Finally, we identified an orphan nuclear receptor, NR0B2 that is overexpressed in NEPC and could be involved in resistance to ARi. NEPC are aggressive tumors with few therapeutic options. These tumors result from transcriptomic alterations and require the development of relevant models that recapitulate the complexity of the disease to identify potential targets for new targeted therapies. ADCs are promising therapies, especially in NEPC, and have shown anti-tumor efficacy in preclinical evaluation
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Гирявенко, Наталія Іванівна, Наталья Ивановна Гирявенко, Nataliia Ivanivna Hyriavenko, Микола Сергійович Линдін, Николай Сергеевич Лындин, Mykola Serhiiovych Lyndin, Владислав Володимирович Сікора, et al. "Synchronous case of the primary neuroendocrine cancer of fallopian tube and serous papillary cancer of ovary." Thesis, Springer, 2019. http://essuir.sumdu.edu.ua/handle/123456789/75206.
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Neuroendocrine tumours commonly occur in the gastrointestinal tract and lungs. They rarely were found in the genital organs. There are a few data about this neoplasia in the fallopian tubes, which is accidentally identified during the morphological study. The aim of our investigation was to demonstrate the case of the primary neuroendocrine cancer of the fallopian tube in combination with the serous papillary cancer of the ovary.
6
Balabanova, Silviya. "The neuroendocrine-like phenotype of gastric myofibroblasts and its significance in cancer." Thesis, University of Liverpool, 2012. http://livrepository.liverpool.ac.uk/6453/.
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Cell-cell communication, and specifically epithelial-mesenchymal signalling, is a key factor determining normal tissue development and organisation in hollow organs such as gastrointestinal tract. Mechanisms governing normal epithelial-mesenchymal communication have been studied for many years, but the changes occurring during tissue damage, infection and inflammation, and in cancer, remain unclear. Myofibroblasts are recognised as key mesenchymal cells involved in this communication in health and in disease. Myofibroblasts produce and secrete many proteins responsible for the assembly of extracellular matrix (ECM), tissue organisation and morphogenesis. Initial studies from this laboratory suggested that myofibroblasts might exhibit regulated secretion. The aim of this project was to determine the secretory mechanisms of myofibroblasts from the upper gut of normal and cancer tissues, and to address their significance in cancer. Gastric myofibroblasts were shown to exhibit calcium-dependent secretion of the small ECM protein, Transforming growth factor-β inducible protein or TGFβig-h3, in response to acute stimulation (30 min) with insulin-like growth factor (IGF)s. Inhibitors of protein synthesis (actinomycin D and cycloheximide) and of protein transport from endoplasmic reticulum (ER) to Golgi (brefeldin A) inhibited basal, but not IGF-stimulated secretion, as seen from Western blot analyses of media. These observations support the idea that evoked secretion occurs from a pre-formed pool of vesicles. Myofibroblasts from the upper gut showed differences in their secretory phenotype; specifically normal myofibroblasts from stomach exhibited regulated secretion, but their counterparts from oesophagus did not. Moreover, gastric cancer-associated myofibroblasts (CAMs) from patients with poor survival tend not to exhibit regulated secretion. These findings suggest a role for the tissue microenvironment in determining the secretory phenotype of myofibroblasts. Secretome-wide analysis of myofibroblasts media collected after IGF stimulation revealed that about 85% of the secretome exhibits evoked release. The relevant proteins belonged to different classes including ECM proteins, ligands, binding proteins, carbohydrate-binding proteins, proteases and protease inhibitors. These data indicate that myofibroblasts may contribute to tissue organisation by rapid release of substances involved in re-modelling the tissue microenvironment. The regulated secretory phenotype of myofibroblasts was associated with the expression of the chromogranin-like protein, secretogranin II. Knock-down of secretogranin II inhibited regulated secretion, whereas over-expression in myofibroblasts that lacked regulated released - induced it. Expression of secretogranin II by myofibroblasts coincided with the expression of dense core secretory vesicles that were similar to those found in neuroendocrine cells. This work indicates that there is a neuroendocrine-like secretory phenotype in myofibroblasts, as illustrated by the expression of neuroendocrine cell protein secretogranin II and the presence of regulated secretion. However, not all normal myofibroblasts exhibit the regulated phenotype, and in gastric cancer the phenotype correlates with early stage of disease. These findings may be exploitable both in the development of novel therapies and in understanding cancer progression.
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Bari, Muhammad Furqan. "Biomarkers for the classification of high grade neuroendocrine lung cancers." Thesis, University of Warwick, 2012. http://wrap.warwick.ac.uk/56420/.
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In the management of lung cancer the most important step beyond establishing the presence a malignant tumour is identifying whether the tumour is small cell lung cancer (SCLC) or one of the variants of non-small cell carcinoma (NSCLC), which includes adenocarcinoma (AD), squamous (SCC), large cell carcinoma (LCC), large cell neuroendocrine carcinoma (LCNEC), typical carcinoids (TC) and atypical carcinoids (AT). SCLC is a high grade neuroendocrine tumour which usually presents as central mass. These tumours are not usually amenable to curative surgical resection and are treated primarily by chemotherapy resulting in a treatment dichotomy of SCLC and NSCLC. The diagnosis of the tumour subtypes is routinely established on cytology or histology samples and in case of AD, LCC and SCC, which are not neuroendocrine tumours, the diagnosis is aided by neuroendocrine markers. However for TC, AT and LCNEC which are neuroendocrine tumours, the diagnosis is based on morphological features alone, which in some cases overlap and result in difficulty in diagnosis. This inter-observer variability is common among the neuroendocrine lung tumours and is highest between SCLC and LCNEC followed by TC and AC. Currently no marker or ancillary stain are clinically in practice which can aid in classification of these neuroendocrine tumours. In an attempt to address this issue, this project evaluated the use of bioinformatics to analyze publicly available high through-put transcriptomic data to identify markers which would aid in the distinction of SCLC from LCNEC. However, the markers identified were found to have low specificity and sensitivity, leading to the conduction of a de novo gene expression study utilizing laser micro-dissection of pure tumour samples of SCLC and LCNEC. This experiment yielded a different set of top ranked discriminator genes of which validation at the protein level by immunocytochemistry supported CDX2, CD99 and CD44 as LCNEC specific markers and BAI3 as a SCLC specific marker.
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McWhinney, Sarah Renee. "Role of tumor suppressor genes in neuroendocrine neoplasias and cardiovascular disease." Columbus, Ohio : Ohio State University, 2005. http://rave.ohiolink.edu/etdc/view?acc%5Fnum=osu1133373765.
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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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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
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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.
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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.
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Ocejo-Garcia, Marta. "Is the neuroendocrine phenotype an early marker in the development of lung cancer?" Thesis, University of Nottingham, 2002. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.272381.
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Leblay, Noémie. "Molecular characterization of rare thoraco-abdominal tumours." Thesis, Lyon, 2018. http://www.theses.fr/2018LYSE1351.
