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1
Ding, Shunli. "Rôle du couple HGF/C-MET dans l'angiogenèse." Paris 7, 2004. http://www.theses.fr/2004PA077188.
2
Moore, Amy Elizabeth. "The role of HGF/Met signalling in colorectal tumorigenesis." Thesis, University of Bristol, 2012. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.544331.
3
Besret, Soizic. "Ligations chimiques : synthèse d'inhibiteurs extracellulaires de la signalisation HGF/SF-MET." Phd thesis, Université du Droit et de la Santé - Lille II, 2011. http://tel.archives-ouvertes.fr/tel-00630962.
Abstract:
Les peptides constituent une famille de biomolécules dont l'utilisation dans différents domaines thérapeutiques (cancer, diabète, sida) s'est fortement développée ces dernières années. Le défi pour les chimistes consiste à y accéder grâce à de nouvelles méthodes fiables et efficaces. La première partie de notre travail a d'abord été orientée vers le développement deux méthodes de ligations non natives efficaces et complémentaires de celles existant. La première méthode, appelée ligation thiocarbamate, permet d'obtenir des peptides alkylthiocarbamate avec de très bons rendements, alors que la seconde, appelée ligation azaGly, aboutit à la formation d'un azaGlypeptide. La seconde partie de cette thèse traite de la conception et synthèse de nouveaux peptides susceptibles d'inhiber la signalisation HGF/SF-MET. Le récepteur à activité tyrosine kinase MET et son ligand, l'HGF/SF (Hepatocyte Growth Factor/Scattor Factor), sont des cibles de choix pour une thérapie anti-cancéreuse. La ligation thiocarbamate, précédemment décrite, et la ligation thioéther plus classique ont été utilisées pour préparer une chimiothèque de peptides sulfonatés d'inhiber cette signalisation de façon extracellulaire. La capacité de liaison des composés de la chimiothèque avec le domaine extracellulaire de MET a été évaluée grâce à la technologie biopuces. L'activité biologique (tests MTT, d'activité kinase) des meilleurs produits a été ensuite évaluée.
4
Murat, Cahue de Bernardis. "Estudo molecular dos componentes da via de sinalização HGF/MET em insulinomas." Universidade de São Paulo, 2013. http://www.teses.usp.br/teses/disponiveis/5/5135/tde-03102013-110107/.
Abstract:
Os insulinomas são os tumores neuroendócrinos pancreáticos funcionantes mais frequentes, entretanto, os aspectos moleculares envolvidos em sua tumorigênese precisam ser melhor esclarecidos. As características morfológicas e histoquímicas dos insulinomas não conseguem predizer completamente seu comportamento biológico, apenas o fenótipo invasivo local e a presença de metástase são as formas confiáveis do diagnóstico maligno. A presente investigação teve por objetivos analisar a expressão gênica por reação em cadeia da polimerase (PCR) em tempo real e a expressão protéica por imuno-histoquímica dos componentes da via de sinalização do fator de crescimento hepatocítico (HGF) e seu receptor (c-MET) em 27 amostras de insulinomas, sendo: 16 tumores benignos grau 1 (G1), seis tumores benignos grau 2 (G2), dois insulinomas malignos grau 3 (G3) e três metástases hepáticas. Além disso, realizou-se a pesquisa de mutações somáticas no gene MET. Observou-se (1) o aumento da expressão dos genes HGF, MET e ST14 (codificante para a matriptase) e a baixa expressão do gene HAI-1 (codificante para a protease inibidora tipo-kunitz do tipo 1) nos insulinomas malignos e metástases quando comparados aos insulinomas benignos G1; (2) uma correlação positiva entre a expressão do mRNA do gene MET e o gene ST14 e índice proliferativo Ki-67, bem como uma correlação inversa entre a expressão do mRNA do gene HAI-1 e os genes MET, HGF, ST14 e o índice mitótico; (3) uma correlação positiva entre a expressão do gene ST14 e a expressão do mRNA do gene HGF; (4) maior expressão protéica de c-MET nos insulinomas malignos G3 em relação aos insulinomas G1/G2 e (5) ausência de mutações nos éxons 2, 10, 14, 16, 17 e 19 do gene MET. Concluiu-se que os genes HGF, MET, ST14 e HAI-1 estão diferencialmente expressos entre insulinomas malignos e benignos, o que pode ter implicações diagnósticas e terapêuticasIn an attempt to better understand the molecular processes involved in the tumourigenesis of islet beta-cells, the present study evaluated the expression of genes belonging to the hepatocyte growth factor and its receptor (HGF/MET) system, namely, MET, HGF; HGFAC and ST14 (encode HGF activator and matriptase, respectively, two serine proteases that catalyze conversion of pro-HGF to active HGF); and SPINT1 and SPINT2 (encode serine peptidase inhibitors Kunitz type 1 and type 2, respectively, two potent inhibitors of HGF activator and of matriptase) in 27 sporadic insulinomas; 16 grade 1 (G1), six grade 2 (G2), two grade 3 (G3) and three hepatic metastases. Quantitative reverse-transcriptase polymerase chain reaction was employed to assess RNA expression of the target genes and immunohistochemical analysis was used to evaluate the expression of MET and SPINT1. Somatic mutations of MET gene were searched by direct sequencing of exons 2, 10, 14, 16, 17 and 19. Overexpression of MET was observed in grouped G3 insulinomas and metastases concomitantly with upregulation of the genes encoding HGF and matriptase and downregulation of SPINT1. Positive correlations were observed between MET RNA expression and Ki-67 proliferation index while a negative correlation was detected between SPINT1 expression and the mitotic index. No somatic mutations were found in MET gene. The final effect of the increased expression of HGF, its activator (matriptase) and its specific receptor (MET) together with a decreased expression of one potent inhibitor of matriptase (SPINT1) is probably a contribution to tumoural progression and malignancy in insulinomas
5
Mekki, Meriem Sarah. "Conséquences de l'hypoxie sur la régulation de la signalisation HGF/SF-MET." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S047/document.
