Dissertations / Theses: 'CD133+'

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Ahmed, Tarek Mohamed Abdel Moneim Mohamed Elsaba. "Role of CD133 in colorectal cancer." Thesis, University of Nottingham, 2011. http://eprints.nottingham.ac.uk/28630/.

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CD133 is a pentaspan transmembrane glycoprotein of ~120 kDa, which was initially used to identify haematopoietic stem cells and, later on, used for the isolation and study of cancer stem cells in many different types of solid tumour including colorectal cancer. Although CD133 expressing cells are thought to represent cancer stem cells, little is known about the exact role of CD133 and the molecular mechanisms underlying control of CD133 expression. This project sought to investigate these questions in colorectal cancer. Initially the expression of CD133 was tested by immunohistochemistry in a two tissue microarray (TMA) sets consisting of (a) 449 cases of primary colorectal cancer, and (b) 45 cases of primary and matched liver metastases. High CD133 expression was marginally associated with shorter overall survival (OS) (p=0.05, Log-rank test) but no difference in expression was found between primary tumours and corresponding metastases. Next, the functional activity of CD133 was evaluated in colorectal cancer (CRC) cell lines by knockdown in cell lines with high CD133 expression. In order to identify appropriate cell lines, the expression of CD133 was tested by quantitative RT -PCR in a series of 29 CRC cell lines and 10 samples of normal mucosa and, in selected cell lines, validated by testing for protein expression by flow cytometry. CD133 mRNA was expressed in 24/29 colorectal cancer cell lines with a heterogenous level of expression. 10 cell lines were chosen on the basis of CD133 mRNA expression level to assess the protein level. CD133 mRNA and protein expression were generally correlated (rs = 0.831, p= 0.003, spearman rank correlation coefficient test) although, interestingly, CD133 mRNA level was higher in normal samples compared with that in cancer cell lines and was significantly higher in cell lines derived from metastatic sites than those derived from site of primary tumour (p=0.009; Mann-whitney test). In addition, it was noted that many cell lines had a stable biphasic phenotype containing CD133+ and CD133- cell populations. This allowed functional analysis of CD133 by sorting the two populations. HT29 was identified as a high expresser of CD133 (95%) and was used for gene-knockdown studies, SW480 had a biphasic population consisting of 42% CD133+ cells and 58% CD133- cells and each population was isolated by cell sorting before functional analysis. Functional assays included proliferation, migration, colony formation and staurosporine induced apoptosis assays. These showed that CD133 expressing cells had greater cell motility (p= 0.04, and p = 0.03, unpaired t-test, for knocked down cells and sorted populations respectively) , enhanced colony forming abilities (p=0.0001, and p=0.003, unpaired t-test for 2D and 3D colony formation respectively using sorted populations only), and increased resistance to staurosporine induced apoptosis (p=0.01, and p=0.008, unpaired t-test, for knocked down and sorted populations respectively) than CD133 negative counterparts. In addition, sorted monophasic populations reverted to a biphasic state in both CD133+/- populations from SW480. Further studies demonstrated that CD133-induced cell motility was independent of E-cadherin, β-catenin, and suggestive of not being regulated by Cten or Wnt, but further work is warranted to verify these results. In addition, regulation of CD133 was partly dependent on STAT3 signalling and on CD133 promoter methylation. Levels of mRNA of some stem cell related genes such as KLF-4, Musashi-1, OCT4, Nanog, and Lgr5 were higher in CD 133 + compared to CD 133 negative cells (p=0.008, p=0.004, p=0.006, p=0.001, and p=0.11; unpaired t-test, respectively) In conclusion, in CRC, CD133 was found to be a significant prognostic factor which enhances cell motility and is associated with features of "stemness". It is a target of ST AT3 signalling and partly regulated by promoter methylation. More in depth studies are warranted to discover the downstream and upstream targets of CD133 before translating these preclinical and laboratory investigations into clinical management of colorectal cancer.

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Marçola, Marina. "Perfil circadiano da expressão de microRNAs em células progenitoras CD133+." Universidade de São Paulo, 2015. http://www.teses.usp.br/teses/disponiveis/41/41135/tde-19052015-092113/.

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Culturas de células primárias diferem de acordo com as condições ambientais nas quais se encontra o doador. Recentemente demonstramos que o ciclo claro/escuro impõe um programa molecular hereditário em cultura celular. Com o intuito de investigar os mecanismos moleculares da memória celular, no presente trabalho isolamos células progenitoras CD133+ de explante de músculo cremaster e investigamos se a expressão de microRNAs (miRNAs), resulta em fenótipos diferentes de acordo com o ciclo claro/escuro. O sequenciamento global de miRNAs utilizando a plataforma SOLiD 4 e analisado pelos programas EdgeR, TargetScan e Metacore resultou na identificação de 541 miRNAs maduros, os quais apresentam dois perfis de expressão distintos de acordo com a hora de obtenção das culturas. miR-1249 e miR-129-2-3p são mais expressos em células obtidas durante o dia e favorecem a manutenção da pluri/multipotência celular. Já células obtidas à noite expressam maior conteúdo dos miR-182, miR-96-5p, miR-223-3p, miR-146a-3p e miR-146a-5p resultando na inibição da resposta inflamatória e no favorecimento da maturação celular quando comparadas às células obtidas de dia. A análise funcional da inibição da resposta inflamatória em células obtidas à noite foi confirmada por PCR array que revelou na menor expressão de genes relacionados à via de sinalização TLR/NF-κB, incluindo Traf6, um alvo do miR-146a. Além disso, a translocação nuclear de NF-κB é reduzida à noite e é inversamente proporcional ao nível de melatonina plasmática. Demonstramos ainda que a melatonina in vitro favorece o estado de pluripotência celular por aumentar a expressão de CD133, miR-1249 e miR-129-2-3p. No entanto, esse efeito depende do contexto celular visto que a expressão de receptores de melatonina também varia de acordo com a hora de obtenção da cultura. Em conjunto, nossos dados sugerem que o ciclo claro/escuro interfere no perfil de expressão de miRNAs e impõe uma variação no fenótipo de células progenitoras CD133+
The phenotype of primary cells in culture varies according to the donor environmental condition. We have recently shown that the light/dark cycle impose a molecular program that is hereditable in culture. In order to evaluate the molecular mechanisms of cellular memory, here we isolated CD133+ progenitor cells from cremaster muscle explants and investigated whether the expression of microRNAs (miRNAs), could result in different phenotypes according the phase of ligh/dark cycle when cells were obtained. The global miRNA sequencing using SOLiD4 Platform, and analyzed by EdgeR, TargetScan and MetaCore, revealed the expression of a total of 541 mature miRNAs, and two distinct miRNAs signatures according to the hour when cells were obtained. miR-1249 and miR-129-2-3p are more expressed during daytime and favor the maintenance of cellular pluri/multipotency. Nighttime cells express higher amounts of miR-182, miR96-5p, miR-223-3p, miR-146a-3p and miR-146a-5p that inhibit the inflammatory response and favor the cellular maturation when compared to daytime cells. The functional analysis of the inflammatory response inhibition during nighttime was confirmed by PCR array and revealed lower expression level of genes related to TLR/NF-κB pathway, including Traf6, a putative target mRNA of miR-146a. Additionally, the nuclear translocation of NF-κB is reduced in nighttime cells and it is inversely correlated to the nocturnal the plasma level of melatonin. We also showed that melatonin in vitro favors the cellular pluri/multipotency, increasing CD133, miR-1249 and miR-129-2-3p expression. However, this effect depends on cellular context, as the expression of melatonin receptors also shows a daily variation. Altogether, our data suggest that the light/dark cycle interferes on miRNAs expression profile and imposes a rhythmic phenotype variation in CD133+ cells

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Damianoff, Karin. "CD133 positive "Cancer Stem Cells" in Gliomen verschiedener Malignitätsgrade." Diss., lmu, 2011. http://nbn-resolving.de/urn:nbn:de:bvb:19-126442.

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Zhai, Xiao Qun. "Biology of adult human normal and leukaemia CD133+ stem cells." Thesis, University of Central Lancashire, 2010. http://clok.uclan.ac.uk/21488/.

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Recently, CD133 has been used extensively as a marker for identification of stem cells from human normal and malignant tissues. Human normal CD 133+ stem cells are capable of multilineage in vitro and in vivo differentiation providing a novel source of stem cells for regenerative therapy, whereas, malignant CD133+ stem cells are a potential therapeutic target for anti-cancer treatment. This PhD thesis investigated the neural differentiation of human adult bone marrow and foetal liver CD133+ stem cells; explored the presence of CD133 and embryonic stem cell marker Oct-4 positive stem cells in adult human normal and malignant tissues, including normal brain tissues, normal and malignant bone marrow stem cells; and evaluated the anti-acute myeloid leukaemia (AML) effect of 5 novel synthetic ajoene compounds using drug-resistant AML cell line for overcoming drug resistance in elderly AML patients. A novel serum-free culture system for inducing neural differentiation of human adult bone marrow and foetal liver CD 133+ stem cells in vitro was demonstrated. Following only two weeks' culture of selected bone marrow CD 133+ cells in serum-free medium supplemented by 50% human astrocyte conditioned medium and other cytokines, 25.5% of bone marrow CD 133+ stem cells differentiated into neural (17.8%) and glial (7.7%) cells. After three weeks' culture of selected foetal liver CD133+ cells in serum-free medium supplemented by several cytokines without astrocyte conditioned medium, only 10.8% of these stem cells differentiated into neural and glial cells. These neural differentiated cells expressed mature neural and glial markers including NF-h, NF-m, NSF and GFAP, and exhibited mature neural morphologies. The astrocyte conditioned medium was the essential ingredient in all effective serum-free culture conditions suggesting it may contain other more potent neural/glial inducing factors. The serumfree culture system is clinically relevant and provides a vehicle for generating neural cells from adult human bone marrow CD 133+ stem cells for the treatment of patients with neurodegenerative diseases. CD 1 33-isoform 2 (CD 133-2) and embryonic stem cell marker Oct-4 expression was revealed in three adult human normal and malignant tissues and cells, including normal brain (substantia nigra and striatum), normal and malignant CD34+ marrow stem cells. There was no expression of CD133-isoform I (CD133-1) in these tissues. The very small population of CD133-2 and Oct-4 positive stem cells in adult human normal substantia nigra and striatum may represent the embryonic remnants and provide a potential source of adult neural stem cells that may be induced to undergo neural diffeentiation for the treatment of neurodegenerative conditions, such as Parkinson's disease. The substantial expression of Oct-4 in adult human normal and drug-resistant myeloid leukaemia KG1a marrow stem cells demonstrates that, alongside CD133, Oct-4 is a novel cancer stem cell marker suggesting the CD 133-2 and Oct-4 positive KGIa cells are the most likely targets in disease development and are novel therapeutic targets for effective treatment of AML. Novel synthetic ajoene compounds were shown to significantly inhibit growth, induce apoptosis plus necrosis, and reduce Bcl-2 expression in human drug-resistant CD34+ AML KG 1 a cells, both alone and in combination with low dose (1 jxM) cytarabine. E/Zbenzyl was the most potent growth inhibition compound,. whereas, Z-ajoene was the most cytotoxic compound. Low dose cytarabine-induced cytotoxicity was significantly enhanced by the five novel compounds in the following order: Z-ajoene > E-ajoene > Ephthalimide> E/Z-benzyl > Z-pthalimide. The combination of Z-ajoene and low dose cytarabine provides a promising combination therapy for elderly AML patients to overcome drug resistance. This PhD thesis provides the basis for appropriate identification and clinical application of stem cells from adult human normal tissues (brain and bone marrow) and foetal liver for autologous transplantation for the treatment of neurodegenerative diseases, such as Parkinson's disease, and also the identification of cancer stem cells in human AML marrow stem cells indicating novel therapeutic targets for anti-cancer treatment. Moreover, it demonstrates significant anti-cancer effect of 5 novel synthetic ajoene compounds in drug-resistant AML cells highlighting their potential for overcoming drug resistance in elderly patients with AML.

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Lechner, Axel. "Die Rolle des Tumorstammzellmarkers CD133 in der Initiierung von Tumoren." Diss., Ludwig-Maximilians-Universität München, 2014. http://nbn-resolving.de/urn:nbn:de:bvb:19-173238.

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Adikibi, Tonye T. "Investigation into the functional role of the stem cell marker CD133." Thesis, Kingston University, 2011. http://eprints.kingston.ac.uk/22964/.

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CD133 is a pentaspan membrane protein found on pseudopodia, microvilli and other plasma protrusions irrespective of cell type in both humans and mice. CD 133 has been classified as a marker of primitive haemopoietic and neural stem cells. At the molecular level it interacts with cholesterol and is located within lipid micro domains known as lipid rafts. Using cellular and molecular techniques we investigated the functional role CD 133 plays in stem cell biology. Prior to commencing the functional experiments, we determined that MUTZ-2, Caco-2 and primary CD34+ cells provided the best characteristics to investigate CD133 function. We established growth conditions, patterns and CD 133 expression for all 3 cell types and concluded that Caco-2 was the preferential cell line based on CD133 expression and cell stability. A number of approaches were used to knock down CD133 usmg a variety of RNAi oligonucleotides. Plasmid vectors were used in an attempt to produce a permanent CD 133 knockout Caco-2 cell line. However, after successfully inserting the plasmid, the cell line failed to proliferate. Ultimately, a 73% CD 133 phenotypic knockdown was achieved using RNAi technology from Santa Cruz, with 50% CD133 re-expression within 5 days, confirmation by both PCR and flow cytometry. Knockdown of CD 133 in Caco-2 cells. resulted in no change in proliferation or adhesive properties to plastic, however a slight increase in cell cycle activity was observed. Gene profiling of CD 133 knocked down Caco-2 and control cells was carried out using microarray technology. This was also applied to cells incubated with monoclonal antibodies against epitopes of CD133, as these are often used as a means of cell isolation for CD133 functional studies. A variety of genes were up and down regulated in both groups when compared to the control cells. CD 133 knockdown caused an up-regulation of genes associated with cell migration, motility, cell cycle, Wnt and tyrosine kinase pathway inhibitors and lipid transport across the membrane and down-regulated cell adhesion genes and apoptotic related genes. Caco-2 cells incubated with monoclonal antibodies against CD 133 showed up regulation in genes associated with cell cycle, migration and DNA replication and down regulation of genes associated with regulation of cell proliferation and apoptosis. This result is significant due to the extensive use ofCD133 antibodies in functional CD133 and CD133+ cell population studies. Confocal studies showed partial co-localisation between the lipid rafts and CD133, removal of the lipid rafts using the drug Beta Methyl Cyclodextrine caused loss of CD 133. However, lipid raft expression remained relatively constant on CD133 knockdown cells. Examining the distribution of CD 133 on Caco-2 cells adhered to fibronectin compared to glass via confocal analysis, showed there is no direct involvement of CD133 with anchorage type cell adhesion. However, considering the confocal analysis showing the association of CD 133 within lipid rafts and the results of microarray, this would imply a more indirect role of CD 133 within the processes of cell adhesion. This study has revealed that that CD133 plays a suppressive role in stem cell biology and play a regulatory role in maintaining quiescence, keeping the early stem and progenitor cells in a non proliferating, non motile state. A number of studies in recent years have attempted to determine the function of CD133 which still remains relatively elusive. However, this study has contributed to a greater understanding of CD133 function and identified key areas for further investigation.

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Bandopadhyay, Gogori. "Funtional analysis of the role of CD133 in high grade glioma progression." Thesis, University of Nottingham, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.537635.

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Donovan, Laura K. "CD133, the holy grail of neuro-oncology, or a promiscuous red herring?" Thesis, University of Portsmouth, 2010. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.516153.