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Les carcinoïdes pulmonaires, les carcinomes neuroendocriniens à grandes cellules (LCNEC) et les mésothéliomes malins sont des tumeurs thoraciques rares, dont l'incidence a augmenté au cours des dernières années. Le diagnostic de ces tumeurs est soumis à la variabilité inter-observateur et les opportunités thérapeutiques sont limitées. De grandes études génomiques visant à les caractériser au niveau moléculaire pourraient aider à mieux comprendre les mécanismes sous-jacents à leur développement et faciliter le diagnostic et le traitement de ces maladies. Mon projet de thèse visait à combler les lacunes dans la compréhension des carcinoïdes pulmonaires, des LCNEC et du mésothéliome péritonéal malin. À la suite des travaux entrepris au cours de ma thèse, nous avons constaté que (1) de la même manière que le mésothéliome pleural, les mésothéliomes péritonéaux sont également caractérisés par des mutations conduisant à la perte d'expression de BAP1, facteur de bon pronostic, (2) les patients atteints d’un LCNEC conservant une expression de RB1 présentent de meilleurs résultats lorsqu’ils sont traité avec une chimiothérapie du cancer du poumon non à petites cellules par rapport à une chimiothérapie du cancer du poumon à petites cellules, (3) les carcinoïdes pulmonaires peuvent être classés en trois groupes moléculaires pertinents sur le plan clinique, et (4) , l'identification de supra carcinoïdes confirme l'existence d'un lien moléculaire entre les néoplasmes neuroendocriniens pulmonaires de faible et de haut gradePulmonary carcinoids, large-cell neuroendocrine carcinomas (LCNEC), and malignant mesotheliomas are rare thoracic tumours, which incidence has been increasing over the past years. The diagnosis of these tumours is subjected to inter-observer variability and the therapeutic opportunities are limited. Large genomic studies to characterize them at a molecular level might help to better understand the mechanisms underlying their development, and to help the diagnosis and treatment of these diseases. My thesis project aimed to fill the gap in the understanding of pulmonary carcinoids, LCNEC, and malignant peritoneal mesothelioma. As result of the work undertaken during my thesis, we found that (1) similarly to pleural mesothelioma, peritoneal mesotheliomas are also characterised by mutations leading to the loss of expression of BAP1, which is a factor of good prognostic, (2) LCNEC patients with a remaining expression of RB1 have a better outcome when treated with non-small cell lung cancer chemotherapy in comparison to small-cell lung cancer chemotherapy, (3) pulmonary carcinoids can be classified in three clinically-relevant molecular groups, and (4), the identification of supra carcinoids supports a molecular link between the low and high-grade lung neuroendocrine neoplasms
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Grönberg, Malin. "Expression of Neuroendocrine Markers in Normal and Neoplastic Tissue with an Emphasis on Ghrelin and Obestatin." Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2010. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-130972.
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The aim of this thesis was to characterize the expression of the peptides ghrelin and obestatin, as well as other neuroendocrine markers in human normal tissues, in invasive breast cancer and a wide panel of neuroendocrine tumors (NETs). In normal tissues the expression of ghrelin and obestatin was mainly localized to the gastric mucosa, and in lesser extent in the remaining gastrointestinal tract, endocrine pancreas and mammary glands. Double immunofluorescence studies demonstrated that ghrelin and obestatin were co-localized in the same cells displaying the same cytoplasmic distribution. In normal breast tissue, ghrelin, obestatin, adrenomedullin, apelin and vesicular monoamine transporter 2 were specifically demonstrated in the luminal epithelial cells. Consecutive sections indicated that mammary epithelial cells could express several of these peptides. Secretogranin II and III were also detected in breast tissue, but their presence was restricted to the outer layer of myoepithelial cells, whereas chromogranin B immunoreactivity was found in both the epithelial and myoepithelial cells. Ghrelin and obestatin immunoreactivity was seen in invasive breast cancer, where the expression could be correlated to factors associated with prognosis. Furthermore, multivariate analysis indicated that ghrelin expression was a possible independent prognostic factor for prolonged recurrence-free and breast cancer-specific survival. In a panel of NETs and endocrine-related disorders it was revealed that ghrelin and obestatin immunoreactivity was primarily found in tumors originating from the respective normal tissues. The two proteins were detected in only a few cases and only occasional tumor cells were immunoreactive. In conclusion, ghrelin and obestatin are localized in the gastrointestinal tract, endocrine pancreas and mammary glands. This thesis has contributed to our understanding of the distribution of ghrelin and obestatin in both normal tissue and tumor cells. A potential role of ghrelin as a prognostic factor in invasive breast cancer has been identified and should be further explored.
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Barazeghi, Elham. "Studies of epigenetic deregulation in parathyroid tumors and small intestinal neuroendocrine tumors." Doctoral thesis, Uppsala universitet, Endokrinkirurgi, 2017. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-330810.
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Deregulation of the epigenome is associated with the initiation and progression of various types of human cancers. Here we investigated the level of 5-hydroxymethylcytosine (5hmC), expression and function of TET1 and TET2, and DNA methylation in parathyroid tumors and small intestinal neuroendocrine tumors (SI-NETs). In Paper I, an undetectable/very low level of 5hmC in parathyroid carcinomas (PCs) compared to parathyroid adenomas with positive staining, suggested that 5hmC may represent a novel biomarker for parathyroid malignancy. Immunohistochemistry revealed that increased tumor weight in adenomas was associated with a more aberrant staining pattern of 5hmC and TET1. A growth regulatory role of TET1 was demonstrated in parathyroid tumor cells. Paper II revealed that the expression of TET2 was also deregulated in PCs, and promoter hypermethylation was detected in PCs when compared to normal parathyroid tissues. 5-aza-2′-deoxycytidine treatment of a primary PC cell culture induced TET2 expression and further supported involvement of promoter hypermethylation in TET2 gene repression. TET2 knockout demonstrated a role for TET2 in cell growth and migration, and as a candidate tumor suppressor gene. In Paper III, variable levels of 5hmC, and aberrant expression of TET1 and TET2 were observed in SI-NETs. We demonstrated a growth regulatory role for TET1, and cytoplasmic expression with absent nuclear localization for TET2 in SI-NETs. In vitro experiments supported the involvement of exportin-1 in TET2 mislocalization, and suggested that KPT-330/selinexor, an orally bioavailable selective inhibitor of exportin-1 and nuclear export, with anti-cancer effects, could be further investigated as a therapeutic option in patients with SI-NETs. In Paper IV, DNA methylation was compared between SI-NET primary tumors and metastases by reduced representation bisulfite sequencing. Three differentially methylated regions (DMR) on chromosome 18 were detected and chosen for further analyses. The PTPRM gene, at 18p11, displayed low expression in SI-NETs with high levels of methylation in the presumed CpG island shores, and in the DMR rather than the promoter region or exon 1/intron 1 boundary. PTPRM overexpression resulted in inhibition of cell growth, proliferation, and induction of apoptosis in SI-NET cells, suggesting a role for PTPRM as an epigenetically deregulated candidate tumor suppressor gene in SI-NETs.
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Senden, Nicole Hubertina Maria. "NSP-reticulons characterization and use for the detection of neuroendocrine differentiation in lung cancer /." Maastricht : Maastricht : Universitaire Pers Maastricht ; University Library, Maastricht University [Host], 1995. http://arno.unimaas.nl/show.cgi?fid=8353.