Abstract:
Le récepteur à activité tyrosine kinase MET et son ligand le facteur de croissance des hepatocytes (Hepatocyte Growth Factor/Scattor Factor (HGF/SF)) sont essentiels pour la migration, la morphogenèse et la survie des cellules épithéliales. En plus de son implication et son importance physiologiques, la dérégulation de la signalisation de MET favorise la progression et l’invasion tumorales dans plusieurs types de cancers. Au sein des tumeurs, l’hypoxie est également un phénomène crucial qui induit une réponse adaptative menant à l’invasion, la métastase cancéreuses et la résistance aux traitements.Nous avons démontré que dans des conditions hypoxiques, la phosphorylation de MET induite par sa liaison au ligand, des mutations activatrices ou sa surexpression, est diminuée de manière importante in vitro et in vivo dans des modèles de tumeurs expérimentales chez la souris. Cette baisse de phosphorylation est très rapide et est réversible quand les cellules sont replacées en normoxie. Alors que la phosphorylation de GAB1, principal partenaire de MET, est également diminuée en hypoxie, l’activation des voies de signalisation en aval AKT et ERK n’est pas affectée et reste bien dépendante de l’activité du récepteur et du recrutement de GAB1. De la même façon, l’HGF/SF induit des réponses de motilité, de dispersion, de morphogenèse et de survie similaires en normoxie et en hypoxie. De manière intéressante, le traitement par deux inhibiteurs de tyrosine kinase (ITK) ciblant MET (PHA-665752 et SU11274) est moins efficace en hypoxie pour inhiber les voies de signalisation AKT et ERK ainsi les réponses cellulaires induites par MET. Comme pour la phosphorylation de MET, la résistance à ces ITK est un phénomène réversible. Ainsi, alors que l’hypoxie n’affecte pas les voies de signalisation en aval ni les effets biologiques, elle diminue la sensibilité de MET aux ITK induisant donc une résistance immédiate. L’ensemble de ces données pourrait fournir de nouvelles perspectives dans l’utilisation des thérapies ciblant MET dans les tumeurs solidesThe receptor tyrosine kinase MET and its ligand the Hepatocyte Growth Factor/Scattor Factor (HGF/SF) are essential for migration, morphogenesis and survival of epithelial cells. Beside its physiological involvement, deregulation of MET signaling has been shown to promote tumor progression and invasion in many cancers. Inside the tumors, hypoxia is also a crucial phenomenon promoting an adaptive response able to induce invasion, metastasis and resistance to treatment.We show that under hypoxia, MET phosphorylation induced by ligand-stimulation, activating mutation or overexpression, is drastically decreased both in cell culture and in experimental tumors. This decrease in MET phosphorylation occurs within minutes and is reversible when cells are returned to normoxia. While phosphorylation of the proximal signaling adaptor GAB1 is also decreased in hypoxia, activation of the downstream kinases ERK and AKT is not affected, but is still dependent on MET receptor activity. Consistently, several cellular responses induced by HGF/SF, including motility, morphogenesis or survival, are still efficiently induced. Interestingly, treatment with two tyrosine kinase inhibitors targeting MET (PHA-665752 and SU11274) are less efficient to inhibit the downstream kinases ERK and AKT and cellular responses induced by MET in hypoxia compared to normoxia. Similarly to MET phosphorylation, this resistance to TKI is a reversible phenomenon. Therefore, while hypoxia does not affect downstream signaling and cellular responses, it decreases MET sensitivity to TKIs targeting the receptor thus providing an immediate resistance. This may provide new insights in the use of MET targeted therapies in solid tumors
6
Tjin, Esther Pit Mien. "The HGF/MET and WNT signaling pathways in B cell differentiation and neoplasia." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host}, 2005. http://dare.uva.nl/document/17835.
7
Stefan, Monica. "Identifizierung eines neuen Interaktionspartners des HGF-Rezeptors c-Met SHIP-1 spielt eine Schlüsselrolle bei der Vermittlung der HGF-induzierten Tubulogenese von Epithelzellen /." [S.l.] : [s.n.], 2001. http://deposit.ddb.de/cgi-bin/dokserv?idn=961707232.
8
Arlt, Franziska. "Das neu identifizierte Gen MACC1 ist ein Regulator des HGF/Met-Signalweges und ist prognostisch für die Metastasierung des Kolonkarzinoms." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2009. http://dx.doi.org/10.18452/15974.