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Every organ in the adult mammalian body harbours a rare population of stem cells. Most tumours arise from the transformation of a single stem cell into a cancer stem cell that has the innate capacity to perpetuate through self-renewal, and to generate mature neoplastic cells of a particular tissue through differentiation in vivo. C0133, a 120kOa transmembrane spanning glycoprotein, was the first in a class of novel pentaspan membrane proteins to be identified in both humans and mice, and was originally characterised as a possible marker of cancer stem cells in the haematopoietic system. Since its first discovery, C0133, independently or in combination with other stem cells markers, has been identified in a variety of human tumours including prostate tumours, breast cancers, colon carcinomas, lung cancers, and brain tumours. However, the belief that C0133 may act as a universal marker of cancer stem cells has been met with a high degree of controversy in the neuro-oncology research community as the precise biological role of C0133 has yet to be established. In vivo, glioblastoma multiforme contains poorly vascularised areas associated with decreasing oxygen tension (hypoxia), recently correlated with poor patient prognosis. In this study, a direct link between decreasing oxygen tension and C0133 expression was established. Furthermore, the in vitro hypoxic micro-environment appeared to facilitate a role in the biological behaviour of the glioma, as well as upregulating the CD133 phenotype. Distinct biological differences were also obvious between the CD133+ve and CD133"ve cell fractions; the CD133 protein appeared to not facilitate a role in cellular adhesion; the C0133"ve cell fraction displayed an increased invasive propensity in comparison to the C0133+ve cells; the II CD133+ve cells did not evoke cellular invasion, instead this cell fraction may be inversely linked to this biological process. Whether the CD133 protein precisely defines cancer stem cells within neoplastic glia remains to be clarified. However, this study has made significant progress towards identifying the functional role of CD133.

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Ott, Sabrina [Verfasser], and Olivier [Akademischer Betreuer] Gires. "Untersuchungen zur Genregulation durch den Tumormarker CD133 / Sabrina Ott ; Betreuer: Olivier Gires." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2017. http://d-nb.info/1127527894/34.

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Luna, Ealber Carvalho Macedo. "ExpressÃo imuno-histoquÃmica de cd133 em displasias epiteliais orais e carcinomas epidermoides orais." Universidade Federal do CearÃ, 2015. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=14830.

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FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico
IntroduÃÃo: CÃlulas-tronco cancerÃgenas constituem uma subpopulaÃÃo de cÃlulas neoplÃsicas que apresentam propriedades fenotÃpicas de diferenciaÃÃo, renovaÃÃo celular e proliferaÃÃo semelhantes Ãs cÃlulas-tronco normais, sendo responsÃveis pela manutenÃÃo tumoral. Objetivo: investigar a imunoexpressÃo de CD133, marcador de cÃlulas-tronco cancerÃgenas, em displasias epiteliais orais e em carcinomas epidermoides orais. Material e MÃtodo: a amostra se constituiu de 15 casos de CEO e 15 casos de DEO, sendo realizada a imuno-histoquÃmica pela tÃcnica da estreptoavidina-biotina, utilizando o anticorpo anti-CD133 (GTX60471, GeneTexÂ, San Antonio, TX, USA), com diluiÃÃo de 1:650 e recuperaÃÃo antigÃnica com citrato PH 6. A anÃlise quantitativa foi realizada por meio da contagem percentual de cÃlulas com imunomarcaÃÃo positiva em cinco campos, no aumento de 400X, utilizando o programa Image J. Os resultados foram obtidos e comparados entre grupos por meio dos testes t de Student e ANOVA multifatorial seguido do pÃs-teste de Bonferroni, tomando como base os nÃveis de significÃncia de 5%. Resultados: a avaliaÃÃo imuno-histoquÃmica evidenciou marcaÃÃo positiva em todos os casos da amostra (100% dos casos). No grupo de DEO, observou-se que 77,6Â16.0 das cÃlulas epiteliais exibiam imunoexpressÃo positiva para CD133 e, no grupo de CEO, verificou-se que 82.6Â7.2 das cÃlulas epiteliais exibiam imunoexpressÃo positiva para CD133; contudo, nÃo houve diferenÃa estatisticamente significativa entre os grupos estudados (p=0.283). Ademais, observou-se que, com relaÃÃo a sexo, localizaÃÃo anatÃmica e grau de displasia, a marcaÃÃo positiva ocorreu da seguinte forma: sexo masculino (DEO: 76.4Â10.9 e CEO: 82.9Â6.3) (p=0.526) e feminino (DEO: 78.0Â17.9 e CEO: 82.1Â8.9) (p=0.588); lÃngua (DEO: 69.6Â23.2 e CEO: 83.5Â9.3) (p=0.217), mucosa jugal (DEO: 84.8Â14.7 e CEO: 79.0Â5.7) (p=0.618) e palato (DEO: 74.5Â6.7 e CEO: 86.8Â10.3); DEO leve (78.0Â18.4), DEO moderada (72.7Â11.4) e DEO severa (80.1Â1.8) (p=0.899). Todavia, nÃo houve diferenÃa estatisticamente significativa entre os grupos estudados. ConclusÃo: sugere-se que a presenÃa dessa subpopulaÃÃo celular pode nÃo ser imprescindÃvel para a determinaÃÃo do fenÃtipo maligno

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Luna, Ealber Carvalho Macedo. "Expressão imuno-histoquímica de cd133 em displasias epiteliais orais e carcinomas epidermoides orais." reponame:Repositório Institucional da UFC, 2015. http://www.repositorio.ufc.br/handle/riufc/13654.

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LUNA, Ealber Carvalho Macedo. Expressão imuno-histoquímica de cd133 em displasias epiteliais orais e carcinomas epidermoides orais. 2015. 61 f. Dissertação (Mestrado em Odontologia) - Faculdade de Farmácia, Odontologia e Enfermagem, Universidade Federal do Ceará, Fortaleza, 2015.
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C ancer stem cells are a subpopulation of neoplastic cells, which have properties phenotypic differentiation, cell renewal and proliferation similar to normal stem cells are r esponsible for tumor support. Objective: To investigate the immunoreactivity of CD133, a marker of cancer stem cells in oral epithelial dysplasia and oral squamous cell carcinoma . Methods: 15 cases were selected as CEO and 15 cases of DEO, being held by immunohistochemistry by the streptavidin - biotin technique, usi ng anti - CD133 antibody (GTX60471, GeneTex®, San Antonio, TX, USA) with dilution of 1: 650 and antigen retrieval with citrate pH 6. the quantitative analysis was performed using the percentage of cells with positive immunostaining count in 5 fields at 4 00X magnification using the Imag e program J. the results were obtained and compared between groups through the Student t test and ANOVA followed by Bonferroni multifactorial post - test, based on the levels of significance of 5%. Results : Immunohistochemical eva luation showed positive staining in all cases the sample (100% of cases). In DEO group, it was observed that 77.6 ± 16.0 epithelial cells exhibited positive immunostaining for CD133 and CEO group was found that 82.6 ± 7.2 epithelial cells exhibited positiv e immunostaining for CD133; however, there was no statistically significant difference between groups (p = 0.283). Moreover, it was observed that, with respect to gender, anatomical location and degree of dysplasia, the positive staining was as follows: ma le (DEO: 76.4 ± 10.9 and CEO: 82.9 ± 6.3) (p = 0.526) and female ( DEO: 78.0 ± 17.9 and CEO: 82.1 ± 8.9) (p = 0588); tongue (DEO: 69.6 ± 23.2 and CEO: 83.5 ± 9.3) (p = 0.217), buccal mucosa (DEO: 84.8 ± 14.7 and CEO: 79.0 ± 5.7) (p = 0.618) and palate (DEO : 74.5 ± 6 .7 and CEO : 86.8 ± 10.3); mild DEO (78.0 ± 18.4), moderate DEO (72.7 ± 11.4) and DEO severe (80.1 ± 1.8) (p = 0899). However, there was no statistically significant difference between groups . Conclusion it is suggested that the presence of this cell subpopulation may not be essential for determining the malignant phenotype .
Células-tronco cancerígenas constituem uma subpopulação de células neoplásicas que apresentam propriedades fenotípicas de diferenciação, renovação celular e proliferação semelhantes às células-tronco normais, sendo responsáveis pela manutenção tumoral. Objetivo: investigar a imunoexpressão de CD133, marcador de células-tronco cancerígenas, em displasias epiteliais orais e em carcinomas epidermoides orais. Material e Método: a amostra se constituiu de 15 casos de CEO e 15 casos de DEO, sendo realizada a imuno-histoquímica pela técnica da estreptoavidina-biotina, utilizando o anticorpo anti-CD133 (GTX60471, GeneTex®, San Antonio, TX, USA), com diluição de 1:650 e recuperação antigênica com citrato PH 6. A análise quantitativa foi realizada por meio da contagem percentual de células com imunomarcação positiva em cinco campos, no aumento de 400X, utilizando o programa Image J. Os resultados foram obtidos e comparados entre grupos por meio dos testes t de Student e ANOVA multifatorial seguido do pós-teste de Bonferroni, tomando como base os níveis de significância de 5%. Resultados: a avaliação imuno-histoquímica evidenciou marcação positiva em todos os casos da amostra (100% dos casos). No grupo de DEO, observou-se que 77,6±16.0 das células epiteliais exibiam imunoexpressão positiva para CD133 e, no grupo de CEO, verificou-se que 82.6±7.2 das células epiteliais exibiam imunoexpressão positiva para CD133; contudo, não houve diferença estatisticamente significativa entre os grupos estudados (p=0.283). Ademais, observou-se que, com relação a sexo, localização anatômica e grau de displasia, a marcação positiva ocorreu da seguinte forma: sexo masculino (DEO: 76.4±10.9 e CEO: 82.9±6.3) (p=0.526) e feminino (DEO: 78.0±17.9 e CEO: 82.1±8.9) (p=0.588); língua (DEO: 69.6±23.2 e CEO: 83.5±9.3) (p=0.217), mucosa jugal (DEO: 84.8±14.7 e CEO: 79.0±5.7) (p=0.618) e palato (DEO: 74.5±6.7 e CEO: 86.8±10.3); DEO leve (78.0±18.4), DEO moderada (72.7±11.4) e DEO severa (80.1±1.8) (p=0.899). Todavia, não houve diferença estatisticamente significativa entre os grupos estudados. Conclusão: sugere-se que a presença dessa subpopulação celular pode não ser imprescindível para a determinação do fenótipo maligno

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Wang, Wenxia, Zhenbo Zhang, Yin Zhao, Zeng Yuan, Xingsheng Yang, Beihua Kong, and Wenxin Zheng. "Enrichment and characterization of ovarian cancer stem cells and its potential clinical application." E-CENTURY PUBLISHING CORP, 2017. http://hdl.handle.net/10150/622725.

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The cancer stem cell (CSC) theory proposes that a minor population in tumor cells with specific features, such as self-renewal and reproducible tumor phenotype could contribute to tumor relapse and chemotherapy resistance. Several studies have convincingly documented the existence of ovarian CSC, but questions related to the biologic behavior and specific biomarkers of ovarian CSC remain to be clarified. In the present study, we firstly established a tumor cell line with capability of regenerating tumors through serial transplantation of ovarian tumor tissue in non-obese/severe combined immunodeficient (SCID) mice. After separation of CD133+ cells with magnetic beads, we compared the phenotype and biologic behavior of CD133+ versus CD133-cells. It was found that the CD133+ cells were much more potent to produce colonies in semi-solid agar culture than CD133-cells. The proportion of the cells in G0/1 cell cycle is much higher in CD133+ cells than in CD133-cells. Furthermore, in vivo experiments demonstrated that the CD133+ cells were capable of repeatedly regenerate tumors in NOD/SCID mice, while the CD133-cells were not. Compared with CD133-cells, the CD133+ cells expressed much higher levels of the stem cell markers Oct4, Sox2, Nanog and Mcl-1. Clinically, among a total of 290 ovarian epithelial cancers, increased level of CD133 expression was positively correlated with a high cancer stage and had a worse 5-year survival rate. Taken together, the results suggest that the CD133+ cells from human ovarian cancer have the characteristics of CSC, which may contribute to ovarian cancer relapse and anti-apoptotic activity. The method of ovarian CSC enrichment we established provides a feasible and practical way of ovarian cancer research in a molecular level. In addition, CD133 may be used as a prognostic marker for ovarian epithelial cancer, which may have a role for future therapeutic effect.

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Bauer, Nicola, Ana-Violeta Fonseca, Mareike Florek, Daniel Freund, József Jászai, Martin Bornhäuser, Christine A. Fargeas, and Denis Corbeil. "New Insights into the Cell Biology of Hematopoietic Progenitors by Studying Prominin-1 (CD133)." Saechsische Landesbibliothek- Staats- und Universitaetsbibliothek Dresden, 2014. http://nbn-resolving.de/urn:nbn:de:bsz:14-qucosa-136136.

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Prominin-1 (alias CD133) has received considerable interest because of its expression by several stem and progenitor cells originating from various sources, including the neural and hematopoietic systems. As a cell surface marker, prominin-1 is now used for somatic stem cell isolation. Its expression in cancer stem cells has broadened its clinical value, as it might be useful to outline new prospects for more effective cancer therapies by targeting tumor-initiating cells. Cell biological studies of this molecule have demonstrated that it is specifically concentrated in various membrane structures that protrude from the planar areas of the plasmalemma. Prominin-1 binds to the plasma membrane cholesterol and is associated with a particular membrane microdomain in a cholesterol-dependent manner. Although its physiological function is not yet determined, it is becoming clear that this cell surface protein, as a unique marker of both plasma membrane protrusions and membrane microdomains, might reveal new aspects of the cell biology of rare stem and cancer stem cells. The aim of this review is to outline the recent discoveries regarding the dynamic reorganization of the plasma membrane of rare CD133+ hematopoietic progenitor cells during cell migration and division
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14

Bauer, Nicola, Ana-Violeta Fonseca, Mareike Florek, Daniel Freund, József Jászai, Martin Bornhäuser, Christine A. Fargeas, and Denis Corbeil. "New Insights into the Cell Biology of Hematopoietic Progenitors by Studying Prominin-1 (CD133)." Karger, 2008. https://tud.qucosa.de/id/qucosa%3A27699.

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Abstract:

Prominin-1 (alias CD133) has received considerable interest because of its expression by several stem and progenitor cells originating from various sources, including the neural and hematopoietic systems. As a cell surface marker, prominin-1 is now used for somatic stem cell isolation. Its expression in cancer stem cells has broadened its clinical value, as it might be useful to outline new prospects for more effective cancer therapies by targeting tumor-initiating cells. Cell biological studies of this molecule have demonstrated that it is specifically concentrated in various membrane structures that protrude from the planar areas of the plasmalemma. Prominin-1 binds to the plasma membrane cholesterol and is associated with a particular membrane microdomain in a cholesterol-dependent manner. Although its physiological function is not yet determined, it is becoming clear that this cell surface protein, as a unique marker of both plasma membrane protrusions and membrane microdomains, might reveal new aspects of the cell biology of rare stem and cancer stem cells. The aim of this review is to outline the recent discoveries regarding the dynamic reorganization of the plasma membrane of rare CD133+ hematopoietic progenitor cells during cell migration and division.
Dieser Beitrag ist mit Zustimmung des Rechteinhabers aufgrund einer (DFG-geförderten) Allianz- bzw. Nationallizenz frei zugänglich.

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15

Pozzobon, Michela. "Isolation, expansion and differentiation of human bone marrow CD133+ cells: plasticity and cardiac regeneration." Doctoral thesis, Università degli studi di Padova, 2008. http://hdl.handle.net/11577/3425024.