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Yan, Ge [Verfasser]. "Therapeutic value of artesunate in neuroendocrine cancer treatment inspired by EGFR expression / Ge Yan." Mainz : Universitätsbibliothek Mainz, 2019. http://d-nb.info/1191197670/34.
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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.
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Guo, Yingbo. "Rôle du cil primaire au cours de la transdifferentiation neuroendocrine du cancer de la prostate." Electronic Thesis or Diss., Université Côte d'Azur, 2024. http://www.theses.fr/2024COAZ6005.
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Le cancer de la prostate est l’un des cancers malins les plus répandus dans le monde, avec 95 % des patients diagnostiqués présentant un adénocarcinome de la prostate sans marqueurs neuroendocriniens. Le cancer neuroendocrinien de la prostate de novo représente un sous-type rare et agressif. Environ 20 % des cas d’adénocarcinome de la prostate évoluent vers le cancer neuroendocrinien de la prostate après un traitement de privation androgénique. Le traitement de privation androgénique bien qu’efficace, peut également induire une différenciation neuroendocrinienne de l'adénocarcinome de la prostate, présentant ainsi un nouveau défi pour le traitement du cancer de la prostate. Bien que de nombreux mécanismes moléculaires de la différenciation neuroendocrinienne aient été décrits, le moment précis de l’occurrence de la différenciation neuroendocrinienne et les facteurs qui la déterminent restent encore largement inconnus.Le cil primaire est un organite non mobile présent dans presque toutes les cellules humaines. Sa perte est observée dans différents cancers, notamment le carcinome rénal à cellules claires (ccRCC) et le cancer de la prostate. Les recherches antérieures de notre équipe ont identifié un sous-groupe particulier de patients développant un ccRCC qui exprimait le cil primaire et présentait une résistance aux traitements. La présence du cil primaire était caractérisée par la signature GLI1+/IFT20+. Une corrélation a été observée entre la présence du cil primaire et l’agressivité du ccRCC. Étant donné que le ccRCC et le cancer de la prostate sont généralement considérés comme des cancers dépourvus du cil primaire, nous avons émis l'hypothèse de l’existence d’un sous-groupe spécifique de patients développant un cancer de la prostate pourrait présenter du cil primaire, associée à une agressivité accrue.Nous avons établi plusieurs approches afin d’augmenter le pourcentage de cellules ciliées à la fois dans les cellules prostatiques normales et les cellules semblables au cancer de la prostate dans des cultures cellulaires en 2D ou 3D. Cette augmentation était associée à l'inhibition de la prolifération et de la croissance de la structure en 3D. Notamment, ces approches ont conservé leur capacité à induire la formation de cils primaires, même dans des conditions hypoxiques. Nos résultats ont confirmé la robustesse de la signature GLI1+/IFT20+ pour augmenter la formation de cils primaires dans les cellules normales, tandis que cette signature était moins prononcée dans les cellules semblables au cancer de la prostate. Dans un modèle de cellules cancéreuses de la prostate, nous avons découvert que la restauration du cil primaire est associée à la transdifférenciation neuroendocrine du cancer de la prostate. De plus, la régulation du cil primaire est corrélée à l'agressivité du cancer.Nos recherches démontrent que le cil primaire est présent dans un sous-groupe de patients exprimant un cancer de la prostate plus agressif, tout comme dans le ccRCC. La caractérisation du cil primaire dans la transdifférenciation du cancer de la prostate offre de nouvelles perspectives sur le traitement du cancer de la prostateProstate cancer is one of the most common malignancy cancers worldwide. 95% of PCa patients are diagnosed with adenocarcinoma of the prostate showing no expression of neuroendocrine markers. De novo neuroendocrine prostate cancer is a rare and aggressive subtype of prostate cancer, characterized by neuroendocrine markers expression. Approximatively 20% of adenocarcinoma cases progress to neuroendocrine prostate cancer following androgen deprivation therapy. The potential side effect of androgen deprivation therapy, resulting in neuroendocrine differentiation of adenocarcinoma of the prostate, brings a novel challenge for prostate cancer treatment. While many molecular mechanisms of neuroendocrine differentiation have been described, the timing of the neuroendocrine differentiation occurrence and how these driving factors result in neuroendocrine differentiation remain unclear.The primary cilium is a non-motile organelle present in nearly all human cells. Loss of primary cilium has been observed in various cancers, including clear cell Renal Cell Carcinoma (ccRCC) and PCa. Previous findings from our research team identified a distinct subgroup of pataients within ccRCC, which retained primary cilium and exhibited resistance to therapy. The presence of primary cilium was characterized by the GLI1+/IFT20+ signature. Under hypoxic conditions, primary cilium was inhibited due to stabilization of HIF-1α, correlating with increased aggressiveness of ccRCC. Considering that both ccRCC and prostate cancer are typically described as cancer lacking PC, we postulated the existence of a unique subgroup in prostate cancer exhibiting primary cilium presence associated with higher aggressiveness.We developed multiple approaches to enhance in the number of primary cilium numbers in both normal prostate cells and prostate cancer-like cells in 2D or 3D cell culture settings. This increase was correlated with a reduction in proliferation and growth of 3D structures. Notably, these methods maintained their effectiveness in inducing primary cilium numbers even under hypoxic conditions. Our findings confirmed the robustness of the GLI1+/IFT20+ signature in increasing primary cilium numbers in normal cells, while this signature was less pronounced in prostate cancer-like cells. In parallel, we discovered that the restoration of primary cilium in prostate cancer cells is associated to the neuroendocrine transdifferentiation of prostate cancer. Furthermore, the regulation of primary cilium is linked to the cancer aggressiveness.Our research provides evidence that primary cilium is present in a more aggressive subgroup of prostate cancer patients, similar to what is observed in ccRCC. Analyzing the role of primary cilium in the transdifferentiation of prostate cancer provides new insights into potential treatment strategies
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Bayourthe, Pierre. "Les carcinomes neuro-endocrines cutanés ou tumeurs à cellules de Merkel : à propos d'une observation." Bordeaux 2, 1991. http://www.theses.fr/1991BOR2M170.
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Fuentes, Jean. "Carcinome neuro-endocrine bronchique et calcitonine : à propos d'un cas." Montpellier 1, 1990. http://www.theses.fr/1990MON11259.
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Pobel, Cédric. "Characterization of de novo metastatic prostate cancer : an ancillary study of the PEACE-1 phase 3 clinical trial." Electronic Thesis or Diss., université Paris-Saclay, 2024. http://www.theses.fr/2024UPASL118.