Abstract:
Das Kolonkarzinom ist eine der häufigsten Tumorerkrankungen weltweit. Etwa 50 % der Patienten entwickeln Fernmetastasen. Diese haben eine sehr schlechte Überlebensprognose. Deshalb fokussiert die Forschung auf die Identifizierung neuer, molekularer Marker für eine verbesserte Metastasierungsvorhersage. Identifizierte Hochrisiko-Patienten könnten somit rechtzeitig eine individualisierte, intensivere Therapie erhalten. MACC1 (Metastasis-associated in colon cancer 1) ist ein neu identifiziertes Gen, das in Kolonkarzinomen und deren Fernmetastasen überexprimiert wird. Die Domänenstruktur von MACC1 ist kennzeichnend für Proteine der Rezeptor-Tyrosinkinase-Signalwege. Ziel dieser Arbeit war die Aufklärung der zellulären Funktion von MACC1 und seiner Rolle in der Tumorprogression sowie die Evaluierung von MACC1 als molekularer Metastasierungsmarker. MACC1-überexprimierende Tumorzellen zeigten in Abhängigkeit von der Domänenstruktur in in vitro Assays ein erhöhtes migratorisches, invasives und proliferatives Potential. Der Einfluss von MACC1 auf die Metastasierungskapazität von Tumorzellen konnte auch im Tiermodell belegt werden. Der Hepatocyte-growth-factor (HGF) induziert die epitheliale-mesenchymale Transition MACC1-exprimierender Zellen und die nukleäre Translokation von MACC1. Die Expression des HGF-Rezeptors Met war in diesen Zellen stark erhöht. Reportergen-Studien bestätigten die transkriptionelle Regulation von Met durch MACC1. Die Analyse humaner Kolonkarzinome ergab eine signifikant höhere MACC1 Expression in Primärtumoren mit metachroner Fernmetastasierung. MACC1 ist ein neu identifizierter Regulator des HGF/Met-Signalweges und trägt somit entscheidend zur Determinierung des metastatischen Potentials von Tumorzellen bei. MACC1 hat großes Potential als neuer, prognostischer Marker für die Metastasierung des Kolonkarzinoms und ist ein Kandidatengen als Ziel effektiver, molekularer Interventionsstrategien zur Metastasierungs-Prävention.Colon cancer is one of the most frequent malignant diseases worldwide. About 50% of the patients develop distant metastasis. These patients have only few therapy options and very poor survival rates. Therefore cancer research focuses on the identification of novel molecular markers to provide a better prognosis of the metastatic risk. Identified high-risk patients would get access to an early, individualized therapy. MACC1 (metastasis associated in colon cancer 1) is a newly identified gene that is overexpressed in colon carcinomas and their distant metastases. The MACC1 domain structure is characteristic for proteins of the receptor tyrosine kinase signalling pathways. Aim of this study was the analysis of the cellular function of MACC1, its role in tumor progression and its evaluation as a molecular, prognostic marker for metastasis. MACC1 overexpressing tumor cells revealed higher migratory, invasive, and proliferative potential in in vitro assays. The impact of MACC1 on the metastatic potential of tumors was also shown in mouse models. The hepatocyte growth factor (HGF) induced epithelial-mesenchymal-transition in MACC1 positive cells and MACC1´s nuclear translocation. Expression of the HGF receptor Met was strongly elevated in these cells. Reporter gene experiments confirmed the transcriptional regulation of Met by MACC1. Analyses in human colon carcinomas showed a significantly higher MACC1 expression in tumors that developed distant metastases. MACC1 is a newly identified regulator of the HGF/Met signalling pathway. It contributes decisively to the metastatic capacity of tumor cells. MACC1 has great potential as new prognostic marker for colon cancer metastasis and is a promising candidate as target for effective, molecular intervention strategies for metastasis prevention.
9
Rocha, Angélica Gomes 1989. "Estudo da expressão proteica da via HGF/c-Met/STAT3 no carcinoma diferenciado da tiroide." [s.n.], 2014. http://repositorio.unicamp.br/jspui/handle/REPOSIP/310289.
Abstract:
Orientadores: Laura Sterian Ward, Antônio Hugo José Fróes Marques CamposDissertação (mestrado) - Universidade Estadual de Campinas, Faculdade de Ciências Médicas
Made available in DSpace on 2018-08-26T01:02:11Z (GMT). No. of bitstreams: 1 Rocha_AngelicaGomes_M.pdf: 1644333 bytes, checksum: e3503fb6e2c8209f7a6696df111d6a78 (MD5) Previous issue date: 2014
Resumo: Marcadores de malignidade, especialmente capazes de distinguir lesões de padrão folicular, que sejam de fácil implantação na rotina do diagnóstico de nódulos tireoidianos, continuam sendo extremamente necessários, dado o crescente aumento de nódulos tireoidianos diagnosticados nos últimos anos. A via HGF/c-Met/STAT3 está relacionada com desenvolvimento e progressão tumoral, sendo que a expressão de c-Met, HGF e de STAT3 foram descritas em grande parte dos carcinomas papilíferos de tireoide (CPT), mas não em tecido tireoidiano normal, sugerindo sua relação com o desenvolvimento e progressão do CPT. Para avaliar a utilidade da expressão proteica de c-Met, HGF, STAT3, e de sua proteína fosforilada (pSTAT3) no diagnóstico e no prognóstico de pacientes com nódulos tireoidianos, analisamos 356 tecidos tireoidianos, sendo 153 carcinomas papilíferos (CPT), dos quais 95 eram clássicos (CPC), 47 carcinomas papilíferos variante folicular (CPVF), e 11 carcinomas papilíferos de células altas (CPCA); 34 carcinomas foliculares (CFT), 34 adenomas foliculares (AF), 124 bócios e 11 tecidos normais. Todos os pacientes foram tratados e acompanhados