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The use of adult stem cells to regenerate damaged tissue circumvents the moral and technical issues associated with the use of those from an embryonic source. Mesenchymal stem cells (MSC) can be isolated from a variety of tissues, most commonly from the bone marrow (BM), and, although they represent a very small percentage of these cells, are easily expandable. Recently, the use of MSC has provided clinical benefit to patients with osteogenesis imperfecta, graft-versushost disease and myocardial infarction. Beside these stem cells, it is known that the bone marrow CD133+ cells play an important role in the hematopoietic compartment. The cells indeed can take part to vascular reconstitution when become endothelial cells (EC), to skeletal muscle fiber regeneration when switch in muscle precursors, and to cardiomyocytes phenotypic conversion when differentiate in cardiomyocytes like cells. While the role on hematopoiesis and vasculogenesis of the selected cells is well established, their ability to differentiate along multiple non-EC lineages has not yet been fully elucidated. The goal of this study is to assert whether human CD133+-BM derived cells, compared with MSCs, are able to differentiate in vitro besides to blood cells, to cell lineages pertinent to the mesoderm germ layers. To this end CD133+ cells have been isolated using a clinically approved methodology and their differentiation potential compared to that of hematopoietic stem cells (HSCs) and mesenchymal stem cells (MSCs) obtained from the same BM samples. In adopted culture conditions, CD133 expression was consistently decreased after passage 2, as well as the expression of the stemnesss markers c-kit and OCT4, whereas expression of Stage Specific Embryonic Antigen 4 (SSEA4) remain consistent on all different conditions. Expanded CD133 were also positive for HLA-ABC, but negative for HLA-DR in accordance to what has been previously reported for MSCs. Moreover they were able to differentiate into adipocytes, myoblasts, endothelial cells, osteocytes, cardiomyocytes and neuronal precursor cells. The results of this study fully support the notion of a wide range differentiation potential of CD133+-BM derived cells, encompassing not only mesodermal but also ectodermic (neurogenic) cell lineages. CD133 antigen could be potentially used to select a cell population with similar characteristics to the MSCs ones; the obtained results remark the great potential of CD133+ cells from BM, and support the existence of a broadly multipotent/pluripotent cell that persists in the adult, and justify the upcoming interest for possible therapeutic applications. In vivo, using a tissue engineering approach, it has been investigated the possibility that a biodegradable and biocompatible collagen polymer, called cardiac patch, applied on the infarction area of nude rat, can give hospitality to stem cells and deliver them to improve cardiac functionality. Cells have been injected into the patch ( model I) and systemically (model II); smooth muscle actina and Von Willebrand antibodies detected many new vases in patch and cryoinjury area (as already found by the research group); about 2% of cells survived and showed good mobility into the collagen patch; improved functionality was detected compared with control animals however no cell engraftment was seen after four week from cell injection either locally or systemically. Summarizing, the two different in vivo models aimed at define both the patch strength after cell injection in model I and the patch trophic effect in model II. Therefore to address these points it will be mandatory to analyze bcl-2 expression on cells treated and un-treated animals, with and without patch, to verify whether the tissue engineering approach with this specific polymer, could enhance the paracrine effect of human CD133+, or suggest a change of the polymer to ameliorate cell survival.

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16

Alves, MarkÃnia KÃlia Santos. "Identifying of molecular alterations associated to expression of CD133, CXCR4, CD44 and OLIG2 and CDKN2A methylation in promoter in astrocytic tumors." Universidade Federal do CearÃ, 2014. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=14421.

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FundaÃÃo Cearense de Apoio ao Desenvolvimento Cientifico e TecnolÃgico
Conselho Nacional de Desenvolvimento CientÃfico e TecnolÃgico
Tumores sÃo populaÃÃes celulares heterogÃneas hierarquicamente organizadas, cujas cÃlulas-tronco possuem importÃncia relevante desde que sÃo cÃlulas com a capacidade de se renovarem e de gerarem linhagens em fases diferentes. Dada a sua importÃncia, a identificaÃÃo de componentes de cÃlulas-tronco Ã essencial para o entendimento da tumorigÃnese. Apesar de marcadores de linhagem neural terem sido identificados, a associaÃÃo destes marcadores com os tumores cerebrais ainda Ã escassa e nos astrocitomas sÃo relacionados principalmente aos glioblastomas. Entre esses marcadores de cÃlulas-tronco,CD133, CXCR4 e CD44 sÃo relacionados Ã formaÃÃo do glioma, migraÃÃo e crescimento; por outro lado, OLIG2 Ã envolvido no destino celular. NÃo existem estudos, atÃ essa data, que avaliam todos esses marcadores juntos e sua relaÃÃo com grau tumoral. Adicionalmente, alteraÃÃes epigenÃticas especÃficas, especialmente a metilaÃÃo em promotor, tem sido identificadas nestes tumores, levando a inativaÃÃo de genes, com destaque o CDKN2A (proteÃna p16INK4A), um supressor tumoral. Apesar de esse mecanismo ser apontado como o principal inativador desse gene, em astrocitomas ainda existem questÃes controversas. Para avaliar essas questÃes, este estudo objetivou determinar a expressÃo e padrÃo de metilaÃÃo em promotor de CDKN2A e sua associaÃÃo com parÃmetros clinico-patolÃgicos e se a presenÃa de cÃlulas-tronco/progenitoras, considerando a expressÃo de CD133, CXCR4, CD44 e OLIG2 poderia definir subpopulaÃÃes de cÃlulas que podem ser usadas como marcadores prognÃsticos. Para isso, em uma sÃrie de 93 astrocitomas de diferentes graus de malignidade, foram estudadas a expressÃo dos marcadores CD133, CXCR4, CD44, OLIG2 e p16INK4A, detectada pela tÃcnica de imunohistoquÃmica, e o padrÃo de metilaÃÃo em promotor de CDKN2A, por PCR especÃfico para metilaÃÃo (PCR-MS). Os dados foram entÃo associados com grau tumoral, localizaÃÃo e outros parÃmetros clinico-patolÃgicos. As anÃlises estatÃsticas foram realizadas usando o teste do X2, teste exato de Fisher, correlaÃÃo de Spearman, agrupamento de k-means e anÃlise de componentes principais, com diferenÃas consideradas significantes com p<0.05. A imunomarcaÃÃo de OLIG2 mostrou a frequÃncia maior de positividade (73,1%), seguido por CXCR4 (60,2%), CD44 (55,9%) e CD133 (45,2%). AnÃlises de correlaÃÃo e agrupamento definiram dois subtipos de populaÃÃo de acordo com os marcadores estudados, um subtipo CXCR4(+)CD133(+)CD44(+) e outro OLIG2(+). Tumores CD133, CXCR4 e CD44 positivos aumentaram de acordo com malignidade. No grau IV, este subtipo de tumores [CD133(+)CXCR4(+)CD44(+)] foi significantemente mais frequente (p=0,008) e tambÃm nos tumores difusos. Adicionalmente, tumores com CXCR4(+) e CD133(+) foram preferencialmente localizados nos hemisfÃrios cerebrais e nos ventrÃculos, e a maioria nos pacientes com idade ≥ 30 anos. Por outro lado, tumores OLIG2(+) foram associados com o cerebelo, que Ã a localizaÃÃo preferencial do astrocitoma pilocÃtico. Uma forte correlaÃÃo negativa entre imunomarcaÃÃo nuclear e citoplasmÃtica e metilaÃÃo em promotor de CDKN2A foi encontrada. AlÃm do mais, uma correlaÃÃo negativa significante entre metilaÃÃo em promotor de CDKN2A e idade foi observada e pacientes do sexo feminino tiveram uma maior frequÃncia significante de CDKN2A metilado em promotor que o sexo masculino. Em conclusÃo, a presenÃa de subpopulaÃÃes de cÃlulas-tronco em astrocitomas Ã indicativa de progressÃo tumoral, cujos marcadores CXCR4, CD133 e CD44 podem ser potencialmente usados em conjunto como marcadores prognÃsticos. A associaÃÃo com localizaÃÃo do tumor e idade tambÃm corroboram esses achados. Adicionalmente, a inativaÃÃo de CDKN2A por metilaÃÃo em promotor Ã um evento frequente em astrocitomas e Ã relacionada Ã idade e sexo dos pacientes.
Currently, the concept that tumors are cell populations organized in a hierarchically heterogenous way in which stem-cells are relevantly important as these cells have the capacity of self-renew and of generating cell lineages in different phases of differentiation. So that, the identification of stem-cell components is essential to tumorigenesis understanding. Althought neural cell lineage markers have been identified, the association among these markers and neurological tumors is still scarce, and taking in consideration the astrocytomas, the association assessements are verified mainly regarding the glioblastomas. Among these stem cell markers, CD133, CXCR4 and CD44 are related to the glioma formation, migration and growth; on the other hand, OLIG2 is involved in cell destination. So far there are no studies evaluating all these markers together and their relationship to tumor grades. Additionally, specific epigenetic alterations, specially promoter methylation, have been widelly identified in these tumors, leading to gene inativation, mostly involving CDKN2A (p16INK4A protein), a tumor suppressor. Althought this mechanism is pointed as this gene main inactivator, there are still controvertial questions regarding the astrocytomas. In order to evaluate these questions, the present study aimed to determine CDKN2A pattern of methylation and expression and their association to clinicalpathological parameters, and if the presence of progenitor/stem-cells, taking CD133, CXCR4, CD44 and OLIG2 expression in consideration, could define subpopulations of cells which might be used as prognostic markers. So, in a series of 93 astrocytomas of different malignity grades, the expression of CD133, CXCR4, CD44, OLIG2 and p16INK4A was analysed by the imunohistochemistry technique, and the CDKN2A methylation status was assessed by methylation specific PCR (MS-PCR). The data was then associated to tumor grades, localization and other clinicalpathological parameters. The statistic analyses were made using X 2 test, Fisher's exact test, Spearman's correlation, kmeans groupment and principal component analyses, using p<0.05 as statistically significance. The imunopositivity of OLIG2 was predominant (73.1%), followed by CXCR4 (60.2%), CD44 (55.9%) and CD133 (45.2%). The correlation and groupment analyses defined two different population subtypes, a CXCR4(+)CD133(+)CD44(+) subtype and a OLIG2(+) subtype. CXCR4(+)CD133(+)CD44(+) tumors became more frequent as malignity grew. In grade IV, this subtype was significantly more frequent (p=0.008), being also in diffuse tumors. Additionally, CXCR4(+) and CD133(+) tumors were preferentially located in brain hemisferes and in the ventricles, and mostly in aged >30 patients. On the other side, OLIG2(+) tumors were associated to the cerebellum, which is the pylocitic tumor preferential localization. A strong negative correlation between nuclear and cytoplasmatic imunopositivity and promoter methylation in CDKN2A was observed. Also, a negative significant correlation between methylated CDKN2A and patient's age was found; moreover, feminine patients presented a higher frequency of methylated CDKN2A. In conclusion, the presence of stemcell subpopulations in astrocytomas indicates tumoral progression, in which CXCR4, CD133 and CD44 may be potentially used together as prognostic markers. The association between tumor localization and patient's age also corroborates these findings. Additionally, the CDKN2A inactivation by promoter methylation is a frequent event in astrocytomas and it is associated to patient's age and gender

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17

Alves, Markênia Kélia Santos. "Identificação de alterações moleculares associadas à expressão de CD133, CXCR4, CD44 E OLIG2 e metilação em promotor de CDKN2A em tumores astrocíticos." reponame:Repositório Institucional da UFC, 2014. http://www.repositorio.ufc.br/handle/riufc/19790.

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ALVES, Markênia Kélia Santos. Identificação de alterações moleculares associadas à expressão de CD133, CXCR4, CD44 E OLIG2 e metilação em promotor de CDKN2A em tumores astrocíticos. 2014. 89 f. Tese (Doutorado em biotecnologia)- Universidade Federal do Ceará, Fortaleza-CE, 2014.
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Currently, the concept that tumors are cell populations organized in a hierarchically heterogenous way in which stem-cells are relevantly important as these cells have the capacity of self-renew and of generating cell lineages in different phases of differentiation. So that, the identification of stem-cell components is essential to tumorigenesis understanding. Althought neural cell lineage markers have been identified, the association among these markers and neurological tumors is still scarce, and taking in consideration the astrocytomas, the association assessements are verified mainly regarding the glioblastomas. Among these stem cell markers, CD133, CXCR4 and CD44 are related to the glioma formation, migration and growth; on the other hand, OLIG2 is involved in cell destination. So far there are no studies evaluating all these markers together and their relationship to tumor grades. Additionally, specific epigenetic alterations, specially promoter methylation, have been widelly identified in these tumors, leading to gene inativation, mostly involving CDKN2A (p16INK4A protein), a tumor suppressor. Althought this mechanism is pointed as this gene main inactivator, there are still controvertial questions regarding the astrocytomas. In order to evaluate these questions, the present study aimed to determine CDKN2A pattern of methylation and expression and their association to clinicalpathological parameters, and if the presence of progenitor/stem-cells, taking CD133, CXCR4, CD44 and OLIG2 expression in consideration, could define subpopulations of cells which might be used as prognostic markers. So, in a series of 93 astrocytomas of different malignity grades, the expression of CD133, CXCR4, CD44, OLIG2 and p16INK4A was analysed by the imunohistochemistry technique, and the CDKN2A methylation status was assessed by methylation specific PCR (MS-PCR). The data was then associated to tumor grades, localization and other clinicalpathological parameters. The statistic analyses were made using X 2 test, Fisher's exact test, Spearman's correlation, kmeans groupment and principal component analyses, using p<0.05 as statistically significance. The imunopositivity of OLIG2 was predominant (73.1%), followed by CXCR4 (60.2%), CD44 (55.9%) and CD133 (45.2%). The correlation and groupment analyses defined two different population subtypes, a CXCR4(+)CD133(+)CD44(+) subtype and a OLIG2(+) subtype. CXCR4(+)CD133(+)CD44(+) tumors became more frequent as malignity grew. In grade IV, this subtype was significantly more frequent (p=0.008), being also in diffuse tumors. Additionally, CXCR4(+) and CD133(+) tumors were preferentially located in brain hemisferes and in the ventricles, and mostly in aged >30 patients. On the other side, OLIG2(+) tumors were associated to the cerebellum, which is the pylocitic tumor preferential localization. A strong negative correlation between nuclear and cytoplasmatic imunopositivity and promoter methylation in CDKN2A was observed. Also, a negative significant correlation between methylated CDKN2A and patient's age was found; moreover, feminine patients presented a higher frequency of methylated CDKN2A. In conclusion, the presence of stemcell subpopulations in astrocytomas indicates tumoral progression, in which CXCR4, CD133 and CD44 may be potentially used together as prognostic markers. The association between tumor localization and patient's age also corroborates these findings. Additionally, the CDKN2A inactivation by promoter methylation is a frequent event in astrocytomas and it is associated to patient's age and gender.
Tumores são populações celulares heterogêneas hierarquicamente organizadas, cujas células-tronco possuem importância relevante desde que são células com a capacidade de se renovarem e de gerarem linhagens em fases diferentes. Dada a sua importância, a identificação de componentes de células-tronco é essencial para o entendimento da tumorigênese. Apesar de marcadores de linhagem neural terem sido identificados, a associação destes marcadores com os tumores cerebrais ainda é escassa e nos astrocitomas são relacionados principalmente aos glioblastomas. Entre esses marcadores de células-tronco,CD133, CXCR4 e CD44 são relacionados à formação do glioma, migração e crescimento; por outro lado, OLIG2 é envolvido no destino celular. Não existem estudos, até essa data, que avaliam todos esses marcadores juntos e sua relação com grau tumoral. Adicionalmente, alterações epigenéticas específicas, especialmente a metilação em promotor, tem sido identificadas nestes tumores, levando a inativação de genes, com destaque o CDKN2A (proteína p16INK4A), um supressor tumoral. Apesar de esse mecanismo ser apontado como o principal inativador desse gene, em astrocitomas ainda existem questões controversas. Para avaliar essas questões, este estudo objetivou determinar a expressão e padrão de metilação em promotor de CDKN2A e sua associação com parâmetros clinico-patológicos e se a presença de células-tronco/progenitoras, considerando a expressão de CD133, CXCR4, CD44 e OLIG2 poderia definir subpopulações de células que podem ser usadas como marcadores prognósticos. Para isso, em uma série de 93 astrocitomas de diferentes graus de malignidade, foram estudadas a expressão dos marcadores CD133, CXCR4, CD44, OLIG2 e p16INK4A, detectada pela técnica de imunohistoquímica, e o padrão de metilação em promotor de CDKN2A, por PCR específico para metilação (PCR-MS). Os dados foram então associados com grau tumoral, localização e outros parâmetros clinico-patológicos. As análises estatísticas foram realizadas usando o teste do X2, teste exato de Fisher, correlação de Spearman, agrupamento de k-means e análise de componentes principais, com diferenças consideradas significantes com p<0.05. A imunomarcação de OLIG2 mostrou a frequência maior de positividade (73,1%), seguido por CXCR4 (60,2%), CD44 (55,9%) e CD133 (45,2%). Análises de correlação e agrupamento definiram dois subtipos de população de acordo com os marcadores estudados, um subtipo CXCR4(+)CD133(+)CD44(+) e outro OLIG2(+). Tumores CD133, CXCR4 e CD44 positivos aumentaram de acordo com malignidade. No grau IV, este subtipo de tumores [CD133(+)CXCR4(+)CD44(+)] foi significantemente mais frequente (p=0,008) e também nos tumores difusos. Adicionalmente, tumores com CXCR4(+) e CD133(+) foram preferencialmente localizados nos hemisférios cerebrais e nos ventrículos, e a maioria nos pacientes com idade ≥ 30 anos. Por outro lado, tumores OLIG2(+) foram associados com o cerebelo, que é a localização preferencial do astrocitoma pilocítico. Uma forte correlação negativa entre imunomarcação nuclear e citoplasmática e metilação em promotor de CDKN2A foi encontrada. Além do mais, uma correlação negativa significante entre metilação em promotor de CDKN2A e idade foi observada e pacientes do sexo feminino tiveram uma maior frequência significante de CDKN2A metilado em promotor que o sexo masculino. Em conclusão, a presença de subpopulações de células-tronco em astrocitomas é indicativa de progressão tumoral, cujos marcadores CXCR4, CD133 e CD44 podem ser potencialmente usados em conjunto como marcadores prognósticos. A associação com localização do tumor e idade também corroboram esses achados. Adicionalmente, a inativação de CDKN2A por metilação em promotor é um evento frequente em astrocitomas e é relacionada à idade e sexo dos pacientes.