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Le cancer de la prostate de novo métastatique sensible à la castration représente 5 à 10% des cancers de la prostate au diagnostic mais est responsable de 50% des décès lié aux cancers de la prostate tous stades confondus. Dans cette étude ancillaire de l'essai PEACE-1, notre hypothèse était que les variants agressifs ou neuroendocrine peuvent être détectés dès le diagnostic. Nous avons rapatrié de façon centralisée les prélèvements en paraffine des biopsies au diagnostic des patients inclus dans PEACE1 (NCT01957436) pour réaliser des analyses d'immunohistochimie (IHC), de séquençage de nouvelle génération (NGS) et de transcriptomique. Parmi les 1172 patients avec un cancer de la prostate de novo métastatique sensible à la castration, 595 avait du matériel centralisé et rapatrié. En IHC, l'expression d'au moins un marqueur neuroendocrine (parmi la synaptophysine, CD56 ou la chromogranine A) était retrouvée pour 26,2% des patients et était indépendamment associée à une survie globale diminuée (HR=1.53, CI95%[1.14-2.06], p=0.005). Aucun biomarqueur ne pouvait prédire le bénéfice de l'abiraterone. L'altération d'au moins deux gènes parmi TP53, PTEN et/ou RB1 était indépendamment associée à un mauvais pronostic (HR=2.63, CI95%[1.10-6.30], p=0.03) . En transcriptomique, nous avons trouvé une sous-expression de la voie du récepteur aux androgènes et une sur-expression de la voie E2F et G2M chez les patients non-répondeurs. Une expression élevée de la signature neuroendocrine et basse de la signature du récepteur aux androgènes était associée à un moins bon pronostic. Au total, nous montrons à un niveau multiomique que des caractéristiques neuroendocrines sont présentes au diagnostic chez les patients avec un cancer de la prostate de novo métastatique sensible à la castration, et que celles-ci sont associées à un mauvais pronosticDe novo metastatic castration sensitive prostate cancer (dnmCSPC) represents 5-10% of PC diagnoses but causes 50% of PC-related deaths. In this ancillary study of the PEACE1 trial, we hypothesized that aggressive or neuroendocrine-like variants could be detected at diagnosis. We centrally retrieved paraffin-embedded biopsies at diagnosis from PEACE1 (NCT01957436) trial patients for immunochemistry (IHC), next generation sequencing (NGS) and transcriptomic analyses. From the 1172 dnmCSPC patients randomized in PEACE-1, 595 had a paraffin-embedded sample collected and centrally reviewed. In IHC, at least oneneuroendocrine marker (among synaptophysin, CD56 or chromogranin A) was expressed in 26.2% of patients and was independently associated with a shorter overall survival (HR=1.53, CI95%[1.14-2.06], p=0.005). No biomarker predicted the benefit of abiraterone. The alteration of at least 2 genes among TP53, PTEN and/or RB1 was independently associated with worse prognosis (HR=2.63, CI95%[1.10-6.30], p=0.03). At a gene expression level, we found an AR pathway under-expression with an E2F and G2M pathway over-expression in non-responder patients. A high neuroendocrine signature and a low androgen receptor signature expression was associated with worse outcomes. Altogether, we show at a multiple omics level that neuroendocrine features are present at diagnosis in dnmCSPC and are associated with worse prognosis
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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
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Sandoval, Díaz Ither, Alarcón Ronald Hernández, Cuervo Fernando Palacios, Rivera Andrea Calderón, Reyes Fátima Espinal, Arones Esperanza Torres, and Elías Andrea Delgado. "Tumor neuroendocrino en cérvix uterino: reporte de caso." Sociedad Chilena de Obstetricia y Ginecología, 2015. http://hdl.handle.net/10757/550713.
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Neuroendocrine tumors of the cervix are extremely rare. Women diagnosed with small cell neuroendocrine carcinoma of the cervix have a higher frequency of metastases in the lymph nodes, lymphovascular invasion, recurrence and worse prognosis compared to those with other types of cervical neoplasia. We report the case of a 58-year-old female, with a history of six years of postmenopausal irregular vaginal bleeding, in addition to symptoms related to chronic anemia. Gynecological examination showed a tumor of 4 cm that occupied the upper third of the vagina and protruded through the cervix initially diagnosed as an abortifacient myoma, and sent to histopathology study. 90% of the tumor was small cell neuroendocrine carcinoma grade III, and the remaining 10% was squamous cell carcinoma. The patient underwent into a radical hysterectomy plus bilateral salpingo-oophorectomy, and bilateral pelvic and para-aortic lymphadenectomy. Histopathologic examination of the surgical specimen found endometrium and myometrium compromised by malignancy. Parametrium, annexes and lymph nodes were free of neoplasia. At microscopy, the result was a grade III neuroendocrine carcinoma (small cell carcinoma, infiltrating), with extensive lymphovascular emboli. The immune-histochemical study showed synaptophysin positive in areas with neuroendocrine differentiation.Los tumores neuroendocrinos de cuello uterino son extremadamente raros. Las mujeres con diagnóstico de carcinoma neuroendocrino de células pequeñas del cuello uterino tienen mayor frecuencia de metástasis en los ganglios linfáticos, invasión linfovascular, recurrencia y peor pronóstico en comparación con aquellos con otros tipos de neoplasias cervicales. Se presenta el caso de una mujer de 58 años, con un tiempo de enfermedad de seis años antes del ingreso, caracterizado por sangrado vaginal irregular posmenopáusica, además de sintomatología relacionada a anemia crónica. En el examen ginecológico, se evidenció tumoración de 4 cm que ocupaba tercio superior de vagina y protruía por el cérvix. Fue diagnosticado como mioma abortivo y enviada a estudio anatomopatológico. El resultado fue carcinoma neuroendocrino de células pequeñas grado III en el 90% y carcinoma epidermoide en el 10%. La paciente fue sometida a histerectomía radical más salpingo-ooferectomía bilateral y linfadenectomía pélvica bilateral y para-aortica. El estudio anatomopatológico de la pieza quirúrgica encontró endometrio y miometrio comprometido por neoplasia maligna. Parametrios, anexos y ganglios linfáticos se encontraron libres de neoplasia. A la microscopía el resultado fue carcinoma neuroendocrino grado III (carcinoma de células pequeñas, infiltrante), con extensa embolia linfovascular. El estudio de inmunohistoquímica arrojó sinaptofisina positivo en las áreas con diferenciación neuroendocrina.
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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.
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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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Larsson, Dhana E. "Analyses of Dose-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell Lines." Doctoral thesis, Uppsala universitet, Institutionen för medicinska vetenskaper, 2011. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-158833.