de acordo com um mesmo protocolo padrão por 1-10 anos (Mo=5 anos). Áreas representativas do tecido foram selecionadas para a construção de uma lâmina de tissue microarray (TMA) que foi submetida à técnica de imunoistoquímica e analisada pelo score de Allred. A expressão citoplasmática de c-Met foi capaz de diferenciar nódulos malignos de benignos (p<0,0001, sensibilidade 86%, especificidade 76%, VPP 77%, VPN 86%); CPT de CF (p=0,0003, sensibilidade 96%, especificidade 31%, VPP 87%, VPN 63%); variante folicular de CPT de CF (p=0,0232 sensibilidade 93%, especificidade 31%, VPP 66%, VPN 77%); assim como variante folicular de CPT de AF (p=0,0003, sensibilidade 93%, especificidade 50%, VPP 68%, VPN 87%). Além disso, a expressão de c-Met se correlacionou com tireoidite (p<0,0001) e multifocalidade (p=0,0028), mas não com presença de cápsula, invasão, tamanho do tumor, estadiamento TNM, e presença de metástase no diagnóstico e na evolução. A expressão nuclear de STAT3 diferenciou os nódulos benignos dos malignos (p<0,0001, sensibilidade 83%, especificidade 74%, VPP 75%, VPN 83%); CF de AF (p=0,0457, sensibilidade 80%, especificidade 52%, VPP 65%, VPN 71%); bócios de CPT variante folicular (p<0,001, sensibilidade 89%, especificidade 65%, VPP 91%, VPN 60%); bócio de CF (p<0,0001, sensibilidade 89%, especificidade 80%, VPP 95%, VPN 60%); bócio de AF (p=0,0005, sensibilidade 89%, especificidade 80%, VPP 95%, VPN 60%). Além disso, a expressão de STAT3 se correlacionou com tireoidite (p=0,0095) e multifocalidade (p<0,0001), mas não com presença de cápsula, invasão, tamanho do tumor, estadiamento TNM, e presença de metástase no diagnóstico e na evolução. A expressão de pSTAT3 e HGF não auxiliou no diagnóstico dos nódulos, e tampouco se correlacionou com características de agressividade dos tumores. Conclui-se que as proteínas c-Met e STAT3 podem ser consideradas marcadores clínicos úteis na rotina de laboratórios, uma vez que foram capazes de diferenciar os nódulos malignos dos benignos, alguns tipos histológicos dos nódulos, além de se correlacionarem com fatores de agressividade dos tumores
Abstract: Malignancy markers, especially the ones that are capable of distinguishing follicular lesions and with easy deployment in the routine diagnosis of thyroid nodules are much needed, given the increasing number of thyroid nodules in recent years. The HGF/c-Met/STAT3 pathway is related to the development and progression of many types of cancers, and c-Met, HGF and STAT3 expression were described in most papillary thyroid carcinomas (PTC), but not in normal thyroid tissue, suggesting it is related with the development and progression of PTC. To evaluate the usefulness of c-Met, HGF, STAT3, and its phosphorylated form (pSTAT3) protein expression in the diagnosis and prognosis of patients with thyroid nodules, we analyzed 356 thyroid tissues, including 153 papillary carcinomas (PTC), 95 classical type, 47 follicular variants of papillary carcinoma, and 11 tall cells carcinomas; 34 follicular carcinomas (FC), 34 follicular adenomas (FA), 124 goiters and 11 normal tissues. All patients were treated and monitored according to the same standard protocol for 1-10 years (Mo = 5 years). Representative tissue areas were selected for the construction of a tissue microarray (TMA) which was subjected to immunohistochemistry and analyzed by the Allred score. The cytoplasmic expression of c-Met was able to differentiate malignant from benign nodules (p <0.0001, sensitivity 86%, specificity 76%, PPV 77%, 86% NPV); PTC from FCT (p = 0.0003, sensitivity 96%, specificity 31%, PPV 87%, 63% NPV); follicular variant of PTC from FCT (p = 0.0232 sensitivity 93%, specificity 31%, PPV 66%, NPV 77%); as well as follicular variant of CPT from FA (p = 0.0003, sensitivity 93%, specificity 50%, PPV 68%, 87% NPV). Furthermore, c-Met expression was correlated to the presence of thyroiditis (p<0.0001) and multifocality (p=0.0028), but not with the presence of capsule, invasion, tumour size, TNM staging, and metastasis at diagnosis or evolution of the disease. The nuclear expression of STAT3 differentiated benign from malignant nodules (p <0.0001, sensitivity 83%, specificity 74%, PPV 75%, NPV 83%); FCT from FA (p = 0.0457, sensitivity 80%, specificity 52%, PPV 65%, NPV 71%); goiter follicular variant of PTC (p <0.001, sensitivity 89%, specificity 65%, PPV 91%, 60% NPV); goiter from FCT (p <0.0001, sensitivity 89%, specificity 80%, PPV 95%, NPV 60%); goiter from FA (p = 0.0005, sensitivity 89%, specificity 80%, PPV 95%, NPV 60%). In addition, STAT3 expression was associated with thyroiditis (p=0.0095) and multifocality (p<0.0001), but not with the presence of capsule, invasion, tumour size, TNM staging, and metastasis at diagnosis or evolution of the disease. The expression of pSTAT3 and HGF did not help the diagnostic of nodules and was not correlated with any tumour characteristic of aggressiveness. We concluded that c-Met and STAT3 could be useful as molecular markers in laboratory routine, helping to differentiate malignant from benign nodules, and some histological types of nodules, and was also associated with some tumour characteristics of aggressiveness
Mestrado
Ensino em Saúde
Mestra em Clínica Médica
10
Chmielowiec, Jolanta. "The role of the Met tyrosine kinase receptor in skin maintenance and regeneration." Doctoral thesis, Humboldt-Universität zu Berlin, Mathematisch-Naturwissenschaftliche Fakultät I, 2007. http://dx.doi.org/10.18452/15690.