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Tang, Kwan-ho, and 鄧鈞豪. "Significance of IL-8 signaling in CD133 mediated tumor initiation and progression of hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2011. http://hub.hku.hk/bib/B47849782.

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A novel theory in the field of tumor biology postulates that cancer growth is driven by a population of stem-like cells, called tumor-initiating cells (TICs). These TICs are believed to display unique survival mechanisms, and account for failure in therapeutic treatments. It is also believed that, effective treatments against the diseases can only be developed through targeting and eliminating these TICs. We previously identified TIC populations derived from hepatocellular carcinoma (HCC) that are characterized by membrane expression of CD133. As findings from our previous studies were mostly based on HCC cell lines, here, we first identified rare CD133+ subpopulations in freshly resected HCC specimens, but not their non-tumor counterparts. We also found increased CD133 expression to be associated with advanced disease stages, increased recurrence rate and poorer overall survival in HCC patients. Next, we describe a novel mechanism by which these cells mediate tumor growth and angiogenesis by systematic comparison of the gene expression profiles between sorted CD133 liver subpopulations through genome-wide microarray analysis. A significantly dysregulated interleukin-8 (IL-8) signaling network was identified in CD133+ liver TICs isolated from HCC clinical samples and cell lines. IL-8 was found to be overexpressed at both the genomic and proteomic levels in CD133+ cells isolated from HCC cell lines or clinical samples. Functional studies found enhanced IL-8 secretion in CD133+ liver TICs to exhibit a greater ability to self-renew, induce tumor angiogenesis and initiate tumors. In further support of these observations, IL-8 repression in CD133+ liver TICs by knockdown or neutralizing antibody abolished these effects. Subsequent studies of the IL-8 functional network identified neurotensin (NTS) and CXCL1 to be also preferentially expressed in CD133+ liver TICs. Exogenous NTS treatment resulted in concomitant up-regulation of IL-8 and CXCL1 with simultaneous activation of p-ERK1/2 and RAF-1, key components of the MAPK signaling pathway. Enhanced IL-8 secretion by CD133+ TICs can in turn activate an IL-8 positive feedback loop through MAPK signaling. Subsequent studies from CD133 sorted cells found only CD133+ TICs, but not CD133- cells were able to response to exogenous NTS / IL-8 stimulations with concomitant up-regulation of CD133, suggested that the preferential expression of NTS / IL-8 signaling cascade was also important in CD133+ TICs self-renewal and maintenance. Further to its role as a liver TIC marker, CD133 also plays functional roles in conferring TICs properties via regulating NTS / IL-8 / CXCL1 / MAPK signaling. These results suggested that CD133+ liver TICs promote angiogenesis, tumorigenesis and selfrenewal through NTS-induced activation of the IL-8 signaling cascade. In conclusion, our findings had identified rare expressions of CD133 in clinical HCC specimens and hence its prognostic values. We also show for the first time the functional roles of CD133 in conferring tumorigenic potential to liver TICs. The characterization of underlying molecular signaling in CD133+ liver TICs in this study should provide not only a better understanding of the mechanisms regulating this specific population of cells but also novel insights that could allow the development of more effective therapeutic treatments of this disease.
published_or_final_version
Pathology
Doctoral
Doctor of Philosophy

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19

Neuwinger, Annette Christiane [Verfasser], and Marc [Akademischer Betreuer] Dahlke. "CD133-positive Tumorstammzellen der Kolonkarzinomlinie CT26 in einem Mausmodell / Annette Christiane Neuwinger. Betreuer: Marc Dahlke." Regensburg : Universitätsbibliothek Regensburg, 2012. http://d-nb.info/1028392567/34.

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Lechner, Axel [Verfasser], and Olivier [Akademischer Betreuer] Gires. "Die Rolle des Tumorstammzellmarkers CD133 in der Initiierung von Tumoren / Axel Lechner. Betreuer: Olivier Gires." München : Universitätsbibliothek der Ludwig-Maximilians-Universität, 2014. http://d-nb.info/1058077236/34.

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Schadel, Dina [Verfasser]. "Comparative studies of recombinant oncolytic viruses for the treatment of CD133-positive tumors / Dina Schadel." Gießen : Universitätsbibliothek, 2020. http://d-nb.info/1216142580/34.

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Loges, Sonja. "Selektion, Ex-vivo-Expansion und Analyse der Differenzierungskapazität humaner CD133-positiver Stammzellen aus dem peripheren Blut." [S.l.] : [s.n.], 2004. http://deposit.ddb.de/cgi-bin/dokserv?idn=972134018.

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Kuta, Piotr [Verfasser]. "In-vitro Charakterisierung des endothelialen Differenzierungspotentials von CD133-positiven Zellen aus Stammzellapheresat und Knochenmark / Piotr Kuta." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2014. http://d-nb.info/1048411044/34.

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Feitosa, Neli Patricia Pereira. "ImunoexpressÃo dos Marcadores de CÃlulas-tronco CD44 e CD133 no CÃncer GÃstrico PrimÃrio e MetÃstases Linfonodais." Universidade Federal do CearÃ, 2015. http://www.teses.ufc.br/tde_busca/arquivo.php?codArquivo=16499.

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CoordenaÃÃo de AperfeiÃoamento de Pessoal de NÃvel Superior
O cÃncer gÃstrico Ã a quarta neoplasia mais comum em todo o mundo, representando a segunda causa de mortalidade por cÃncer. Apesar do tratamento com cirurgia e quimioterapia, a sobrevida global em cinco anos de pacientes com cÃncer gÃstrico permanece baixa. Uma possÃvel explicaÃÃo para ineficÃcia da terapia Ã a presenÃa de cÃlulas-tronco cancerosas, uma subpopulaÃÃo de cÃlulas tumorais que apresentam caracterÃsticas de cÃlulas-tronco. Estas cÃlulas, assim como as cÃlulas tronco embrionÃrias, sÃo consideradas imortais, podem se auto-renovar e se transformar em qualquer cÃlula do corpo. VÃrios marcadores, incluindo CD44 e CD133, tÃm sido relatados como marcadores de cÃlulas-tronco, normais e cancerosas, e utilizados para isolar cÃlulas cancerosas de tumores sÃlidos. O objetivo desse trabalho foi avaliar a expressÃo de CD44 e de CD133, no cÃncer gÃstrico primÃrio e metÃstases linfonodais, atravÃs de imunohistoquÃmica, e relacionÃ-la com as variÃveis clÃnico-patolÃgicas de tipo histolÃgico, sexo, idade, localizaÃÃo anatÃmica, dimensÃo do tumor, invasÃo angiolinfÃtica, infiltraÃÃo perineural, classificaÃÃo TNM (TN) e acometimento linfonodal. Este estudo foi desenvolvido a partir de um conjunto de 72 casos de adenocarcinoma gÃstrico, dos Arquivos do ServiÃo de Patologia e Medicina Legal da Universidade Federal do CearÃ (DPML-UFC). Utilizou-se a tÃcnica de tissue microarray asociada Ã imunohistoquÃmica com anticorpo monoclonal anti-CD44 e policlonal anti-CD133. Foram considerados positivos os casos que apresentaram uma ou mais cÃlulas com imunomarcaÃÃo citoplasmÃtica e/ou membranar. Foi observado que 30% das amostras foram positivas para o CD44. NÃo foram encontradas diferenÃas estatisticamente significantes entre as variÃveis clÃnico-patolÃgicas estudadas e a imunoexpressÃo de CD44. A imunoexpressÃo do CD133 foi positiva em 24% das amostras. O grau de invasÃo do tumor apresentou dados com tendÃncia estatisticamente significante (p=0,0505), de forma inversa. Nas demais variÃveis, nÃo foi encontrada nenhuma diferenÃa estatisticamente significante. A imunoexpressÃo de CD133 na mucosa histologicamente normal foi maior do que no tumor primÃrio e na metaplasia intestinal, com diferenÃa estatÃstica significante (p=0,0159 e p=0,0058, respectivamente). A imunoexpressÃo de CD133 no adenocarcinoma gÃstrico tipo intestinal foi significativamente maior na mucosa histologicamente normal do que na metaplasia (p=0,0260). A frequÃncia da expressÃo desses marcadores Ã muito variÃvel, e mesmo nas amostras consideradas positivas, o percentual de cÃlulas coradas tambÃm Ã variÃvel, e em geral muito baixo.
Gastric cancer is the fourth most common cancer worldwide, accounting for the second leading cause of cancer mortality. Despite treatment with surgery and chemotherapy, the overall five-year survival of patients with gastric cancer remains low. One possible explanation for the ineffectiveness of therapy is the presence of cancer stem cells, a subpopulation of tumor cells that have stem cell characteristics. It has been reported that these, as well as embryonic stem cells, are immortal, can self-renew and to differentiate to be transformed in any cell type in the body. Several markers, including CD44 and CD133, have been reported as stem cell markers in both normal and cancerous cells and have been used to isolate cancer cells from solid tumors. The aim of this study was to evaluate the expression of CD44 and CD133 in primary gastric cancer and lymph node metastases by immunohistochemical and to relate it to clinicopathologic variables as histological type, gender, age, anatomical site, tumor size, angiolymphatic invasion, infiltration perineural, TNM classification (TN) and lymph node involvement. This study was developed from a set of 72 cases of gastric adenocarcinoma, from the Archives of Pathology and Forensic Medicine of the Federal University of CearÃ Service (DPML-UFC). Tissue microarray and immunohistochemistry were utilized, with anti-CD44 monoclonal antibody and polyclonal anti-CD133. The cases with one or more cells with cytoplasmic and / or membrane immunostaining were considered positives. It was observed that 30% of the samples were positive for CD44. No statistically significant differences were found between the clinical and pathological variables studied and the immunoreactivity of CD44. Regarding the immunoreactivity of CD133, the present study showed that 24% of samples were positive. The degree of tumor invasion presented data showing a statistically significant trend (p = 0.0505), in reverse. The other variables, we found no statistically significant difference. The immunoreactivity of CD133 in histologically normal mucosa was higher than in the primary tumor and intestinal metaplasia, with statistically significant difference (p = 0.0159 and p = 0.0058, respectively). The CD133 immunostaining in intestinal type gastric carcinoma was significantly higher than in the histologically normal mucosal metaplasia (p = 0.0260). The frequency of expression of these markers is highly variable, and even in the samples considered positive, the stained cells percentage is also variable, and very low overall.

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25

Santeramo, I. "Characterization of renal CD133+ cells and their therapeutic efficacy in a model of acute kidney injury." Thesis, University of Liverpool, 2016. http://livrepository.liverpool.ac.uk/3003477/.

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Renal ‘progenitor’ cells expressing CD133 have been proposed as cellular therapeutics for treating patients with kidney disease. In the literature, CD133+ cells isolated from adult kidneys showed the expression of nephron progenitor markers (Pax2), and broad differentiation plasticity, being able to differentiate towards epithelial cells and podocytes. Most importantly, when injected into preclinical models of kidney injury, CD133+ cells integrated into damaged renal tissue and improved renal health. Nevertheless, the evidence for CD133 being a bona fide renal progenitor marker is conflicting. In this study, five renal biopsies belonging to children (from 6 months to 10 years old) were used. The localization of CD133 was consistent with previous studies, as the expression of CD133 was demonstrated on the cells of the Bowman’s capsule and in scattered tubular cells. From each sample, a bulk renal population was isolated and was initially characterized for the presence of the CD133 marker. Once placed in culture, most of the renal cells started expressing CD133. A further phenotypical characterization revealed that the vast majority of the cells expressed epithelial (EpCam, E-Cadherin, CD24), and some mesenchymal (CD73, CD44) markers. Also, the CD133+ population appeared heterogeneous for the expression of other markers. Most notably, CD13, a marker of fully differentiated tubular cells, was found to be significantly expressed in part of the CD133+ cells, suggesting that either fully differentiated cells started expressing CD13 de novo, or the CD133+ were committed towards a tubular fate. The bulk population was sorted by FACS into CD133+ and CD133- sub-populations which were compared in additional experiments to explore the progenitor-like features of the CD133+ cells. First, the ability of both CD133+ and CD133- sub-populations to differentiate towards podocytes in vitro was investigated. Both sub-populations were found to express the podocyte markers, nephrin and podocin, to a similar extent following stimulation with retinoic acid. However, the assay did not prove to be consistent and it was not used any further. Secondly, the potential of both CD133+ and CD133- sub-populations to integrate into ex vivo reaggregated mouse kidney rudiments was determined. Surprisingly, the majority of both cell types died in the chimeric rudiments within two days in culture. Neither the surviving CD133+ nor the CD133- cells showed any propensity to integrate into developing renal structures. Unexpectedly, the CD133+ cells were found to clump on top of the rudiment and had a negative impact on the developing rudiment, whereas the CD133- cells did not. Alongside with the test of the human cells in the chimeric rudiments, the assay itself was modified to suit the imaging of the rudiments in a Light-sheet fluorescent microscope (LSFM). 3D embryonic renal organoids were efficiently produced and the development of their structures could be successfully monitored through the LSFM in proof-of-concept experiments. The final aim of this work was to assess the therapeutic efficacy of the CD133+ and CD133- sub-populations in a rat model of cisplatin-induced acute kidney injury. The renal function was monitored using a non-invasive transcutaneous device that measures the half-life of an exogenously administered renal marker, FITC-Sinistrin, alongside to the measurement of conventional biomarkers, serum creatinine, and urea. Following intravenous (IV) injection, both CD133+ and CD133- cells ameliorated renal function and preserved renal histology. The data suggest that the human cells passed through the lungs, and probably reached the kidneys. However, no cells were alive at the end of the study (14 days), but traces of PKH26 were retrieved in lungs and, to a lesser extent, in the kidneys, suggesting the possible involvement of paracrine mechanisms, possible through extracellular vesicles in the observed functional amelioration. Additional biodistribution studies showed that soon after the IV injection the human cells were identified in the lungs of the animals, but not in the kidneys. Phagocytic cells, identified through the marker CD68, were observed around the human cells in the lungs as early as 1 hour after the injection. By 24 hours, clusters of CD68+ cells could be found, but not human cells. Therefore, the data suggest that the human cells die in the lungs and that the macrophages might play an active role in the disappearance. Taken together, this work shows that the expression of CD133 does not confer any advantage to the nephrogenic potential ex vivo or to the therapeutic efficacy in vivo. Moreover, since the cells were shown to be entrapped in the lungs, the renal repair is probably mediated by cell-derived factors, rather than by CD133+ cells homing to the kidneys and generating specialised renal cells. The role of macrophages in the resolution or regenerative mechanisms should be considered and further examined in future preclinical studies of cellular therapies for kidney diseases.