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Cancer is a disease with poor response rates on available treatments. Problems with resistance and intolerance against cancer drugs are major reasons for failure of the drugs. The need to discover new cancer drugs is important. In this thesis screening of new cancer drugs and evaluation of their mechanism of action are discussed. The aim of the thesis was to find new compounds active against neuroendocrine tumors (NETs). In paper I, we screened 1280 substances on two bronchial carcinoid cell lines and one pancreatic carcinoid cell line. Eleven of these compounds were found to have antitumor activity at low concentrations. The most active agents were brefeldin A, emetine, bortezomib and idarubicin, having IC50 values (the concentration of the drug where > 50% of the cells die) < 1μM. In addition, sanguinarine, Bay11-7085, mitoxantrone, doxorubicin, β-lapachone, NSC 95397 and CGP- 74514A were active with IC50 values < 10 μM. In paper II, additional studies have been undertaken to investigate the combination effect of the most active drugs with conventional cytotoxic drugs used in clinical practice. If synergistic or additive effects are found, drugs with different mechanism of action and toxicity profiles may be combined, making it possible to reduce the toxic effects yet maintaining the antitumor activity. In paper III, studies were undertaken to find the mechanistic action, apoptosis or necrosis, of the drugs NSC 95397, brefeldin A, bortezomib and sanguinarine in NETs. All four drugs were shown to induce caspase-3 activity and nuclear fragmentation/condensation in the neuroendocrine tumor cell lines, indicating that their antitumor activity was induction of apoptosis. In paper IV, the mechanism of action was studied for CGP-74514A and emetine. Both drugs worked by induction of apoptosis. In addition, their cytotoxic activity was studied in a three-dimensional model, the in vitro hollow fiber model. The Hollow Fiber model permits more realistic simulation of in vivo drug effects in a controlled system providing data that more accurately reflects biological responses. Our results showed that the hollow fiber model may be suitable for studies of new drugs in the neuroendocrine tumor cell lines.Title corrected from: Analyses of Dos-Response and Mechanistic Action of Different Anti-Cancer Drugs for Neuroendocrine Tumor Cell Lines
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Erramouspe, Pasilio Pablo Joaquin. "The Facilitates Chromatin Transcription (FACT) complex as a novel target for the treatment of Neuroendocrine Prostate Cancer." Thesis, Queensland University of Technology, 2022. https://eprints.qut.edu.au/229973/1/Pablo%20Joaquin_Erramouspe%20Pasilio_Thesis.pdf.
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This thesis is about the role of The Facilitates Chromatin Transcription (FACT) complex as a potential target for Neuroendocrine Prostate Cancer (NEPC). I studied FACT complex in different models representing the main stages of prostate cancer progression and found that FACT complex expression correlated to the lethal NEPC phenotype. The FACT-inhibiting drug, CBL1037, was more effective at reducing cell viability as compared to the standard-of-care chemotherapy drugs, cisplatin and carboplatin. Significantly lower dose of CBL0137 was required to achieve 50% cell death. These results are promising and support further investigation of CBL0137 as anti-cancer therapy in late-stage prostate cancer.
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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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Wang, Da-Gong. "Expression of oncogenes and a breast cancer associated protein, pS2, in human neuroendocrine tumours : implication for tumourigenesis." Thesis, Queen's University Belfast, 1996. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.361236.
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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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Capodanno, Ylenia. "Identifying therapeutic implications of cancer stem cells in human and canine insulinoma." Thesis, University of Edinburgh, 2018. http://hdl.handle.net/1842/31175.
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Pancreatic neuroendocrine tumours (PNETs) are the most common neuroendocrine tumours diagnosed in humans and dogs. Due to the highly heterogeneous nature of these tumours, definitive data are still lacking over the molecular mechanisms involved in their cancerous behaviour. This study focused on insulinoma (INS), as it is the most commonly diagnosed PNET in human and veterinary oncology. INS is an insulin-producing tumour that causes a hypoglycaemic syndrome related to the excessive insulin production. In humans, it is often a small benign neoplasm readily curable by surgical resection whereas, in dogs, INS is often malignant. Despite current treatment modalities, malignant canine and human INS have a poor prognosis as patients tend to develop metastases in liver and lymph nodes that do not respond to current therapies. From a comparative oncology perspective, the close resemblance of canine and human malignant INS makes canine INS an interesting study model for human INS. Cancer stem cells (CSCs) are critical for the engraftment and chemoresistance of many tumours. Although CSCs have been isolated from a range of solid tumours, a comprehensive characterisation of INS CSCs has not yet been reported. In this study, it was confirmed that INS CSCs can be enriched and are potential targets for novel INS therapies. Highly invasive and tumourigenic human and canine INS CSCs were successfully isolated and exhibited greater resistance to chemotherapy, which may play a significant role in the poor prognosis of this disease. To date, the mechanisms by which tumours spread and the clinical causes of chemoresistance remain only partially understood. Here, RNA-sequencing analysis was performed over a small set of canine INS tumour samples in order to identify mechanisms involved in INS carcinogenesis through different stages of the disease. Preliminary data showed that distinct gene profiles characterised early and late stage of canine INS. Interestingly, differential gene expression and gene pathways analysis, highlighted that sets of genes involved in pancreatic embryogenesis and insulin secretion were overexpressed in canine primary INS lesions compared with normal pancreas. The Notch pathway is fundamental in pancreatic embryogenesis and it has been previously associated with carcinogenesis of neuroendocrine tumours and with the CSC phenotype. Protein analysis showed that the Notch pathway is activated in both human and canine INS CSCs, particularly when treated with chemotherapy, indicating that the Notch pathway may be involved in chemoresistance. Additionally, it was demonstrated that inhibition of the Notch pathway decreased INS CSCs' survival and chemoresistance, both in vitro and in vivo. These findings provide preclinical evidence that anti-Notch therapy may improve outcomes for patients with malignant INS.
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Yu, Di. "Adenovirus for Cancer Therapy : With a Focus on its Surface Modification." Doctoral thesis, Uppsala universitet, Klinisk immunologi, 2013. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-203662.
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Adenovirus serotype 5 (Ad5) is widely used as an oncolytic agent for cancer therapy. However, its infectivity is highly dependent on the expression level of coxsackievirus-adenovirus receptor (CAR) on the surface of tumor cells. We engineered Ad5 virus with the protein transduction domain (PTD) from the HIV-1 Tat protein (Tat-PTD) inserted in the hypervariable region 5 (HVR5) of the hexon protein in the virus capsid. Tat-PTD-modified Ad5 shows a dramatically increased transduction level of CAR-negative cells and bypassed fiber-mediated transduction. It also overcomes the fiber-masking problem, which is caused by release of excess fiber proteins from infected cells. To achieve specific viral replication in neuroblastoma and neuroendocrine tumor cells, we identified the secretogranin III (SCG3) promoter and constructed an adenovirus Ad5PTD(ASH1-SCG3-E1A) wherein E1A gene expression is controlled by the SCG3 promoter and the achaete-scute complex homolog 1 (ASH1) enhancer. This virus shows selective and efficient killing of neuroblastoma cell lines in vitro, and delays human neuroblastoma xenograft tumor growth on nude mice. To further enhance the viral oncolytic efficacy, we also switched the fiber 5 to fiber 35 to generate Ad5PTDf35. This vector shows dramatically increased transduction capacity of primary human cell cultures including hematopoietic cells and their derivatives, pancreatic islets and exocrine cells, mesenchymal stem cells and primary tumor cells including primary cancer initiating cells. Ad5PTDf35-based adenovirus could be a useful platform for gene delivery and oncolytic virus development. Viral oncolysis alone cannot completely eradicate tumors. Therefore, we further armed the Ad5PTDf35-D24 virus with a secreted form of Helicobacter pylori Neutrophil Activating Protein (HP-NAP). Expression of HP-NAP recruits neutrophils to the site of infection, activates an innate immune response against tumor cells and provokes a Th1-type adaptive immune response. Established tumor on nude mice could be completely eradicated in some cases after treatment with this virus and the survival of mice was significantly prolonged.