Abstract:
Met und der korrespondierende Ligand HGF/SF sind im hyperproliferativen Epithelium von Hautwunden exprimiert. Aus diesem Grund ist es wahrscheinlich, dass der Rezeptor und sein Ligand in autokriner Weise wechselwirken und wichtige Funktionen für den Heilungsprozess der Haut besitzen. Unter Verwendung der Keratin 14 Cre-Rekombinase konnte ein „Knockout“ des Met-Rezeptors spezifisch in der Epidermis erzielt werden. In der Tat zeigten die Ergebnisse, dass Met für die Re-epithelisierung in Wundschlussprozessen essentiell ist, da in den an der Wundheilung beteiligten Keratinozyten keine Rekombination des Met-Gens stattgefunden hat. In Met-Mausmutanten war der Wundschlussprozess verlangsamt, denn er erfolgte ausschließlich durch wenige Keratinozyten, in denen die Cre-Rekombinase keine Rekombination bewirkte. Met konnte als erstes Gen identifiziert werden, das absolut erforderlich für Re epithelisierungsprozesse von Wunden ist. Diese Arbeit trägt daher wesentlich zum Verständnis der Regulation von Wundheilungsprozessen bei.Met and its ligand, HGF/SF are expressed in the hyperproliferative epithelium of the wound. This suggests that receptor and ligand may act in an autocrine manner to promote wound healing in the skin. Using Keratin 14 cre recombinase, Met receptor was specifically knockout in the epidermis. In this way, it was demonstrated that Met receptor is essential for wound healing process and that keratinocytes, which contributed to the wound closure were Met-postitive. In the Met mutant mice, wound closure was slightly attenuated, but occurred exclusively by a few keratinocytes that had escaped recombination. Met is therefore the fist gene, which is absolutely required for re-epithelialization of the wound. This finding is fundamental for understanding the regulation of wound healing process.
11
Lagoutte, R. "Novel heparin mimics as inhibitors of HGF-induced activation of Met : design, synthesis and biological evaluation." Thesis, University of Salford, 2010. http://usir.salford.ac.uk/26766/.
Abstract:
In chapter one, hepatocyte growth factor HGF, its receptor, the tyrosine kinase Met and their biological implications are introduced, and the structure and role of the glycosaminoglycans (GAGs) heparan sulfate and heparin are described. An account of the previous work on the project is given, setting aims for this project. In chapter two, the syntheses of the two best compounds of the first generation of mimics is described, thereby resolving the structural ambiguities of those compounds. An efficient sulfation methodology is described. Docking results for the two mimics to NK1 using AutoDock Vina are reported. In chapter three, the design of a new generation of compounds is described, based on conformational restrictions: results of a virtual screen of 36 compounds are reported along with a newly written script for automated virtual screening. In chapter four, efforts towards the synthesis of 2-substituted chroman derivatives are described: an easy two-step methodology for the preparation of chroman-2-ones is described, from which a three-step sequence allows access to various 2-substituted chromans. In chapter five, efforts towards the synthesis of 3- and 4-substituted chroman derivatives are described. In chapter six, attempts to apply the 2-substituted chroman derivative prepared in chapter four to the total synthesis of erythrococcamide B are described. A new one-step methodology for the preparation of 2-allyl chroman derivatives from chroman-2-ones, via reductive allylation using EtsSiH-lnBrs-allylTMS, is reported with its application to the synthesis of Erythrococcamide B. In chapter seven, conclusions are drawn and directions for future work proposed.
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Vasconcelos, Artur Cunha. "Avaliação da via de sinalização HGF/C-MET em neoplasias benignas e malignas de glândulas salivares." reponame:Biblioteca Digital de Teses e Dissertações da UFRGS, 2014. http://hdl.handle.net/10183/102475.
Abstract:
As neoplasias de glândula salivar (NGS) são tumores raros que despertam interesse por sua diversidade histopatológica e comportamento clínico. A compreensão da patobiologia assim como, dos mecanismos envolvidos no comportamento invasivo destas lesões é necessária para melhor entender a biologia das NGS e posteriormente delinear novas estratégias terapêuticas. A presente tese foi dividida em dois artigos. O objetivo do primeiro estudo foi descrever os dados demográficos, clinicopatológicos e de prognóstico das NGS diagnosticados em um centro de atenção terciário. Para tal, foi realizada uma análise retrospectiva utilizando os dados de arquivos e de prontuários. Foram identificados 109 casos de NGS cuja média de idade dos pacientes foi de 46.47 anos e a relação homens:mulheres foi de 0.94:1. As glândulas salivares maiores foram mais acometidas (75.2%) e os tumores benignos os mais prevalentes (75.2%) sendo o adenoma pleomórfico o tumor benigno mais comum e o carcinoma adenóide cístico o principal maligno. O objetivo do segundo estudo foi analizar o padrão de expressão da via de sinalização do HGF/c-Me/PI3K em NGS e correlacionar com o perfi proliferativo e desfechos clínicos das lesões. Foram construídos microarranjos de tecido (TMAs) de 93 casos de NGs e as lâminas foram submetidas a análise imunoistoquímica para HGF, p-Met, p-Akt e Ki67. Foi observada maior expressão de HGF nos tumores benignos (p=0.04), enquanto que as protínas p-Met (p=0.03), p-Akt (p=0.00) e Ki-67 (p=0.00) foram mais expressas nos tumores malignos. Nas neoplasias malignas houve maior ativação da via HGF observada pela maior expressão do seu receptor fosforilado (p-Met) bem como, maior ativação da via do PI3k pela fosforilação de Akt (p-Akt) resultando em um maior perfil proliferativo. Pode-se concluir que a via de sinalização do HGF/c-Met/PI3k parece estar ativa nas NGS regulando a proliferação especialmente nas neoplasias malignas.Salivary gland tumors (SGT) are rare yet interesting neoplasms due to their histopatological diversity and clinical behavior. Understanding the pathobiology as well as the mechanisms involved in the invasive behavior of these lesions is needed to better comprehend the biology of SGT and further delineate new therapeutic strategies. This thesis was divided in two papers. The aim of the first study was to describe the demographic, clincopathological and prognostic data of SGT diagnosed in a tertiary care center. For this purpose, a retrospective analysis using data from the archives and records was performed. One hundred and nine cases of SGT were identified. The patients mean age was 46.47 years and the male:female ratio was 0.91:1. The major salivary glands were the most affected (75.2%) and the benign SGT were more prevalent (78%) being pleomorphic adenoma the most common benign tumor and adenoid cystic carcinoma the most common malignant tumor. The objective of the second study was to analyze the expression pattern of HGF/c-Met/PI3K signaling pathway in SGT and correlate the findings with the proliferative profile and clinical outcomes of cases. Tissue microarrays (TMAs) of 93 cases of SGT were constructed; the slides were submitted to immunohistochemical analysis for HGF, p-Met, p-Akt and Ki-67. Increased expression of HGF was observed in benign tumors (p = 0.04), while p-Met (P = 0.03), p-Akt (p = 0:00) and Ki-67 (p = 0:00) were most expressed in malignant tumors. In salivary glands carcinomas there was a higher activation of the HGF pathway observed by the higher expression of its phosporylated receptor (p-Met) as well as the higher activation of PI3k pathway through Akt (p-Akt) phosphorilation, resulting in a higher proliferative profile. It can be concluded that HGF/c-Met/PI3K signaling pathway appears to be active in SGT regulating the proliferation specially in malignant tumors.