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Feitosa, Neli Patricia Pereira. "Imunoexpressão dos marcadores de células-tronco CD44 e CD133 no câncer gástrico primário e metástases linfonodais." reponame:Repositório Institucional da UFC, 2015. http://www.repositorio.ufc.br/handle/riufc/15803.

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FEITOSA, Neli Patricia Pereira. Imunoexpressão de marcadores de células -tronco, CD44 e CD133, no câncer gástrico primário e metástases linfonodais. 2015. 68 f. Dissertação (Mestrado em Patologia) - Faculdade de Medicina, Universidade Federal do Ceará, Fortaleza, 2015.
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Gastric cancer is the fourth most common cancer worldwide, accounting for the second leading cause of cancer mortality. Despite treatment with surgery and chemotherapy, the overall five-year survival of patients with gastric cancer remains low. One possible explanation for the ineffectiveness of therapy is the presence of cancer stem cells, a subpopulation of tumor cells that have stem cell characteristics. It has been reported that these, as well as embryonic stem cells, are immortal, can self-renew and to differentiate to be transformed in any cell type in the body. Several markers, including CD44 and CD133, have been reported as stem cell markers in both normal and cancerous cells and have been used to isolate cancer cells from solid tumors. The aim of this study was to evaluate the expression of CD44 and CD133 in primary gastric cancer and lymph node metastases by immunohistochemical and to relate it to clinicopathologic variables as histological type, gender, age, anatomical site, tumor size, angiolymphatic invasion, infiltration perineural, TNM classification (TN) and lymph node involvement. This study was developed from a set of 72 cases of gastric adenocarcinoma, from the Archives of Pathology and Forensic Medicine of the Federal University of Ceará Service (DPML-UFC). Tissue microarray and immunohistochemistry were utilized, with anti-CD44 monoclonal antibody and polyclonal anti-CD133. The cases with one or more cells with cytoplasmic and / or membrane immunostaining were considered positives. It was observed that 30% of the samples were positive for CD44. No statistically significant differences were found between the clinical and pathological variables studied and the immunoreactivity of CD44. Regarding the immunoreactivity of CD133, the present study showed that 24% of samples were positive. The degree of tumor invasion presented data showing a statistically significant trend (p = 0.0505), in reverse. The other variables, we found no statistically significant difference. The immunoreactivity of CD133 in histologically normal mucosa was higher than in the primary tumor and intestinal metaplasia, with statistically significant difference (p = 0.0159 and p = 0.0058, respectively). The CD133 immunostaining in intestinal type gastric carcinoma was significantly higher than in the histologically normal mucosal metaplasia (p = 0.0260). The frequency of expression of these markers is highly variable, and even in the samples considered positive, the stained cells percentage is also variable, and very low overall.
O câncer gástrico é a quarta neoplasia mais comum em todo o mundo, representando a segunda causa de mortalidade por câncer. Apesar do tratamento com cirurgia e quimioterapia, a sobrevida global em cinco anos de pacientes com câncer gástrico permanece baixa. Uma possível explicação para ineficácia da terapia é a presença de células-tronco cancerosas, uma subpopulação de células tumorais que apresentam características de células-tronco. Estas células, assim como as células tronco embrionárias, são consideradas imortais, podem se auto-renovar e se transformar em qualquer célula do corpo. Vários marcadores, incluindo CD44 e CD133, têm sido relatados como marcadores de células-tronco, normais e cancerosas, e utilizados para isolar células cancerosas de tumores sólidos. O objetivo desse trabalho foi avaliar a expressão de CD44 e de CD133, no câncer gástrico primário e metástases linfonodais, através de imunohistoquímica, e relacioná-la com as variáveis clínico-patológicas de tipo histológico, sexo, idade, localização anatômica, dimensão do tumor, invasão angiolinfática, infiltração perineural, classificação TNM (TN) e acometimento linfonodal. Este estudo foi desenvolvido a partir de um conjunto de 72 casos de adenocarcinoma gástrico, dos Arquivos do Serviço de Patologia e Medicina Legal da Universidade Federal do Ceará (DPML-UFC). Utilizou-se a técnica de tissue microarray asociada à imunohistoquímica com anticorpo monoclonal anti-CD44 e policlonal anti-CD133. Foram considerados positivos os casos que apresentaram uma ou mais células com imunomarcação citoplasmática e/ou membranar. Foi observado que 30% das amostras foram positivas para o CD44. Não foram encontradas diferenças estatisticamente significantes entre as variáveis clínico-patológicas estudadas e a imunoexpressão de CD44. A imunoexpressão do CD133 foi positiva em 24% das amostras. O grau de invasão do tumor apresentou dados com tendência estatisticamente significante (p=0,0505), de forma inversa. Nas demais variáveis, não foi encontrada nenhuma diferença estatisticamente significante. A imunoexpressão de CD133 na mucosa histologicamente normal foi maior do que no tumor primário e na metaplasia intestinal, com diferença estatística significante (p=0,0159 e p=0,0058, respectivamente). A imunoexpressão de CD133 no adenocarcinoma gástrico tipo intestinal foi significativamente maior na mucosa histologicamente normal do que na metaplasia (p=0,0260). A frequência da expressão desses marcadores é muito variável, e mesmo nas amostras consideradas positivas, o percentual de células coradas também é variável, e em geral muito baixo.

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DIOGUARDI, MARIO. "Il ruolo delle Cancer Stem Cell nel carcinoma orale a cellule squamose." Doctoral thesis, Università di Foggia, 2016. http://hdl.handle.net/11369/363214.

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Il carcinoma a cellule squamose della regione testa collo presenta un elevato tasso di mortalità, a causa dell’elevato tasso di recidive e della elevata resistenza ai comuni protocolli chemio e radio terapici. Queste caratteristiche sarebbero attribuibili ad una sottopopolazione di cellule indifferenziate, presente all’interno del tumore, definita Cancer Stem Cell (CSC), che sembrano essere in grado di andare incontro a differenziamento ed autorinnovamento, risultando responsabili dell’elevata invasività e della capacità metastatica. Il mio obiettivo è stato quello di cercare un marker specifico per l’identificazione di questa sottopopolazione all’interno del carcinoma a cellule squamose della regione testa collo, utilizzando marker putativi di cellule staminali come CD133 e CD44.I risultati hanno mostrato una significativa sovraregolazione dei marker putativi delle cellule staminali in tumori formati da popolazioni arricchite di CSC in confronto con tumori osservati dopo l’iniezione di cellule parentali, sia nei livelli di RNA che proteici, e in questo studio, sia i livelli di CD133 e CD44 sono risultati aumentati nel carcinoma, quindi potrebbero essere utilizzati nella diagnosi del carcinoma della regione testa collo, ma sono necessari ulteriori studi in vivo con una casistica più ampia per poterlo affermare

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Brescia, P. "THE ROLE OF CD133 IN THE IDENTIFICATION AND MAINTENANCE OF CANCER STEM CELLS DERIVED FROM HUMAN GLIOBLASTOMA." Doctoral thesis, Università degli Studi di Milano, 2012. http://hdl.handle.net/2434/214788.

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Glioblastoma multiforme (GBM) is the most common and lethal type of brain tumor in adults. There are some evidences that it is maintained by a population of cells, namely cancer stem cells, able to self-renew and propagate the tumor. Despite recent advances in surgical and therapeutic treatment, no tangible improvements have been made to prolong the patients’ survival. The role of the cell surface CD133 as a cancer stem cell marker in brain tumors has been widely investigated, since it identifies cells within glioblastomas able to initiate neurosphere growth and form heterogeneous tumors when transplanted in immune-compromised mice. However, evidences of CD133-negative cells exhibiting similar properties have been reported, making definitive conclusions on the correlation between tumor-initiating capabilities of glioma stem cells and CD133 expression difficult to drawn. Moreover, the functional role of CD133 in cancer stem/progenitor cells is not known. We analyzed the efficiency of CD133 in the identification and isolation of glioblastoma stem cells and we investigated its functional role, studying the biological effects of CD133 down-regulation in GBM-derived neurospheres in vitro and in vivo. We observed that CD133 is homogenously expressed in the cytoplasm of the cells composing the neurospheres, while its expression on the cell surface is highly variable. Cloning of single CD133-positive and CD133-negative cells demonstrated that CD133 shuttles dynamically between the plasmamembrane and the cell cytoplasm and no hierarchical relation can be established. Knockdown of CD133 by lentiviral-mediated short hairpin RNAs (shRNA) reduces the self-renewal and tumorigenic capacity of the GBM-derived neurosphere cells. Taken together, our data suggest that cell surface CD133 is not useful for the isolation of glioblastoma stem cells, since a complex regulation of its expression in terms of protein levels and cellular localization exists. However, CD133 may contribute to the maintenance and the tumorigenic potential of glioblastoma stem cells. This implies that CD133 could be used as a therapeutic target in glioblastomas, regardless of its expression on cell surface.

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Blöcker, Svea Maria [Verfasser]. "Einfluss des Proteasomeninhibitors Bortezomib auf die in-vitro-Proliferation und Differenzierung CD133 positiver Progenitorzellen / Svea Maria Blöcker." Lübeck : Zentrale Hochschulbibliothek Lübeck, 2012. http://d-nb.info/1024106373/34.

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30

Häggblad, Sahlberg Sara. "Colorectal cancer and radiation response : The role of EGFR, AKT and cancer stem cell markers." Doctoral thesis, Uppsala universitet, Institutionen för radiologi, onkologi och strålningsvetenskap, 2014. http://urn.kb.se/resolve?urn=urn:nbn:se:uu:diva-222836.

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The primary treatment for colorectal cancer is surgery. Radiotherapy and chemotherapy, sometimes combined, are also frequently used to diminish recurrence risk. In response to radiation exposure, several cellular signaling cascades are activated to repair DNA breaks, prevent apoptosis and to keep the cells proliferating. Several proteins in the radiation response and cell survival pathways are potential targets to enhance the effects of radiation. The epidermal growth factor receptor (EGFR), which is frequently upregulated in colorectal cancer and exhibits a radiation protective function, is an attractive target for treatment. EGFR is activated by radiation which in turn activates numerous signaling pathways such as the PI3 kinase/AKT cascade, the RAS/RAF/ERK pathway and STAT leading to tumor cell proliferation. EGFR is also believed to interact with proteins in the DNA repair process, such as DNA-PKcs and MRE11. The cytotoxic effect of an affibody molecule (ZEGFR:1907)2, with high affinity to EGFR, in combination with radiation produced a small, but significant, reduction in survival in a KRAS mutated cell line. However, not in the BRAF mutated cell line. The next step was therefore to target proteins downstream of EGFR such as AKT. There was an interaction between AKT and the DNA repair proteins DNA-PKcs and MRE11 and both AKT1 and AKT2 were involved in the radiation response. The knockout of both AKT isoforms impaired the DNA double strand break rejoining after radiation and suppression of DNA-PKcs increased the radiations sensitivity and decreased the DNA repair further. The AKT isoforms also affected the expression of cancer stem cell markers CD133 and CD44 which are associated with the formation of metastasis as well as radiation and drug resistance. The CD133 expression was associated with AKT1 but not AKT2, whereas the CD44 expression was influenced by the presence of either AKT1 or AKT2. AKT was also involved in cell migration, cell-adhesion and metabolism. Overall, these results illustrate the complexity in response to radiation and drugs in cells with different mutations and the need for combining inhibitors against several targets such as EGFR, AKT, DNA-PKcs, CD133 or CD44.

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Giegerich, Anna [Verfasser], Eric Thomas [Gutachter] Hahnen, and Thorsten [Gutachter] Simon. "Identification of CD133-positive cell populations within glioma cell lines / Anna Giegerich ; Gutachter: Eric Thomas Hahnen, Thorsten Simon." Köln : Deutsche Zentralbibliothek für Medizin, 2021. http://d-nb.info/1236928091/34.

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32

DENBOBA, AYELE ARGAW. "Human Endogenous Retrovirus-K affects cellular plasticity and generation of stem-like CD133+ cells in melanoma cancer cells." Doctoral thesis, Università degli Studi di Roma "Tor Vergata", 2013. http://hdl.handle.net/2108/203227.

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Background: Malignant melanoma is one of the most aggressive types of skin cancers and its exact etiology is not yet clear. Tumor cell plasticity and the putative cancer stem cell subpopulations that express stem cell markers such as CD133 have been associated with melanoma tumor initiation and progression. Likewise, human endogenous retrovirus-K (HERV-K) has been linked to aggressiveness and immune evasion of metastatic melanoma. The exact mechanism leading to abnormal HERV-K gene expression in melanoma is not yet clearly elucidated. However, environmental factors such as stress conditions seem to be involved along with mechanisms interfering with the immune system. Protein mutations are no longer considered as sole drivers of melanoma tumors, which implies studying the role of HERV-K activation in melanoma development and progression is important to understand melanomagenesis and find a possible therapeutic target. Objective of the study: To investigate the potential role of HERV-K activation in cellular plasticity and stemness features of melanoma cells upon the modification of the microenvironment conditions. Materials and methods: Four metastatic and one primary melanoma cell lines were used in this study; cell lines TVM-A12 and TVM-A12-CD133+ were established in our laboratory. Different cell culture media were used to assess the cellular modification of cells upon the modification of the microenvironment. Flow cytometry, RT-PCR analysis, RNA interference assay, sphere-forming assay and migration/invasion assays were used to assess cell phenotypic modifications, expression of HERVK, stemness and metastatic features of the cell lines, respectively. SPSS software version 17 was used for the statistical analysis and statistical significance was set at P< 0.050. Results: The peculiar plasticity features of TVM-A12 cells were indicated by their ability to show specific differentiated and non-adherent grape-like cellular aggregate phenotypes in specific differentiation and serum-free stem cell media, respectively. The grape-like cellular aggregates were also accompanied by increased activation of HERV-K expression and generation of the stem-like CD133+ subpopulations melanoma cells. Interestingly, silencing of HERV-K expression in TVM-A12 cells by RNA interference significantly abolished the generation of the stem-like CD133+ subpopulations, dysregulated the grape-like cellular aggregates phenotype and suppressed their proliferation. Correspondingly, TVM-A12-CD133+ cell line was able to show cellular plasticity upon the modification of the microenvironments and displayed a significantly higher self-renewing, migration and invasion capacity than the heterogeneous TVM-A12 cell lines. More interestingly, treatment of TVM-A12 and TVM-A12-CD133+ with the NNRTIs, nevirapine and efavirenz, inhibited the expression of HERV-K and significantly induced high levels of apoptosis in TVM-A12-CD133+ cells. Conclusion: Therefore, taking these evidences together, this study demonstrated for the first time that the plasticity of melanoma cancer cells and their potential to generate the stem-like CD133+ cells under stress conditions are dependent upon HERV-K expression. Hence, given the relevance of the putative CD133+ cancer stem cells in melanoma progression we suggest HERV-K expression as a potential target of melanoma therapy in order to enhance the anti-metastatic effects and improve patient survival.

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Tong, Man, and 唐旻. "Clinical relevance, functional significance and therapeutic implication of annexin A3 in CD133⁺ liver cancer stem cells driven hepatocellular carcinoma." Thesis, The University of Hong Kong (Pokfulam, Hong Kong), 2014. http://hdl.handle.net/10722/208052.

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34

Martin, Marion. "Analyse de la méthylation de l'ADN des cellules CD133+ dans le cancer du foie et son interaction avec la voie de signalisation TGF-b." Phd thesis, Ecole normale supérieure de lyon - ENS LYON, 2013. http://tel.archives-ouvertes.fr/tel-00942762.