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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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Dannoon, Shorouk Lewis Michael R. Jurisson Silvia. "Structure-activity relationship of octreotide analogues labeled with rhenium and technetium-99m." Diss., Columbia, Mo. : University of Missouri--Columbia, 2009. http://hdl.handle.net/10355/7019.
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Title from PDF of title page (University of Missouri--Columbia, viewed on Feb 25, 2010). The entire thesis text is included in the research.pdf file; the official abstract appears in the short.pdf file; a non-technical public abstract appears in the public.pdf file. Dissertation advisor: Dr. Silvia Jurisson and Dr. Mike Lewis. Vita. Includes bibliographical references.
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Franceschini, Gian Marco. "The DNA methylation landscape of metastatic prostate cancer: from characterization to liquid biopsy applications." Doctoral thesis, Università degli studi di Trento, 2023. https://hdl.handle.net/11572/364210.
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Epigenetic alterations are observed in virtually all cancer types, yet there is limited understanding of their role in tumorigenesis and evolution. The role of DNA methylation has been particularly elusive in this context. While this epigenetic mark has been extensively profiled in healthy and cancerous samples, our ability to understand its relationship with underlying biological processes is still limited. Moreover, recent advancements in the profiling of cell-free DNA in circulation have sparked renowned attention toward tissue-specific and cancer-specific DNA methylation patterns. In this thesis, I present results to improve and refine the computational characterization of DNA methylation in cancer, focusing on metastatic castration-resistant prostate cancer. The first contribution is the development and performance assessment of Rockermeth, a computational methodology to leverage large-scale DNA methylation profiling data to nominate robust differentially methylated regions (DMRs). Rocker-meth can retrieve biologically relevant DNA methylation changes, as demonstrated by extensive integrative analyses with gene expression, chromatin states, and genomic annotations. The second contribution is the generation of a map of DNA methylation changes across prostate cancer progression. The application of Rockermeth and other tailored methodologies can be used to trace the critical evolutionary steps of this disease, from the healthy tissue to the most lethal metastatic AR-independent counterpart. The main result is the evidence of the ability of DNA methylation to capture a snapshot of the active transcription factors in each state of the disease, offering orthogonal information compared to standard genomic sequencing. The third contribution is the design and development of NEMO, a tailored liquid biopsy sequencing panel approach to allow non-invasive neuroendocrine castration-resistant prostate cancer detection in patients with metastatic disease. Based on previous results and the comprehensive analysis of multiple datasets, I designed a set of informative genomic regions to estimate disease burden and evidence of neuroendocrine transdifferentiation. The actual implementation of the NEMO panel produced a scalable and cost-effective strategy, which has been extensively benchmarked using both in silico and in vitro approaches. The application of NEMO to patient-derived cfDNA samples demonstrated accurate tumor content estimation and robust detection of neuroendocrine disease, making it a promising instance of liquid biopsy for CRPC.
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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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Gauerke, Jennifer Leigh. "Genetic Evaluation of Patients and Families with Concern for Hereditary Tumor Syndromes within the OSU James Multidisciplinary Neuroendocrine/Thyroid Cancer." The Ohio State University, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=osu1555086532080802.
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Zuazo, Gaztelu Iratxe. "Dual effect of Semaphorin 4D blockade in neuroendocrine tumor malignization: from vessels to macrophages." Doctoral thesis, Universitat de Barcelona, 2018. http://hdl.handle.net/10803/664077.
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Tumor progression is a complex conundrum of events that involve not only tumor cells, but also their surrounding microenvironment. Accounting to the natural dependency of tumors on angiogenesis, its therapeutic targeting remains a valid stroma-directed strategy in the fight against cancer. However, standard antiangiogenics fail to produce enduring beneficial effects due to the appearance of resistance, often as a consequence of intratumor hypoxia triggered by vessel trimming. In the case of neuroendocrine tumors (NETs), which are characterized by their low aggressiveness, high heterogeneity and vessel content, new therapeutic approaches are being explored to overcome such hurdles, where conventional therapies stumble. In this context, blockade of semaphorin 4D (Sema4D), a proangiogenic molecule with homeostatic roles in the immune system, by a monoclonal antibody (anti-Sema4D) has proved beneficial antitumor effects in the RIP1-Tag2 preclinical mouse model of pancreatic NET (PanNET). Unfortunately, the decrease in tumor burden and increase in survival of anti-Sema4D treated mice followed an increase in local invasiveness and metastasis. Contrary to the thoroughly described mechanisms governing malignization after antiangiogenic therapies, no intratumoral hypoxia was detected after Sema4D blockade.
In this doctoral thesis, aiming to decipher this novel form of resistance by which anti- Sema4D treatment acts as a double-edged sword in PanNETs, the two systems involved in Sema4D signaling were studied: the vascular and the immune system. We first described a beneficial antiangiogenic effect, characterized by structural changes in tumor vessels mediated by a pericyte-endothelial cell crosstalk. Incidentally, we found that the aggressive phenotype involved the recruitment of Sema4D-positive tumor-associated macrophages (TAMs) to the tumor ecosystem, which, after becoming activated by anti- Sema4D treatment, triggered tumor cell migration and invasion. Mechanistically, functional characterization of Sema4D-positive TAMs’ secretome revealed cytokine CXCL12 to be one of the molecules involved in the proinvasive program, suggesting the implication of CXCL12/CXCR4 signaling. Comprehensive clinical validation further shed light on the implication of both macrophage-derived Sema4D and CXCR4 in the malignization steps of tumor development in PanNET patients, which undoubtedly unleashes a new range of approaches merging the immunotherapy and the antiangiogenic fields in their shared fight against cancer.Considerando la dependencia natural de los tumores por la angiogénesis, su explotación como diana dirigida contra el microambiente en el tratamiento del cáncer, supone una válida estrategia terapéutica. No obstante, los antiangiogénicos estándar fracasan a la hora de producir efectos duraderos debido a la aparición de resistencia, habitualmente como consecuencia de la hipoxia intratumoral. En el caso de los tumores neuroendocrinos (NETs), caracterizados por su alta heterogeneidad y alto contenido vascular, donde la terapia convencional falla, están siendo explorados nuevos abordajes terapéuticos. En este contexto, el bloqueo de la semaforina 4D (Sema4D), una molécula proangiogénica con un papel homeostático en el sistema inmune, utilizando un anticuerpo monoclonal (anti- Sema4D) ha demostrado efectos antitumorales beneficiosos, en un modelo murino de cáncer de páncreas neuroendocrino (PanNET). Lamentablemente, al descenso en el volumen tumoral y al aumento en la supervivencia de los ratones tratados con anti- Sema4D les siguen un aumento en la invasión local y la metástasis. Al contrario de lo esperado, no se detectó hipoxia intratumoral tras el bloqueo de la Sema4D. Con el objetivo de descifrar esta nueva forma de resistencia, en la cual, el tratamiento anti-Sema4D actúa como un arma de doble filo en PanNETs, estudiamos los dos sistemas implicados en la señalización vía Sema4D: el sistema vascular y el inmune. Primeramente, describimos un efecto antiangiogénico beneficioso, caracterizado por un cambio estructural de los vasos tumorales, y mediado por una comunicación cruzada entre células endoteliales y pericitos. A continuación, encontramos que el fenotipo agresivo involucra el reclutamiento de macrófagos positivos para Sema4D al ecosistema tumoral, los cuales, tras activarse por el tratamiento anti-Sema4D, potencian la migración e invasión de las células tumorales. La caracterización funcional de los macrófagos desveló la contribución de la citoquina CXCL12 al programa proinvasivo, sugiriendo una implicación de la señalización vía CXCL12/CXCR4. Finalmente, una validación clínica integral en pacientes de PanNETs arrojó luz sobre la participación de Sema4D derivada de los macrófagos y CXCR4 durante el desarrollo tumoral. En conjunto, nuestros datos reconducen el abanico de estrategias terapéuticas existentes hacia un nuevo enfoque que combina la inmunoterapia y la antiangiogénesis en la lucha común contra el cáncer.