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Pante, Guido. "Mitogen-inducible-gene-6 is an endogenous inhibitor of HGF/Met-induced cell migration and neurite growth." Diss., lmu, 2005. http://nbn-resolving.de/urn:nbn:de:bvb:19-42005.
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Derksen, Patrick William Bernd. "Regulation of cell growth in multiple myeloma a role for the HGF/MET and WNT signaling pathways /." [S.l. : Amsterdam : s.n.] ; Universiteit van Amsterdam [Host], 2003. http://dare.uva.nl/document/70285.
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Genestine, Schmitt Matthieu. "Etude fonctionnelle du système HGF/Met au cours du développement normal et pathologique du système nerveux central." Aix-Marseille 2, 2009. http://theses.univ-amu.fr.lama.univ-amu.fr/2009AIX22072.pdf.
Abstract:
Les signaux participant au développement embryonnaire du système nerveux central peuvent à nouveau intervenir à l’âge adulte, notamment lors d’une pathologie. Nous avons analysé si le couple HGF/Met peut avoir de telles fonctions. Aussi, nous avons généré des souris porteuses d’une mutation conditionnelle de Met spécifique du système nerveux. Nous avons montré que 1) dans le cerveau, Met participe à l’établissement de l’équilibre entre circuits excitateurs et inhibiteurs et 2) dans la moelle épinière, HGF/Met sont requis in vivo pour la survie d’un sous-type de motoneurones. Nous avons aussi montré l’intérêt du rôle neuroprotecteur de Met dans deux conditions pathologiques : un modèle murin de la sclérose latérale amyotrophique et dans la rétine après axotomie du nerf optique. Cette étude a montré que le système HGF/Met possède des propriétés trophiques spécifiques lors du développement des MNs et permet dans le cas d’une neurodégénérescence de protéger les neurones contre l’apoptoseSignals involved in development of the embryonic central nervous system can also play a role during adulthood, particularly in some pathologies. In order to analyze whether the HGF/Met system would have such functions, we generated met conditional mutant mice in which met is specifically removed in the nervous system. Using these mice, we have shown that 1) in the brain, Met is part of a system which controls the balance between excitatory and inhibitory circuits and 2) in the spinal cord, HGF/Met signaling is required in vivo for the survival of a specific subtype of motor neurons (MNs). We have also demonstrated the neuroprotective effect of HGF/Met in two pathological conditions such as the amyotrophic lateral sclerosis and after optic nerve axotomy. In conclusion, this work has allowed us to show the trophic properties of HGF/Met during normal development of specific subtypes of MNs, and its neuroprotective effect in neurodegenerative mouse models
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Le, Goff Arnaud. "Systèmes protéolytiques ciblant la protéine multi-adaptatrice GAB1 dans la régulation de la signalisation HGF/SF-MET." Thesis, Lille 2, 2011. http://www.theses.fr/2011LIL2S026.