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Au sein des tumeurs, y compris pour le carcinome hépatocellulaire (CHC), des sous-populations de cellules néoplasiques ont révélé une grande capacité à initier de nouvelles tumeurs et à induire des métastases. Les premières études sur ces cellules ont rapidement montré que la présence de ces cellules était déterminante dans le développement tumoral et elles ont donc été renommées " cellules souches cancéreuses " (CSCs). Malheureusement les mécanismes impliqués dans la maintenance de ces CSCs ne sont que partiellement compris. Par ailleurs dans le CHC un lien a été établi entre les signaux du facteur de croissance de transformation (Transforming Growth Factor, TGF-ß) provenant du microenvironnement tumoral et certaines populations de cellules cancéreuses dont la présence est corrélée à un faible pronostic. La façon dont TGF-ß peut ainsi établir et modifier un phénotype cellulaire dans le CHC reste néanmoins obscure. La méthylation de l'ADN étant un acteur majeur dans la mise en place des programmes cellulaires, notre but a été de caractériser le méthylome de CSCs hépatiques et son lien avec la capacité de TGF-ß à induire des CSCs. Nous nous sommes appuyés sur l'expression du marqueur CD133 pour définir la population de CSCs hépatiques. Afin comprendre l'importance des marques de méthylation de l'ADN dans les CSCs hépatiques, nous avons dans un premier temps déterminé quelle était la signature des cellules CD133+ au niveau de la méthylation de l'ADN en utilisant des puces de méthylation à grande échelle. Les sites CpG différentiellement méthylés ont montré un enrichissement pour d'une part des voies de signalisation déjà identifiées dans les CSCs et, d'autre part, pour des voies de signalisation associées au processus inflammatoire dont la voie TGF-ß/SMAD. Par la suite, nous avons montré que TGF-ß pouvait induire de façon permanente les cellules CD133+ contrairement à une autre cytokine influente dans le cancer du foie, l'interleukine 6. Cette augmentation de cellules CD133+ induite par TGF-ß est associée à des changements de méthylation de l'ADN sur l'ensemble du génome et qui sont, de plus, maintenus au cours des divisions cellulaires. La comparaison entre les deux méthylomes (liés aux cellules CD133+ et à l'action de TGF-ß) a exposé une signature commune significative indiquant que TGF-ß pourrait promouvoir le phénotype de CSC via le processus de méthylation de l'ADN. Mais nous avons également déterminé qu'une grande partie des effets sur la méthylation induits par TGF-ß était totalement indépendante de l'induction de cellules CD133+. Enfin, nous avons observé que les sites de méthylation sensibles au signal de TGF-ß étaient regroupés de façon significative au niveau de régions " enhancer " qui régulent la transcription des gènes. Par ailleurs, ces sites incluaient également des gènes précédemment identifiés comme cibles de TGF-ß mais aussi des gènes codant pour des acteurs épigénétiques de premier ordre comme les méthyltransférases de l'ADN. Ces résultats constituent la première description d'une signature de méthylation de l'ADN induite par TGF-ß permettant une reprogrammation stable vers un profil épigénétique de CSC hépatiques.

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Grundmann, Franziska Sophie. "Unterschiedlicher Anstieg von CD34-, KDR/CD34-, CD133/CD34- und CD117/CD34-positiven Zellen im peripheren Blut von Patienten mit akutem Myokardinfarkt." Köln Deutsche Zentralbibliothek für Medizin, 2009. http://d-nb.info/99986890X/34.

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Grandini, Elena <1981&gt. "Valutazione dell'efficacia dell'infusione intraepatica di cellule staminali (SC) autologhe CD133+ in pazienti affetti da cirrosi ed insufficienza epatica di grado avanzato." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6196/1/Grandini_elena_tesi%5B1%5D.pdf.

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Numerose evidenze sperimentali hanno dimostrato il contributo delle cellule staminali (SC) di derivazione midollare nei processi di rigenerazione epatica dopo danno tissutale. E’ cresciuto pertanto l’interesse sul loro potenziale impiego in pazienti con cirrosi. Questo studio si proponeva di valutare la fattibilità e la sicurezza della reinfusione intraepatica di cellule staminali midollari autologhe CD133+ in 12 pazienti con insufficienza epatica terminale. Previa mobilizzazione nel sangue periferico mediante somministrazione di granulocyte-colony stimulating factor (G-CSF) alla dose di 7,5 mcg/Kg/b.i.d. e raccolta per leucoaferesi (solo se la concentrazione di CD133 + SC era > 8/μL), le cellule CD133+ altamente purificate sono state reinfuse in arteria epatica a partire da 5x104/Kg fino a 1x106/kg. Nei tre giorni successivi è stato somministrato G-CSF per favorire l’espansione e l’attecchimento delle cellule. Durante la fase della mobilizzazione e quella della reinfusione sono stati eseguiti saggi biologici quali: caratterizzazione fenotipica delle SC circolanti, saggi clonogenici, valutazione della concentrazione sierica del Hepatocyte Growth Factor (HGF), Stromal-Derived Factor-1 (SDF-1) ed il Vascular-Endotelial Growth Factor (VEGF) e caratterizzazione fenotipica delle CD133+SC purificate. Fino ad oggi sono stati reinfusi 12 pazienti. Questi dati preliminari suggeriscono che è possibile mobilizzare e reinfondere un numero considerevole di SC autologhe CD133+ altamente purificate in pazienti con ESLD . Gli studi biologici mostrano che: il numero di progenitori ematopoietici ed endoteliali circolanti è aumentato dopo il trattamento con G–CSF; le SCs CD133+ altamente purificato esprimono marcatori emopoietici ed endoteliali; la concentrazione sierica di HGF, SDF-1, VEGF e la capacità clonogenica di progenitori emopoietici sono aumentati durante la mobilitazione e nelle fasi di reinfusione; il potenziale clonogenico dei progenitori endoteliali mostra espressione variabile.
Bone marrow (BM) stem cells (SCs) have been shown to contribute to liver cell populations and this has sparked interest in the field of autologous SCs infusion as a possible treatment for cirrhosis. The aim of this study was to evaluate the feasibility and safety of intrahepatic reinfusion of increasing numbers of autologous BM-derived CD133+ SCs into hepatic artery of 12 patients with end-stage liver disease (ESLD). For this purpose, granulocyte-colony-stimulating factor (G-CSF) at 7.5 µg/Kg/b.i.d. was administered subcutaneously (sc) from day 1 until completing the peripheral blood stem cells (PBSCs) collection. PBSCs collection started on day 5 only if the CD133+SCs concentration was >8/µL. CliniMacs device was used for the positive selection of CD133+SCs from PB of mobilized standard-volume leukapheresis. After SCs mobilization, highly purified autologous G-CSF-mobilized CD133+SCs were reinfused through hepatic artery. CD133+CSs were administered according to body weight starting from 5x104/Kg and increased every 3 patients up to 1x106/Kg. G-CSF at 5µg/Kg/day was administered sc for 3 days after reinfusion of SCs for their expansion and to induce a selective proliferative advantage in vivo. Biological assays (circulating SCs phenotype, clonogenic assays, serum concentration of hepatocyte growth factor [HGF], stromal-derived factor-1 [SDF-1] and vascular-endotelial growth factor [VEGF]) were done during the mobilization and reinfusion phases together with the phenotypic characterization of the isolated CD133+SCs. Up to date, 12 patients have been reinfused. These preliminary data suggest that it is feasible to mobilize and reinfuse a substantial number of highly purified autologous CD133+ SCs in patients with ESLD. Biological studies show that: circulating hematopoietic and endothelial progenitors are increased after G-CSF treatment; highly purified CD133+CSs express hematopoietic and endothelial markers; serum concentration of HGF, SDF-1, VEGF and clonogenic capability of hematopoietic progenitors are increased during the mobilization and reinfusion phases; clonogenic potential of endothelial progenitors shows variable expression.

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37

Grandini, Elena <1981&gt. "Valutazione dell'efficacia dell'infusione intraepatica di cellule staminali (SC) autologhe CD133+ in pazienti affetti da cirrosi ed insufficienza epatica di grado avanzato." Doctoral thesis, Alma Mater Studiorum - Università di Bologna, 2014. http://amsdottorato.unibo.it/6196/.

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Numerose evidenze sperimentali hanno dimostrato il contributo delle cellule staminali (SC) di derivazione midollare nei processi di rigenerazione epatica dopo danno tissutale. E’ cresciuto pertanto l’interesse sul loro potenziale impiego in pazienti con cirrosi. Questo studio si proponeva di valutare la fattibilità e la sicurezza della reinfusione intraepatica di cellule staminali midollari autologhe CD133+ in 12 pazienti con insufficienza epatica terminale. Previa mobilizzazione nel sangue periferico mediante somministrazione di granulocyte-colony stimulating factor (G-CSF) alla dose di 7,5 mcg/Kg/b.i.d. e raccolta per leucoaferesi (solo se la concentrazione di CD133 + SC era > 8/μL), le cellule CD133+ altamente purificate sono state reinfuse in arteria epatica a partire da 5x104/Kg fino a 1x106/kg. Nei tre giorni successivi è stato somministrato G-CSF per favorire l’espansione e l’attecchimento delle cellule. Durante la fase della mobilizzazione e quella della reinfusione sono stati eseguiti saggi biologici quali: caratterizzazione fenotipica delle SC circolanti, saggi clonogenici, valutazione della concentrazione sierica del Hepatocyte Growth Factor (HGF), Stromal-Derived Factor-1 (SDF-1) ed il Vascular-Endotelial Growth Factor (VEGF) e caratterizzazione fenotipica delle CD133+SC purificate. Fino ad oggi sono stati reinfusi 12 pazienti. Questi dati preliminari suggeriscono che è possibile mobilizzare e reinfondere un numero considerevole di SC autologhe CD133+ altamente purificate in pazienti con ESLD . Gli studi biologici mostrano che: il numero di progenitori ematopoietici ed endoteliali circolanti è aumentato dopo il trattamento con G–CSF; le SCs CD133+ altamente purificato esprimono marcatori emopoietici ed endoteliali; la concentrazione sierica di HGF, SDF-1, VEGF e la capacità clonogenica di progenitori emopoietici sono aumentati durante la mobilitazione e nelle fasi di reinfusione; il potenziale clonogenico dei progenitori endoteliali mostra espressione variabile.
Bone marrow (BM) stem cells (SCs) have been shown to contribute to liver cell populations and this has sparked interest in the field of autologous SCs infusion as a possible treatment for cirrhosis. The aim of this study was to evaluate the feasibility and safety of intrahepatic reinfusion of increasing numbers of autologous BM-derived CD133+ SCs into hepatic artery of 12 patients with end-stage liver disease (ESLD). For this purpose, granulocyte-colony-stimulating factor (G-CSF) at 7.5 µg/Kg/b.i.d. was administered subcutaneously (sc) from day 1 until completing the peripheral blood stem cells (PBSCs) collection. PBSCs collection started on day 5 only if the CD133+SCs concentration was >8/µL. CliniMacs device was used for the positive selection of CD133+SCs from PB of mobilized standard-volume leukapheresis. After SCs mobilization, highly purified autologous G-CSF-mobilized CD133+SCs were reinfused through hepatic artery. CD133+CSs were administered according to body weight starting from 5x104/Kg and increased every 3 patients up to 1x106/Kg. G-CSF at 5µg/Kg/day was administered sc for 3 days after reinfusion of SCs for their expansion and to induce a selective proliferative advantage in vivo. Biological assays (circulating SCs phenotype, clonogenic assays, serum concentration of hepatocyte growth factor [HGF], stromal-derived factor-1 [SDF-1] and vascular-endotelial growth factor [VEGF]) were done during the mobilization and reinfusion phases together with the phenotypic characterization of the isolated CD133+SCs. Up to date, 12 patients have been reinfused. These preliminary data suggest that it is feasible to mobilize and reinfuse a substantial number of highly purified autologous CD133+ SCs in patients with ESLD. Biological studies show that: circulating hematopoietic and endothelial progenitors are increased after G-CSF treatment; highly purified CD133+CSs express hematopoietic and endothelial markers; serum concentration of HGF, SDF-1, VEGF and clonogenic capability of hematopoietic progenitors are increased during the mobilization and reinfusion phases; clonogenic potential of endothelial progenitors shows variable expression.

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38

Jabero, Marvin Frank. "Investigation for the Identification of Transient Amplifying/Stem Cell Pool in Oral Mucosa." The Ohio State University, 2010. http://rave.ohiolink.edu/etdc/view?acc_num=osu1276788518.

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Oliveira, Lucila Habib Bourguignon [UNESP]. "Avaliação do perfil de expressão gênica de células CD34+ e células CD CD133+ isoladas de medula óssea e de sangue de cordão umbilical." Universidade Estadual Paulista (UNESP), 2008. http://hdl.handle.net/11449/86617.

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Made available in DSpace on 2014-06-11T19:22:21Z (GMT). No. of bitstreams: 0 Previous issue date: 2008-08-19Bitstream added on 2014-06-13T19:07:44Z : No. of bitstreams: 1 oliveira_lhb_me_arafcf.pdf: 553720 bytes, checksum: b0f8f04b07802f8bf467e43259c87fba (MD5)
Coordenação de Aperfeiçoamento de Pessoal de Nível Superior (CAPES)
Universidade Estadual Paulista (UNESP)
A maior expressão de alvos transcricionais e componentes da via NFkB é uma característica distintiva das células-tronco hematopoéticas (CTH) CD34+ de sangue de cordão umbilical (SCU) comparadas às CTH CD34+ de medula óssea (MO) e pode estar relacionada com o estado mais primitivo das CTH dos neonatos. No entanto, as células CD34+ são um grupo heterogêneo de célulastronco (CT) e progenitoras em diferentes estágios de maturação e diferenças na composição celular entre MO e SCU poderiam contribuir para os resultados mencionados. Estudos recentes têm identificado o marcador de superfície CD133, como um marcador de CT mais primitivas, expresso em uma subpopulação de células CD34bright, com um sugestivo potencial de hemangioblasto. Com o objetivo de caracterizar a composição celular de MO e SCU e identificar mecanismos moleculares envolvidos com a maior primitividade das células CD133+, propusemos avaliar o perfis imunofenotípico (quanto à expressão de CD34 e CD133) por citometria de fluxo e de expressão gênica de células CD34+ e células CD133+ selecionadas imunomagneticamente, de ambas as fontes, pelas técnicas de microarray e PCR em tempo real. Nossos resultados revelaram que enquanto a maioria das células CD133+ são CD34+, independente da fonte, as células CD34+ de SCU possuem uma porcentagem significativamente maior de células CD133+ do que às células CD34+ de MO. A análise de clusterização revelou que as células CD133+ de MO se agrupam com as células de SCU (CD34+ e CD133+), enquanto as CD34+ de MO aparecem como um grupo distinto. A comparação dos perfis de expressão gênica entre as células CD133+ e as células CD34+, revelou a hiper-expressão...
A higher expression of transcription targets and components of the NF-kB pathway is a distinctive feature of umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSC) when compared to bone marrow (BM) CD34+ HSC and this could be related to the more primitive state of the newborn’s HSC. However, CD34+ cells represent a heterogeneous group of cells composed by stem and progenitors cells in different developmental stages, and differences in cellular composition between both sources could contribute for these finding. The surface marker CD133 has been identified as a very primitive marker, expressed in a subpopulation of CD34bright, with a proposal hemangioblast potential. Thus, in attempt to better characterize the cellular composition of UCB and BM and to identify molecular mechanisms related to the more primitive characteristics of CD133+ cells, we proposed to evaluate the immunophenotypic profile (expression of CD34 and CD133) by flow-cytometry and the gene expression profiles of immunomagnetically selected CD34+ and CD133+ cells, from both sources, by microarray and Real time PCR. Our results highlighted that, while almost all CD133+ cells are CD34+ independently of the evaluated source, the UCB CD34+ cells showed a significantly higher proportion of CD133 expression, compared to BM CD34+ cells. After obtaining the expression profiles from distinct HSC pooled samples generated by microarrays, cluster analysis showed that BM CD133+ cells preferentially grouped with UCB cells (CD34+ and CD133+) instead of BM CD34+ cells, which appeared as a very distinct profile The comparison between CD133+ and CD34+ samples revealed the over-expression of 47 transcriptional factors (TF) in CD133+ cells, many of them well-known and related... (Complete abstract click electronic access below)

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40

Oliveira, Lucila Habib Bourguignon. "Avaliação do perfil de expressão gênica de células CD34+ e células CD CD133+ isoladas de medula óssea e de sangue de cordão umbilical /." Araraquara : [s.n.], 2008. http://hdl.handle.net/11449/86617.