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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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Bery, Fanny. "Rôle de la signalisation calcique et de la transition épithélio-mésenchymateuse dans l’agressivité et la différenciation neuroendocrine du cancer de la prostate." Electronic Thesis or Diss., Tours, 2021. http://www.theses.fr/2021TOUR5010.
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La transition épithélio-mésenchymateuse (TEM) participe à l’agressivité du cancer de la prostate (CaP). Nous avons identifié une nouvelle voie de signalisation impliquée dans la progression tumorale et initiée par le TGFβ et l’hypoxie, deux inducteurs de la TEM. Il existe une boucle calcium dépendante entre Zeb1, facteur clé de la TEM, et le canal SK3, pouvant être inhibée par l’acide linoléique et l’acide eicosapentaénoïque, acides gras inversement corrélés à l’agressivité du CaP. Les thérapies ciblant le récepteur aux androgènes peuvent induire des réponses adaptatives telles que la TEM et la différenciation neuroendocrine (NE). Nous avons montré que le récepteur sensible au calcium est un marqueur et un promoteur de la différenciation NE des cellules du CaP. Dans les CaP résistants à la castration, nous avons observé une augmentation de l’expression de Zeb1 et SK3. L’enzalutamide, hormonothérapie de nouvelle génération, peut induire l’expression de ces deux gènes et favoriser la différenciation NE. Le ciblage du canal SK3 pourrait constituer une stratégie thérapeutique pour lutter contre la progression et l’agressivité du CaPEpithelial to mesenchymal transition (EMT) is involved in prostate cancer (PCa) aggressiveness. We identified a new signalling pathway involved in tumor progression and initiated by TGFβ and hypoxia, two EMT inducers. We demonstrated a calcium dependent loop between Zeb1, a key EMT factor, and SK3 channel, inhibited by linoleic and eicosapentaenoic acids, two fatty acids inversely associated with PCa aggressiveness. Therapies targeting the androgen receptor can induce adaptative responses such as EMT and neuroendocrine (NE) differentiation. We showed that the calcium sensing receptor is a marker and driver of NE differentiation of PCa cells. In castration-resistant PCa, we observed an increase in the expression of Zeb1 and SK3. Enzalutamide, a new generation hormonotherapy, can induce Zeb1 and SK3 expression and promote NE differentiation of PCa cells. Targeting SK3 channel could be a therapeutic strategy to prevent PCa progression and aggressiveness
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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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Rainey, Amanda Nichole. "Anatomical Analysis of Tachykinin-Related Peptide Distribution in the Thoracic Ganglion of the Crab, Cancer borealis." Miami University / OhioLINK, 2019. http://rave.ohiolink.edu/etdc/view?acc_num=miami1564242169221564.
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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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Hutchinson, Alexander B. "Identification of response pathways of prostate cancer cell lines in Hans Clevers Media." Thesis, Queensland University of Technology, 2017. https://eprints.qut.edu.au/103982/4/Alexander%2520Blaine_Hutchinson_Thesis.pdf.
Full textAbstract:
Prostate cancer has been extremely difficult to grow in vitro, however recent development of a novel media has improved success rates of propagating tumour cells in the laboratory. This project aimed to define pathways regulated by this media in different prostate cancer cells in order to identify critical factors needed for prostate cancer survival. Both common and cell line-specific responses to the media were identified, demonstrating that not all prostate cancer cells respond the same way or have the same requirements. These unique responses must be considered when cells grown in this media are used to explore potential new treatment targets.
45
Ferguson, Mary L. "Angiogenesis in human lung tumours." Thesis, University of Oxford, 2008. http://ora.ox.ac.uk/objects/uuid:865de25c-1ac3-4a30-85fa-a9fc677bfcc2.
Full textAbstract:
Angiogenesis, the growth of new blood vessels, is vital to tumour growth. Prevailing dogma has been that tumours cannot grow without angiogenesis. Based on this premise, anti-angiogenic drugs are used clinically. However, the principle of angiogenesis as an absolute requirement for tumour growth has been challenged with reports that many tumours are entirely or partially non-angiogenic. This study describes and quantifies characteristics of non-angiogenic non-small cell lung tumours, demonstrates non-angiogenic growth in small-cell/neuroendocrine lung tumours and investigates the underlying pathogenetic processes by comparison with angiogenic lung tumours. Hypoxia is an important stimulus for angiogenesis. Differences in response to hypoxia may determine whether a tumour produces new vessels. In order to test this, levels of. necrosis, often considered a surrogate marker of hypoxic stress, were quantified but no difference in quantity of necrosis was found Moreover, immunohistochemical investigation of hypoxia and angiogenesis factors provided no unambiguous explanation for the differences in angiogenesis. Significant differences were seen, however, in fibrosis and inflammation, which were both greater in angiogenic tumours. Differences were greater for lymphocytes rather than cells of the ‘innate’ immune system. This provided an alternative hypothesis: angiogenesis occurs during wound healing and in the growth of granulation tissue, so it is possible that tumour angiogenesis is a response to factors produced by immune cells rather than the tumour itself. A tumour’s angiogenic status may, therefore, be determined by the response it provokes from the immune system. Further work to test this theory would compare levels of immunogenic factors such as Tumour Necrosis Factor and tumour cell surface antigens such as the HLA class I molecules. The study concludes with an investigation into the molecular basis of non-angiogenic growth using the technique of comparative genomic hybridisation (CGH) which allows amplifications and deletions of areas of DNA to be calculated. High-resolution array CGH was evaluated against conventional CGH, and the results compared with previous RNA studies from our laboratory. These revealed a set of genes with consistent changes in both RNA and DNA, several of which form part of known angiogenic and inflammatory pathways.
46
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.
Full textAbstract:
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
47
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/.
Full textAbstract:
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
48
Subnis, Utkarsh B. "Stress management for cancer survivors using a technologically adapted psychosocial intervention: A randomized trial determining the effect of expressive writing on psychoneuroimmunology based outcomes." VCU Scholars Compass, 2014. http://scholarscompass.vcu.edu/etd/3596.