Abstract:
La protéine multi-adaptatrice GAB1 (GRB2-associated binder-1) est essentielle pour transmettre la signalisation et les réponses biologiques du récepteur tyrosine kinase MET activé par son ligand, l’HGF/SF (Hepatocyte Growth Factor/Scatter Factor), et joue un rôle positif dans de nombreuses autres voies de signalisation cellulaires. Son implication majeure dans la signalisation HGF/SF-MET s’explique par le fait que GAB1 est un partenaire direct de MET, notamment via un domaine d’interaction spécifique avec la partie C-terminale de MET, tandis que GAB1 est un acteur moléculaire indirect pour d’autres récepteurs, y compris certains portant également une activité tyrosine kinase. Au cours de ma thèse, nous avons documenté par des approches d’extinction de l’expression de GAB1 (siRNA) dans divers types cellulaires, son rôle indispensable dans la signalisation HGF/SF-MET, à la fois pour l’induction des voies Ras/ERK et PI3K/Akt. Ces résultats sont en accord avec les travaux permettant de conclure que GAB1 amplifie la signalisation HGF/SF-MET. De manière originale, nous avons montré que GAB1 joue également un rôle important dans des conditions conduisant à l’inactivation de la signalisation HGF/SF-MET. D’une part, nous avons établi que suite à l’activation de MET par l’HGF/SF, le récepteur induit la dégradation de GAB1 par le système ubiquitine-protéasome et que ce processus participe activement à la régulation négative de l’activation de la voie Ras/ERK. D’autre part, nous avons démontré que GAB1, comme MET, est une cible fonctionnelle des caspases activées lors de stress apoptogènes. Lors d’un stress modéré, des clivages caspases-dépendants de GAB1 conduisent à la génération d’un fragment stable, p35-GAB1, contenant le domaine d’interaction avec MET et présentant une activité anti-apoptotique liée notamment à sa capacité à maintenir l’activation de la voie de survie PI3K/Akt. Lors de stress extrêmes ou prolongés, il est possible que p35-GAB1 présente une activité pro-apoptotique. Nous avons donc mis en évidence que GAB1 occupe une place primordiale dans la signalisation HGF/SF-MET à la fois pour transmettre et pour réguler en retour ces signaux de transduction en fonction du contexte cellulaire.Pour conclure, il est clair que la signalisation HGF/SF-MET joue un rôle physiologique essentiel et sa dérégulation est associée à la progression tumorale et métastatique de nombreux cancers. En accord avec notre démonstration de la contribution majeure de GAB1 dans tous les aspects de la signalisation HGF/SF-MET, il est envisageable que GAB1 puisse contribuer à la tumorigenèse dépendante de l’activation du récepteur MET et représenter, de ce fait, une cible d’intérêt pour de nouvelles approches thérapeutiques anti-cancéreusesThe docking protein GAB1 (GRB2-associated binder-1) is essential for transmitting signals and biological responses of the MET receptor tyrosine kinase activated by its ligand, HGF/SF (Hepatocyte Growth Factor/Scatter Factor), and plays a positive role in many other cell signaling pathways. Its major involvement in HGF/SF-MET signaling can be explained by the fact that GAB1 is a direct partner of MET, in particular through a specific interaction domain with the C-terminus of MET, while GAB1 is an indirect molecular player for other receptors, including some of them with intrinsic tyrosine kinase activity.During my thesis work, we have documented through RNA interference-mediated extinction of GAB1 expression in various cell types, its crucial role in HGF/SF-MET signaling, both for the induction of Ras/ERK and PI3K/Akt pathways. These results are consistent with other data supporting the conclusion that GAB1 amplifies HGF/SF-MET signaling. In an original way, we have shown that GAB1 also plays an important role in conditions leading to the inactivation of HGF/SF-MET signaling. First, we demonstrated that, following its activation by HGF/SF, MET receptor induces GAB1 ubiquitin-proteasome-mediated degradation and that this process is actively involved in the down-regulation of Ras/ERK pathway downstream of MET. Furthermore, in line with our previous demonstrations that the MET receptor is a functional target of caspases, we established that GAB1 is also degraded and cleaved by caspases in response to stress. Under mild stress conditions, caspase-dependent cleavages of GAB1 lead to the generation of a stable fragment, p35-GAB1, containing the MET binding domain and exhibiting anti-apoptotic functions due to its ability to maintain activation of the PI3K/Akt survival pathway. In case of extreme or prolonged stress, it is possible that p35-GAB1 shows a pro-apoptotic activity. We have therefore highlighted that GAB1 plays a key role in HGF/SF-MET signaling for both transmit and feedback regulate signal transduction, depending on cellular context.Finally, it is clear that HGF/SF-MET signaling plays an essential physiological role and its deregulation is associated with tumor progression and metastasis of many cancers. According to our demonstration of the major contribution of GAB1 in all aspects of HGF/SF-MET signaling, it is possible that GAB1 may contribute to MET receptor activation-dependent tumorigenesis and thus, represent a target of interest for new anti-cancer therapeutic approaches
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Daudigeos, Dubus Estelle. "EVALUATION DE L’INHIBITION DE L’ANGIOGENESE DANS LE NEUROBLASTOME ET CARACTERISATION DE MECANISMES DE RESISTANCE." Thesis, Paris 11, 2014. http://www.theses.fr/2014PA11T096.