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Orientador: Dimas Tadeu Covas
Banca: Dimas Tadeu Covas
Banca: Rodrigo Alexandre Panepucci
Banca: Haroldo Wilson Moreira
Resumo: A maior expressão de alvos transcricionais e componentes da via NFkB é uma característica distintiva das células-tronco hematopoéticas (CTH) CD34+ de sangue de cordão umbilical (SCU) comparadas às CTH CD34+ de medula óssea (MO) e pode estar relacionada com o estado mais primitivo das CTH dos neonatos. No entanto, as células CD34+ são um grupo heterogêneo de célulastronco (CT) e progenitoras em diferentes estágios de maturação e diferenças na composição celular entre MO e SCU poderiam contribuir para os resultados mencionados. Estudos recentes têm identificado o marcador de superfície CD133, como um marcador de CT mais primitivas, expresso em uma subpopulação de células CD34bright, com um sugestivo potencial de hemangioblasto. Com o objetivo de caracterizar a composição celular de MO e SCU e identificar mecanismos moleculares envolvidos com a maior primitividade das células CD133+, propusemos avaliar o perfis imunofenotípico (quanto à expressão de CD34 e CD133) por citometria de fluxo e de expressão gênica de células CD34+ e células CD133+ selecionadas imunomagneticamente, de ambas as fontes, pelas técnicas de microarray e PCR em tempo real. Nossos resultados revelaram que enquanto a maioria das células CD133+ são CD34+, independente da fonte, as células CD34+ de SCU possuem uma porcentagem significativamente maior de células CD133+ do que às células CD34+ de MO. A análise de clusterização revelou que as células CD133+ de MO se agrupam com as células de SCU (CD34+ e CD133+), enquanto as CD34+ de MO aparecem como um grupo distinto. A comparação dos perfis de expressão gênica entre as células CD133+ e as células CD34+, revelou a hiper-expressão... (Resumo completo, clicar acesso eletrônico abaixo)
Abstract: A higher expression of transcription targets and components of the NF-kB pathway is a distinctive feature of umbilical cord blood (UCB) CD34+ hematopoietic stem cells (HSC) when compared to bone marrow (BM) CD34+ HSC and this could be related to the more primitive state of the newborn's HSC. However, CD34+ cells represent a heterogeneous group of cells composed by stem and progenitors cells in different developmental stages, and differences in cellular composition between both sources could contribute for these finding. The surface marker CD133 has been identified as a very primitive marker, expressed in a subpopulation of CD34bright, with a proposal hemangioblast potential. Thus, in attempt to better characterize the cellular composition of UCB and BM and to identify molecular mechanisms related to the more primitive characteristics of CD133+ cells, we proposed to evaluate the immunophenotypic profile (expression of CD34 and CD133) by flow-cytometry and the gene expression profiles of immunomagnetically selected CD34+ and CD133+ cells, from both sources, by microarray and Real time PCR. Our results highlighted that, while almost all CD133+ cells are CD34+ independently of the evaluated source, the UCB CD34+ cells showed a significantly higher proportion of CD133 expression, compared to BM CD34+ cells. After obtaining the expression profiles from distinct HSC pooled samples generated by microarrays, cluster analysis showed that BM CD133+ cells preferentially grouped with UCB cells (CD34+ and CD133+) instead of BM CD34+ cells, which appeared as a very distinct profile The comparison between CD133+ and CD34+ samples revealed the over-expression of 47 transcriptional factors (TF) in CD133+ cells, many of them well-known and related... (Complete abstract click electronic access below)
Mestre

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Michaelis, de Vasconcellos Lena [Verfasser], Michael [Gutachter] Klein, and Rüdiger [Gutachter] Krauspe. "Intramyokardiale Transplantation autologer CD133+ Knochenmarkszellen nach endogenem Laser-induzierten ventrikulären Enhancement im Rahmen Aortokoronarer Bypassoperationen / Lena Michaelis de Vasconcellos ; Gutachter: Michael Klein, Rüdiger Krauspe." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2018. http://d-nb.info/1161941533/34.

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42

Thole, Alessandra Alves. "Análise da expressão de TNF-α e CD133 no pâncreas após o transplante de células de medula óssea em camundongos hiperalimentados durante a lactação." Universidade do Estado do Rio de Janeiro, 2010. http://www.bdtd.uerj.br/tde_busca/arquivo.php?codArquivo=1982.

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Estudos populacionais, assim como modelos animais demonstram que além dos fatores já conhecidos, como uma dieta não balanceada e sedentarismo, insultos nutricionais no período gestacional ou durante a lactação, causam alterações metabólicas importantes que levam ao surgimento da obesidade, Diabetes Mellitus tipo 2 (DM2) e doenças cardiovasculares em longo prazo. Nesse estudo, analisamos o pâncreas de camundongos hiperalimentados adultos (150 dias) e camundongos hiperalimentados jovens (21 e 28 dias). Os camundongos hiperalimentados de 21 dias receberam transplante de células mononucleares de medula óssea (CMO) e o resultado desse transplante foi observado aos 28 dias, quando os animais foram sacrificados. Nós investigamos: a apoptose das células beta através do fator pró-apoptótico Bax; a proliferação das células da ilhota pancreática através do antígeno nuclear de proliferação celular (PCNA); a expressão da citocina TNF-α, relacionado com a resistência à insulina em animais obesos e a expressão de células tronco CD133 com o objetivo de estudar a participação dessa célula na renovação da massa de células beta durante o estabelecimento da DM2. As análises das proteínas citadas no pâncreas foram realizadas através de microscopia de luz, microscopia confocal, microscopia eletrônica e Western blotting. O peso dos animais, a morfometria das ilhotas pancreáticas, bem como os níveis de glicose e insulina plasmáticos também foram determinados. Nossos resultados confirmaram que os camundongos hiperalimentados adultos apresentavam elevados níveis de glicose e insulina plasmática quando comparados ao grupo controle. Além disso, camundongos hiperalimentados adultos apresentaram aumento na expressão de Bax, indicando apoptose das células beta, maior expressão de TNF-α nas ilhotas pancreáticas, e presença de células CD133 nas ilhotas e ductos pancreáticos de camundongos hiperalimentados. Ao analisarmos os animais com 21 dias também observamos elevados níveis de glicose e insulina plasmática no grupo hiperalimentado. Após o transplante de CMO, os camundongos hiperalimentados apresentaram os níveis de glicose e insulina normalizados em relação ao grupo controle, porém os níveis de TNF-α no pâncreas continuavam elevados. A expressão de células CD133 foi observada tanto aos 21 quanto aos 28 dias nas ilhotas pancreáticas nos grupos hiperalimentados. Porém, a expressão estava aumentada no pâncreas dos animais que receberam transplante de CMO aos 28 dias. Portanto, podemos concluir que camundongos hiperalimentados durante a lactação quando adultos se encontram em um estágio inicial do estabelecimento da DM2, com hiperglicemia e hiperinsulinema, ilhotas pancreáticas hipertrofiadas, evidência de apoptose das células beta, neogênese de células beta a partir de células do ducto pancreático, replicação de células beta já existentes e células tronco endógenas marcadas com CD133. Nos camundongos jovens, além dos parâmetros também observados nos animais adultos, observamos os benefícios das CMO para o restabelecimento da glicemia e insulinemia nos camundongos hiperalimentados. Além disso, demonstramos pela primeira vez, células CD133 marcadas com insulina nas ilhotas pancreáticas. O aumento da expressão de células CD133 no pâncreas de camundongos hiperalimentados que mantinham níveis elevados de TNF-α e receberam transplante de CMO, nos sugere a importância dessa citocina para o recrutamento e diferenciação das células tronco CD133 para melhoria do percurso da diabetes.
Population studies as well as animal models show that besides the factors already known as an unbalanced diet and sedentary lifestyle, nutritional insults during pregnancy or during lactation, causes important metabolic changes that lead to the emergence of obesity, type 2 diabetes mellitus (DM2) and cardiovascular diseases in long-term. In this study, we analyzed the pancreas of overfed adult mice (150 days) and young mice (21 and 28 days). At day 21, overfed mice were transplanted with bone marrow mononuclear cells (BMCs) and the results of this transplantation were observed at day 28. We investigated beta-cell apoptosis through pro-apoptotic factor Bax, the proliferation of pancreatic islet cells by proliferating cell nuclear antigen (PCNA), expression of TNF-α which has been linked to insulin resistance in obese animals and the expression of CD133 stem cells, in order to study the participation of this cell on the recovery of beta-cell mass during the establishment of DM2. The protein analysis, were performed using light microscopy, Confocal microscopy, electron microscopy and Western blotting. The animals weight, morphology of pancreatic islets, as well as plasma levels of glucose and insulin were also determined. Our results confirmed that adult overfed mice had high levels of blood glucose and insulin when compared to control mice. Moreover, overfed adult mice showed an increased expression of Bax, indicating apoptosis of beta cells, also confirmed by transmission electron microscopy, increased expression of TNF-α in pancreatic islets when compared with the control group, and interestingly we observed the presence of CD133 cells in the pancreas of overfed mice. By analyzing the animals with 21 days, we also observed high levels of blood glucose and insulin in the overfed group, but we did not observe Bax expression at this lifetime. The expression of TNF-α was also increased in the pancreas of overfed mice at day 21. After BMCs transplantation, the overfed group showed normal levels of blood glucose and insulin when compared with the control group, but the levels of TNF-α remained high. The expression of CD133 cells was observed in the pancreatic islets both at 21 and 28 days in overfed groups. However, the expression of CD133 was increased in the pancreas of animals that received BMCs transplantation at day 28. Therefore, we conclude that overfed mice when adults are at an early stage of stablishment of DM2 with hyperglycemia and hyperinsulinemia, pancreatic islet hypertrophy, evidence of apoptosis and neogenesis of beta cells from pancreatic duct cells, replication of existing beta cells and endogenous stem cells. In young mice, further the parameters observed in adult animals, we observed the benefits of the BMCs for the restoration of glucose and insulin in overfed mice. Moreover, we demonstrated for the first time the CD133 stem cells in pancreatic islets in colocalization with insulin, suggesting that CD133 could be a progenitor beta cell marker in pancreas. Also, the increased expression of CD133 cells in the pancreas of overfed mice with elevated levels of TNF-α after BMCs transplantation, suggests the importance of this cytokine for the recruitment and recovery of CD133 stem cells to improve the course of diabetes.

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43

Köhl, Vera [Verfasser]. "Characterization of a novel Lin-CD34+CD133+CD41+ HSPC population in Myelofibrosis patients and establishment of a long-term co-culture system / Vera Köhl." Hamburg : Staats- und Universitätsbibliothek Hamburg Carl von Ossietzky, 2021. http://d-nb.info/1236695267/34.

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44

Grundmann, Franziska Sophie [Verfasser]. "Unterschiedlicher Anstieg von CD34-, KDR/CD34-, CD133/CD34- und CD117/CD34-positiven Zellen im peripheren Blut von Patienten mit akutem Myokardinfarkt / Franziska Sophie Grundmann." Köln : Deutsche Zentralbibliothek für Medizin, 2009. http://d-nb.info/99986890X/34.

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45

Bertazza, Loris. "Analisi delle Cellule Tumorali Circolanti nel carcinoma gastrico e nelle metastasi epatiche da cancro del colon-retto: ruolo di Survivin e CD133 come fattori prognostici." Doctoral thesis, Università degli studi di Padova, 2011. http://hdl.handle.net/11577/3427460.

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Background At present the only prognostic system routinely employed for the management of gastric cancer patients is the TNM staging classification, that identifies broad risk categories with a significant prognostic variability within each stage, which makes TNM a suboptimal predictive tool on the single patient basis. Only 10-20% of patients with liver metastases from colorectal cancer is resectable with radical intent and 60-70% will develop a relapse despite apparently curative surgery. Both these classes of patients therefore would benefit from additional treatments after surgery such as adjuvant chemotherapy. We need new prognostic factors that can identify patients at high risk to be submitted to treatment. Aim of the study To study circulating tumor cells by gene profiling the peripheral blood in order to identify prognostic biomarkers that add independent prognostic power to the conventional staging systems. This might allow for a better stratification of patients’ risk and thus a better therapeutic management of gastric cancer and metastatic colorectal cancer patients, especially in the adjuvant setting. Patients, materials and methods 70 patients, affected with gastric adenocarcinoma at different TNM stages of disease who underwent radical surgery and 50 patients undergoing liver resection for metastases from colorectal cancer (stage IV) were enrolled in the study. Immediately before surgery, a sample of peripheral blood was withdrawn from each patient. For each sample, RNA was extracted and utilized for quantitative real time PCR evaluation of the expression of the following genes: CK19, CEA, VEGF, and Survivin for gastric cancer patients; CK19, CK20, CEA, VEGF, EGFR, CD133 and Survivin for colorectal liver metastases patients. Univariate and multivariate survival analysis was performed to investigate on the prognostic role of these biomarkers. Results After stepwise variable selection, Cox multivariate analysis of survival showed a significant association between overall survival and both TNM stage ad Survivin gene expression levels in peripheral blood of gastric cancer patients, while multivariate analysis confirmed the statistically significant association between both the radical resection and the transcriptional levels of CD133 and overall survival in colorectal liver metastases patients. In addition, Survivin transcriptional levels were higher in patients with gastric cancer as compared to the calibrator reference (obtained from the peripheral blood of healthy donors) in 98.6% of cases; analogously, CK19 was upregulated in 97.1% of cases. These findings support the hypothesis that the peripheral blood gene profile might be utilized also as a diagnostic marker in gastric cancer. Concluding remarks The positive findings of this pilot study are the basis for larger prospective studies in larger groups of gastric cancer and colorectal liver metastases patients, aimed to validate the prognostic power of Survivin and CD33 expression in peripheral blood of these two groups, respectively. Moreover it would be interesting to further explore also the potential diagnostic value of the peripheral blood gene profile in gastric cancer.
Presupposti dello studio Attualmente l'unico sistema prognostico utilizzato in clinica per i pazienti con cancro gastrico è la stadiazione TNM, che crea classi di rischio con prognosi significativamente diversa, ma con un’alta variabilità del rischio all’interno delle singole classi, risultando così uno strumento prognostico non ottimale a livello di singolo paziente. Solo il 10-20% dei pazienti con metastasi epatiche da carcinoma del colon-retto (CRC) risulta resecabile con intento radicale e di questi il 60-70% svilupperà una recidiva nonostante l’intervento potenzialmente curativo. Entrambe queste classi di pazienti necessitano di trattamenti aggiuntivi alla chirurgia come la chemioterapia adiuvante. Sono quindi necessari fattori prognostici nuovi, che permettano di individuare i pazienti ad alto rischio da indirizzare alla terapia. Scopo dello studio Studiare le cellule tumorali circolanti, attraverso il profilo di espressione genica nel sangue periferico, per individuare fattori prognostici indipendenti, in modo da rendere migliore la stratificazione del rischio e di conseguenza la cura dei pazienti con adenocarcinoma gastrico e con metastasi epatiche da carcinoma del colon-retto, con particolare riguardo alla selezione dei pazienti da trattare con terapia adiuvante. Pazienti, materiali e metodi Nello studio sono stati inclusi 70 pazienti con adenocarcinoma gastrico in diverso stadio TNM sottoposti a gastrectomia con intento radicale e 50 pazienti con metastasi epatiche da CRC sottoposti a chirurgia. Prima dell’intervento chirurgico, a ogni paziente è stato eseguito un prelievo di sangue venoso periferico, se ne è estratto l’RNA totale ed il corrispondente cDNA è stato utilizzato per l’analisi di espressione genica mediante PCR quantitativa. Per i pazienti con carcinoma gastrico sono stati valutati i geni CK19, CEA, VEGF, Survivin; per i pazienti con metastasi epatiche da CRC sono stati valutati i geni CK19, CK20, CEA, VEGF, EGFR, CD133 e Survivin. Per valutare il ruolo prognostico di ogni marcatore sono state effettuate le analisi di sopravvivenza uni- e multivariata. Risultati All’analisi multivariata secondo Cox della sopravvivenza globale, dopo selezione stepwise, sono risultati fattori prognostici indipendenti per i pazienti con cancro gastrico la stadiazione TNM e l’espressione del gene codificante per Survivin, mentre per i pazienti con CRC metastatico sono risultati fattori prognostici indipendenti la radicalità dell’intervento e l’espressione di CD133 nel sangue periferico. Inoltre Survivin era maggiormente espressa nei pazienti con carcinoma gastrico rispetto al calibratore (ottenuto dal sangue di donatori sani) nel 98.6% dei casi; analogamente CK19 era maggiormente espressa nel 97.1% dei casi. Questi dati supportano la possibilità dell’utilizzo dell’espressione genica nel sangue periferico anche come marcatore diagnostico del carcinoma gastrico. Conclusioni I risultati positivi di queste analisi costituiscono la base per la conduzione di più ampi studi prospettici nelle due patologie considerate, al fine di poter validare il valore prognostico dell’espressione di Survivin e CD133 nel sangue periferico dei pazienti rispettivamente con carcinoma gastrico e con CRC metastatico. Sarebbe inoltre di sicuro interesse confermare il significato diagnostico del profilo genico del sangue periferico nel cancro gastrico.