Full textAbstract:
Patients with cancer transitioning from completing their final cancer treatments to survivorship are particularly at risk for experiencing psychosocial stress, and the Institute of Medicine (IOM) has referred to these cancer patients as “lost in transition.” In this study, patients with cancer in their transition phase after completing their final radiation treatment were defined as cancer survivors (CS). CS must deal with chronic stressors such as the fear of cancer recurrence as well as the resumption of their roles in their family and work lives. Chronic stress impacts the nervous system and increases secretion of stress hormones (e.g. cortisol) from the endocrine system, which in turn influences immune function. These systems are particularly relevant for CS since research has shown associations between abnormal cortisol patterns and increased mortality in breast CS and immune dysfunction in CS can increase susceptibility to infections. The theoretical framework of psychoneuroimmunology (PNI), which describes the interactions between the psychosocial, neuroendocrine and immune systems, guided the choice of outcomes for this study. The IOM has identified a lack of theory-driven interventions for managing psychosocial stress in CS. We reviewed the literature and identified two major types of PNI-based psychosocial interventions for cancer patients, namely cognitive-behavioral and complementary medical. One promising brief and inexpensive psychosocial intervention was expressive writing, which involved participants disclosing their deepest thoughts and feelings regarding their cancer in four 20-30 minute writing sessions over four consecutive days. We conducted a two-arm randomized controlled trial to determine the efficacy of an online expressive writing (EW) intervention delivered to CS who were 2-12 months post-radiation treatment completion. The results of this study revealed that EW was effective in regulating stress in our sample of CS over a period of six weeks as measured by lowered salivary cortisol levels and lowered self-reported fear of cancer recurrence. Online EW is a low-cost and convenient approach for delivering stress-management interventions for CS during survivorship. However, coordinated efforts are needed from health researchers, professionals and policy makers to define standardized approaches for testing psychosocial interventions and using PNI biomarkers to help develop evidence-based psychosocial cancer-care for CS during survivorship.
49
Boichard, Amélie. "Caractérisation moléculaire des formes métastatiques de carcinome médullaire de la thyroïde." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T015/document.
Full textAbstract:
Le carcinome médullaire de la thyroïde (CMT) est une tumeur neuroendocrine rare, se développant à partir des cellules sécrétant la calcitonine. Cette tumeur survient dans un contexte familial dans un tiers des cas. Toutes les formes germinales et près de 40% des formes sporadiques sont causées par une mutation ponctuelle activatrice de l’oncogène RET, codant pour un récepteur membranaire à activité tyrosine kinase. Les événements oncogéniques à l’origine des formes sporadiques non mutées RET restent mal définis, à l’exception de mutations activatrices des oncogènes RAS découvertes récemment.Le pronostic péjoratif du CMT est essentiellement lié à un envahissement ganglionnaire précoce. A ce titre, la chirurgie initiale est souvent insuffisante et les formes métastatiques ont longtemps été considérées en impasse thérapeutique. L’avènement récent des inhibiteurs séléctifs de tyrosine kinases (ITK) a apporté un nouvel élan à la prise en charge des tumeurs réfractaires, certains d’entre eux incluant dans leur spectre d’action le récepteur RET. Mais l’optimisation de ces traitements requiert une connaissance préalable des mécanismes moléculaires sous-jacents au développement tumoral.Dans ce contexte et en nous appuyant sur une collection importante de prélèvements humains, nous avons cherché à approfondir la decription du ‘paysage génomique’ du CMT.Dans un premier temps, nous avons évalué les anomalies structurales ponctuelles et chromosomiques présentées par les CMT. Nous avons montré, par optimisation de méthodes de séquençage, que les mutations des gènes RET et RAS interviennent dans plus de 96% des cas et que ces évènements sont mutuellement exclusifs. Ces mutations permettent de distinguer plusieurs groupes d’agressivité et de réponse aux traitements par ITK. Nous avons également observé - par technique d’hybridation génomique comparative - des anomalies de grande ampleur récurrentes dans cette pathologie : les délétions du bras court du chromosome 1 et des chromosomes entiers 4 et 22 apparaissent comme étant des évènements précoces et indépendants de la tumorigenèse du CMT.Dans un second temps, nous avons déterminé - par approche de type biopuce - les profils d’expression de microARN dans les CMT. Certains de ces régulateurs post-transcriptionnels majeurs semblent liés au caractère invasif de la tumeur, et notamment les miR-21, miR-199 et miR-129. Nous avons également démontré le potentiel d’utilisation des microARN miR-21 et miR-199 en tant que biomarqueurs circulants du CMT. L’impact fonctionnel des formes précurseurs mir-21 et mir-129 a ensuite été évalué par transfection dans les modèles cellulaires TT et MZ-CRC1.Les observations ainsi obtenues offrent de nombreuses perspectives d’études. Elles permettent la définition de marqueurs tissulaires distinguant a priori les tumeurs métastatiques et/ou réfractaires aux thérapies. Enfin, elles mettent en lumière de nouvelles pistes pour la découverte de cibles thérapeutiques additionnelles dans cette pathologieMedullary thyroid carcinoma (MTC) is a rare neuroendocrine tumor, arising from calcitonin-secreting cells. This cancer occurs in a family context in a third of cases. All inherited forms and nearly 40% of sporadic forms are caused by activating point-mutations in the RET oncogene, coding for a tyrosine-kinase receptor. Other oncogenic events causing sporadic cases remain unclear, but activating mutations of RAS oncogenes have been discovered recently.Prognosis of MTC is essentially linked to early lymph node occurrence. Initial surgery of metastatic forms is often insufficient and patients are considered in therapeutic dead-end. The recent advent of selective tyrosine-kinase inhibitors (TKIs) has brought a new impetus to the management of refractory tumors, some of them targeting the RET receptor. Optimization of these treatments require improving knowledge of the underlying molecular mechanisms of tumor development.In this context and helped by a large collection of human specimens, we have sought to deepen the description of genomic landscape of MTC.At first, we evaluated the structural and chromosomal abnormalities presented by MTC. We showed, by optimizing sequencing methods, that RET and RAS mutations are involved in over 96% of the cases, these events are mutually exclusives. These mutations can distinguish several groups of aggressiveness and of response to TKI treatments. We also observed, by comparative genomic hybridization techniques, recurrent abnormalities such as deletion of the short arm of chromosome 1 and loss of entire chromosomes 4 and 22. These losses appear to be early events of tumorigenesis MTC.In a second step, we determined - by a microarray approach – the microRNA expression profile of MTC. Some of these post-transcriptional regulators seem related to tumor invasiveness, such as miR-21, miR-199 and miR-129. We demonstrated the potential of microRNAs miR-21 and miR-199 as circulating diagnosis biomarkers of MTC. The functional impact of the precursor forms mir-21 and mir-129 was then evaluated by transfection in TT and MZ- CRC1 cellular models.Observations obtained pave the way for a lot of new potential studies. They allow the definition of tissue biomarkers distinguishing metastatic forms or refractory patients. Finally, they highlight new pathways for the discovery of additional therapeutic targets in this disease
50
Lallet-Daher, Hélène. "Implication du canal potassique calcium dépendant à conductance intermédiaire IKca1 dans la cancerogenèse humaine." Electronic Thesis or Diss., Lille 1, 2008. http://www.theses.fr/2008LIL10135.
Full textAbstract:
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