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Hewabostanthirige, Dhanushka. "Loss of Id4 Promotes Stemness In Prostate Cancer Cells." DigitalCommons@Robert W. Woodruff Library, Atlanta University Center, 2019. http://digitalcommons.auctr.edu/cauetds/182.

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Inhibitor of differentiation 4 (ID4), a member of the helix-loop-helix family of transcriptional regulators has emerged as a tumor suppressor in prostate cancer (PCa). Recent studies have shown that Id4 is highly expressed in the normal prostate and decreases in prostate cancer due to epigenetic silencing. Id4 knockdown in androgen sensitive LNCaP cells has been shown to lead to castration resistant prostate cancer (CRPC) in vitro and in vivo. Id4-/- mice leads to underdeveloped prostate with PIN like lesions without the loss of Androgen Receptor (AR) expression. In this study we demonstrate that the loss of ID4 expression in PCa cell line LNCaP and DU145 may promote tumorigenesis by promoting stemness. LNCaP cells with stably silenced ID4 ((-)ID4) using retroviral based shRNA and LNCaP transfected with non-specific shRNA were used to perform colony forming assay and prostatosphere formation using matrigel. Expression of cancer stem cell markers was determined using western blotting and immunocytochemistry (ICC). FACS analysis was used to sort stem cells and determine the ID4 expression. Xenograft study was performed on SCID mice using CD133 positive LNCaP cells. LNCaP(-)ID4 and DU145 cells lacking ID4 showed increased holoclone as well as decreased paraclone formation, which are believed to be derived from stem cells and differentiated cells respectively, as compared to non-silencing control in the colony forming assay. There was also an increase in prostatosphere development in the LNCaP (-) ID4 cells indicating that the loss of ID4 is responsible for promoting the LNCaP cells towards cancer stem cells. The results were further validated via western blotting and ICC using known cancer stem cell markers on the holoclones and paraclones formed by these cells. Xenograft study showed that 10,000 cells from CD133 positive LNCaP cells developed tumor on SCID mice. This study reports for the first time that loss of ID4 increases holoclone and prostatosphere formation indicating that Id4 may contribute to promoting stemness in prostate cancer cells.

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Bumblauskaitė, Jurga. "Ligonių, kuriems atlikta širdies persodinimo operacija, kraujo T limfocitų membranos žymenų CD16/56, CD103, CD134 ekspresijos pokyčiai." Master's thesis, Lithuanian Academic Libraries Network (LABT), 2011. http://vddb.laba.lt/obj/LT-eLABa-0001:E.02~2008~D_20110709_152242-89800.

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Po pirmosios širdies transplantacijos 1967 metais, ši operacija iš eksperimentinio gydymo tapo šiuolaikiniu, pažangiu sunkių širdies ligų gydymo būdu. Širdis šiuo metu yra trečias pagal dažnumą transplantuojamas organas JAV. UNOS (angl. Unaited Network for Organs Sharing) duomenimis JAV kasmet atliekama 2700 širdies transplantacijos operacijų. Tyrimai rodo, kad pirmuosius metus po operacijos išgyvena apie 85% pacientų, pirmus trejus metus – 75% pacientų. ISHLT (angl. International Society for Heart and Lung Transplantation) registravimo duomenys rodo, kad šiuo metu pasaulyje gyvena apie 50 000 žmonių, turinčių širdies transplantatą [20]. Nepakankamas donorų skaičius skatina mokslininkus ieškoti alternatyvių širdies ligomis sergančių pacientų gydymo būdų. Šiuo metu daug dėmesio skiriama kamieninių ląstelių tyrimams ir galimam jų pritaikymui įvairiom ligom gydyti. Su eksperimentiniais pelių modeliais parodyta, kad kamieninės ląstelės, implantuotos į širdies raumenį, geba diferencijuotis į kardiomiocitus ir kraujagyslių endotelio ląsteles ir atkurti pažeistą raumenį. Taučiau publikuota ir nemažai nesėkmių, susijusių su kamieninių ląstelių terapija, pvz.: neprigyjimas implantuotoje vietoje, nepilna diferencijacija [59]. Žmogaus mezenchiminių kamieninių ląstelių auginimas užtrunka, o gydymo dažnai prireikia tuoj pat [50]. Šios ir daug kitų problemų reikalauja daugybės tyrimų ir eksperimentų, todėl transplantacija kol kas išlieka pagrindiniu gydymo būdu, prailginančiu pacientų... [toliau žr. visą tekstą]
The ame of this work was to evaluate the changes of the expresion of T lymphocyte CD16/56, CD103, CD134 surface markers in the blood of the patients who underwent heart transplantation. For this purpose we collected heparinized blood samples of 21 patients with cardiac transplant and 29 healthy volunteers. 9 patients out of 21 underwent acute cardiac transplant rejection. Blood samples of these patients were tested using flow cytometry 10 days before heart rejection and on the day when rejection was uphold. Our results showed that the expresion of T lymphocyte CD16/56 surface molecule is higher on the rejection day then in controle group. Exspresion of CD103 marker is higher 10 days before rjection than on the rejection day and is lower then in healthy volunteers. Expresion of CD134 marker is higher before transplant rejection and higher then in healthy controles. Monitoring of CD3+CD103+ and CD+CD134+ cells in the blood after heart transplantation could be helpful in prediction of heart transplant rejection.

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Bourseau, Erika. "De la compréhension du comportement des cellules initiatrices de cancer dans les glioblastomes au développement d'une nanomédecine adaptée. Focalisation sur le marqueur de cellules souches cancéreuses AC133 / CD133." Phd thesis, Université d'Angers, 2011. http://tel.archives-ouvertes.fr/tel-00662253.

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La mise en évidence de cellules initiatrices de cancer dans les glioblastomes et l'existence de cellules souches cancéreuses (CSCs) étayent la présomption que l'échec des stratégies anti-tumorales classiques puisse être attribué à un problème de cible cellulaire. Dans le contexte des thérapies ciblées, l'émergence des nanomédecines offre des perspectives pour la délivrance de principes actifs vers les CSCs ou leur microenvironnement (ou niche) en vue d'une meilleure efficacité, spécificité et sécurité biologique. Douées d'autorenouvellement et capables de générer des clones néoplasiques radio et chimiorésistants, les CSCs n'ont toutefois pas de marqueur exclusifs connus sinon des marqueurs associés permettant d'enrichir ces populations et de potentiellement établir un ciblage notamment locorégional au sein de ces tumeurs. En nous focalisant sur l'épitope AC133, marqueur de CSCs associé à des glycosylations de la protéine CD133 ou prominine-1, l'objectif de cette thèse a été: i) de comprendre la situation biologique traduite par l'expression d'AC133 (témoin d'initiation de tumeurs, d'agressivité tumorale ou d'hypoxie) ii) de développer une nanomédecine reconnaissant l'épitope AC133, iii) de déterminer, au regard de sa distribution au niveau de protrusions membranaires, le rôle fonctionnel de CD133/AC133. A partir de modèles in vitro et in vivo de glioblatomes humains implantés dans le cerveau de souris immunodéprimées (SCID), nos résultats établissent qu'AC133 est un témoin de non exposition chronique à une pression partielle élevée en oxygène (21% O2 versus 3% O2). Dans ce contexte la stratégie shRNA knockdown démontre que HIF-1α est un des régulateurs de l'expression d'AC133. L'absence d'AC133 à 21% O2 au sein de populations non triées de cellules de glioblastomes n'est pas reliée à l'initiation de tumeur mais en revanche associée à une perte d'agressivité tumorale. La cible AC133 a donc été choisie pour développer des nanocapsules lipidiques (NCLs) capables de reconnaitre des CSCs. A l'aide d'un polymère bifonctionnel, le DSPE-PEG2000-maleimide et de l'anticorps monoclonal AC133, une lipo-immunoglobuline (DSPE-PEG2000-maleimide- AC133), a été synthétisée puis post-insérée dans des NCLs permettant l'obtention d'immuno-NCLs. Ces nano-objets ont démontré leur fonctionnalité par leur spécificité de liaison à des cellules Caco-2 exprimant constitutivement AC133. Enfin, dans une dernière étude focalisée sur le rôle de AC133/CD133 dans l'endocytose, nous démontrons par siRNA knockdown sur des cellules Caco-2 que AC133/CD133 inhibe l'internalisation cellulaire de transferrine et de NCLs. De manière intéressante, l'augmentation de la concentration extracellulaire en fer, connue pour diminuer l'expression du récepteur de la transferrine, régule également négativement celle d'AC133, indiquant un rôle d'AC133/CD133 dans l'endocytose et dans le métaboslime du fer. L'ensemble de ce travail de thèse a donc permis de développer de nouveaux nano-outils et de mieux appréhender leur utilité pour l'application de nanomédicines visant à éliminer et/ou modifier leur comportement de CSCs AC133 positives.

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Bourseau-Guilmain, Erika. "De la compréhension du comportement des cellules initiatrices de cancer dans les glioblastomes au développement d'une nanomédecine adaptée : Focalisation sur le marqueur de cellules souches cancéreuses AC133 / CD133." Angers, 2011. http://tel.archives-ouvertes.fr/tel-00662253/fr/.

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La mise en évidence de cellules initiatrices de cancer dans les glioblastomes et l'existence de cellules souches cancéreuses (CSCs) étayent la présomption que l'échec des stratégies anti-tumorales classiques puisse être attribué à un problème de cible cellulaire. Dans le contexte des thérapies ciblées, l'émergence des nanomédecines offre des perspectives pour la délivrance de principes actifs vers les CSCs ou leur microenvironnement (ou niche) en vue d'une meilleure efficacité, spécificité et sécurité biologique. Douées d'autorenouvellement et capables de générer des clones néoplasiques radio et chimiorésistants, les CSCs n'ont toutefois pas de marqueur exclusifs connus sinon des marqueurs associés permettant d'enrichir ces populations et de potentiellement établir un ciblage notamment locorégional au sein de ces tumeurs. En nous focalisant sur l'épitope AC133, marqueur de CSCs associé à des glycosylations de la protéine CD133 ou prominine-1, l'objectif de cette thèse a été: i) de comprendre la situation biologique traduite par l'expression d'AC133 (témoin d'initiation de tumeurs, d'agressivité tumorale ou d'hypoxie) ii) de développer une nanomédecine reconnaissant l'épitope AC133, iii) de déterminer, au regard de sa distribution au niveau de protrusions membranaires, le rôle fonctionnel de CD133/AC133. A partir de modèles in vitro et in vivo de glioblatomes humains implantés dans le cerveau de souris immunodéprimées (SCID), nos résultats établissent qu'AC133 est un témoin de non exposition chronique à une pression partielle élevée en oxygène (21% O2 versus 3% O2). Dans ce contexte la stratégie shRNA knockdown démontre que HIF-1α est un des régulateurs de l'expression d'AC133. L'absence d'AC133 à 21% O2 au sein de populations non triées de cellules de glioblastomes n'est pas reliée à l'initiation de tumeur mais en revanche associée à une perte d'agressivité tumorale. La cible AC133 a donc été choisie pour développer des nanocapsules lipidiques (NCLs) capables de reconnaitre des CSCs. A l'aide d'un polymère bifonctionnel, le DSPE-PEG2000-maleimide et de l'anticorps monoclonal AC133, une lipo-immunoglobuline (DSPE-PEG2000-maleimide- AC133), a été synthétisée puis post-insérée dans des NCLs permettant l'obtention d'immuno-NCLs. Ces nano-objets ont démontré leur fonctionnalité par leur spécificité de liaison à des cellules Caco-2 exprimant constitutivement AC133. Enfin, dans une dernière étude focalisée sur le rôle de AC133/CD133 dans l'endocytose, nous démontrons par siRNA knockdown sur des cellules Caco-2 que AC133/CD133 inhibe l'internalisation cellulaire de transferrine et de NCLs. De manière intéressante, l'augmentation de la concentration extracellulaire en fer, connue pour diminuer l'expression du récepteur de la transferrine, régule également négativement celle d'AC133, indiquant un rôle d'AC133/CD133 dans l'endocytose et dans le métaboslime du fer. L'ensemble de ce travail de thèse a donc permis de développer de nouveaux nano-outils et de mieux appréhender leur utilité pour l'application de nanomédicines visant à éliminer et/ou modifier leur comportement de CSCs AC133 positives
The discovery of cancer initiating cells in glioblastomas and the existence of cancer stem cells (CSCs) suggest that failure of current anti-tumor strategies could be attributed to a problem of target cell. In the context of targeted therapies, the emergence of nanomedicines offer new perspectives for drug delivery to CSCs or their microenvironment (or niche) thus getting more efficacy, specificity and biological safeness. Capable to self-renew and to generate radio and chemo-resistant neoplastic clones, CSCs do not have, however, specific markers but instead associated markers allowing their enrichment and potentially their targeting notably for loco-regional therapies. By focusing on the AC133 epitope, that is a CSC marker associated to glycosylation on the protein CD133 or prominin-1, the aim of this PhD thesis was to contribute understanding on: i) What the expression of AC133 is accounting for (tumor initiation, tumor aggressiveness or hypoxia) ii) If it is possible to recognize AC133 by nanocarriers iii) What is, regarding its distribution among membrane protrusions, the functional role of CD133/AC133. From in vitro and in vivo models of human glioblastomas implanted in the brain of immunodeprived mice (SCID), our data established that AC133 is a witness of non-chronic exposure to high oxygen tension (21% O2 versus 3% O2). In this context, the shRNA knockdown strategy allowed demonstrating that HIF-1α regulates AC133 expression. The lack of AC133 expression at 21% O2 within non sorted glioma cell populations is not related to the tumor initiation but instead associated to a loss of tumor aggressiveness. The AC133 target was therefore chosen to develop lipid nanocapsules (LNCs), capable of recognizing CSCs. By mean of a bifunctionnal a polymer (DSPE-PEG2000-maleimide) and the monoclonal antibody AC133, a lipo-immunoglobulin (DSPE-PEG2000-maleimide-AC133) was synthesized and post-inserted within LNCs, thus allowing the obtention of immuno-LNCs. Those nano-objects demonstrated their functionalities by their specificity of binding to Caco-2 cells, which constitutively express AC133. Finally, by giving attention to the role of AC133/CD133 in endocytosis, we demonstrated by siRNA knockdown on Caco-2 cells that AC133/CD133 inhibits the cell internalization of transferrin and NCLs. Interestingly, increase of extracellular iron concentration, known to disminish the expression of the tranferrin receptor, equally regulated negatively those of AC133, thus supporting a role for AC133/CD133 in endocytosis and in iron metabolism. Taken together, those PhD data allowed to develop a new nano-tool and to better apprehend its usefulness for the application of naomedicines aiming to eradicate and/or to modify the behaviour of CSCs expressing AC133

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Pinchuk, Iryna [Verfasser], am Esch Jan [Gutachter] Schulte, and Johannes [Gutachter] Bode. "Etablierung eines xenogenen Modells der warmen Leberischämie zur Untersuchung hepatisch-vaskulärer Adhäsion und Extravasation humaner CD133+ Knochenmarkstammzellen unter dem Einfluss von Thrombozyten / Iryna Pinchuk ; Gutachter: Jan Schulte am Esch, Johannes Bode." Düsseldorf : Universitäts- und Landesbibliothek der Heinrich-Heine-Universität Düsseldorf, 2020. http://d-nb.info/1214439667/34.

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Dissertations / Theses on the topic 'CD133+'

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