Abstract:
Adulte ou pédiatrique, les tumeurs solides ont besoin d’oxygène et de nutriments pour se développer et métastaser. Leur apport est assuré par la néo-vascularisation tumorale issue d’un processus multifactoriel appelé l’angiogénèse. Son équilibre est maintenu par une balance entre facteurs pro- et anti-angiogéniques. Elle fait partie des principales cibles pour traiter les cancers et l’inhibition de la voie VEGF en est un facteur clé. Cependant, la réponse aux agents anti-angiogéniques a montré, malgré des résultats encourageants, un effet transitoire associé à l’apparition d’une résistance adaptative de la tumeur.Nous avons étudié l’inhibition de l’angiogénèse et les mécanismes potentiels d’échappement dans les tumeurs pédiatriques solides, et principalement dans le neuroblastome. Le neuroblastome est une tumeur originaire de la crête neurale et atteint généralement l’enfant jeune. Nous avons exploré l’effet anti-tumoral de l’inhibition sélective des récepteurs 1, 2, 3 du VEGF à l’aide de l’inhibiteur à tyrosine kinase axitinib dans divers modèles précliniques de neuroblastome. L’axitinib a montré une activité anti-tumorale modérée associée à une inhibition de la vascularisation. Néanmoins, après un traitement prolongé in vitro, les cellules tumorales IGR-N91-Luc deviennent résistantes à l’axitinib. Elles prolifèrent normalement mais secrètent de «l’ hepatocyte growth factor» (HGF) et activent la voie MAPK. In vivo, le traitement prolongé par axitinib entraîne le développement d’un phénotype plus agressif de la tumeur avec l’augmentation du nombre d’animaux présentant des métastases, associée à une activation de la voie SRC. Ceci nous a conduit à explorer l’effet d’une inhibition ciblant principalement VEGFR2 et MET (récepteur à l’HGF) avec le cabozantinib. Ainsi nous avons contrôlé le développement tumoral en inhibant la néo-vascularisation et l’activation de SRC, et induit la mort cellulaire dans le modèle orthotopique IGR-N91-Luc et inhibé le développement métastatique dans le modèle systémique IMR-32-Luc. Par ailleurs, nous avons étendu notre exploration à d’autres facteurs jouant un rôle dans l’angiogénèse comme FGFR ou PDGFR car ils représentent, comme MET, de puissants oncogènes. Pour cibler simultanément VEGFR et PDGFR, nous avons utilisé l’inhibiteur multi-kinase regorafenib. In vivo, à des doses bien tolérées qui permettent un traitement prolongé, le regorafenib a montré une activité anti-tumorale significative. Cet effet a été associé principalement à une forte inhibition de la vascularisation mais également à l’induction de la mort cellulaire. En élargissant notre étude à d’autres modèles de tumeurs pédiatriques, nous avons observé que son activité est indépendante du type histologique. Compte tenu du caractère oncogénique de PDGFR, nous avons évalué cet inhibiteur dans des modèles présentant une amplification du gène PDGFRA, qui entraine une surexpression et une activation forte du récepteur. Combiné avec des thérapies standards capables d’induire des dommages à l’ADN telles que l’irradiation ou l’irinotecan, l’effet du regorafenib a été potentialisé, notamment dans les modèles amplifiés pour le gène PDGFRA se traduisant par des régressions tumorales. Ces évaluations précliniques soutiennent le développement d’une nouvelle stratégie thérapeutique pour les enfants atteints de tumeurs solidesSolid tumors either adult or pediatric need oxygen and nutrients to grow and metastasize. Their input is provided by tumor neovascularization after a multifactorial process called angiogenesis. Balance is maintained by equilibrium between pro and anti-angiogenic factors. It is one of the main targets for treating cancers and the inhibition of the VEGF pathway is a key factor. However, despite encouraging results, the response to anti-angiogenic agents showed a transient effect associated with the development of an adaptive tumor resistance. We studied the inhibition of angiogenesis and potential escape mechanisms in solid pediatric tumors, mainly in neuroblastoma. Neuroblastoma is a solid tumor derived from the neural crest and it usually affects childhood. We investigated the anti-tumor effect of selective inhibition of VEGF receptors 1, 2, 3 using the tyrosine kinase inhibitor axitinib in various preclinical neuroblastoma l models. Axitinib showed a moderate anti-tumor activity associated with the inhibition of vascularization. However, after prolonged treatment in vitro, tumor cells IGR-N91-Luc become resistant to axitinib. They proliferate normally but secrete the "hepatocyte growth factor" (HGF) and activate the MAPK pathway. In vivo, prolonged treatment by axitinib results in the development of a more aggressive tumor phenotype with an increase in the number of animals exhibiting metastases associated with an activation of SRC signaling. This led us to explore the effect of inhibiting concomitant VEGFR2 and MET (HGF receptor), main cabozantinib targets. So we stabilized tumor growth by inhibiting the neovascularization and activation of SRC, induced cell death in the orthotopic model IGR-N91-Luc and inhibited metastatic development in the IMR-32-Luc systemic model. In addition, we extended our exploration of other factors that play a role in angiogenesis like FGFR or PDGFR because they represent, like MET, powerful oncogenes. To simultaneously target VEGFR and PDGFR, we used the multi-kinase inhibitor regorafenib. In vivo, at well-tolerated doses that allow prolonged treatment, regorafenib showed significant anti-tumor activity. This effect was mainly associated with a strong inhibition of vascularization, but also (with) induction of cell death. By expanding our study to other models of pediatric tumors, we observed that its activity was independent of histologic type. Given the oncogenic character of PDGFR, we evaluated the inhibitor in models which present a PDGFRA gene amplification, which results in a strong activation of the receptor. Combined with standard therapies that can induce DNA damages such as irinotecan or radiation, the effect of regorafenib was potentiated, mainly in PDGFRA gene amplified models, where tumor regressions were obtained. These preclinical evaluations support the development of a new therapeutic strategy for children with solid tumors
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Schmitz, Katja [Verfasser]. "Molekularpathologische Charakterisierung von MET- und HGF-Alterationen als potentielle prädiktive Biomarker in Weichgewebstumoren und gastrointestinalen Stromatumoren / Katja Schmitz." Köln : Deutsche Zentralbibliothek für Medizin, 2015. http://d-nb.info/1072153289/34.
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Oliveira, Antonio Talvane Torres de [UNIFESP]. "Avaliação do marcador tumoral c-met/HGF no prognóstico do câncer colorretal através da técnica da imuno-histoquímica." Universidade Federal de São Paulo (UNIFESP), 2006. http://repositorio.unifesp.br/handle/11600/9131.
Abstract:
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Previous issue date: 2006-12-31Objetivo: Avaliar o significado prognóstico do marcador tumoral c-met/HGF, através da técnica imuno-histoquímica, em doentes portadores de adenocarcinoma colorretal submetidos a tratamento cirúrgico. Métodos: Estudo retrospectivo de 286 doentes,portadores de adenocarcinoma colorretal, atendidos e operados no Hospital do Câncer de Barretos, de 1993 a 2002. A expressão tissular do marcador tumoral foi avaliada utilizando-se o anticorpo monoclonal antiproteína c-met/HGF, com a técnica da estreptavidina-biotina-peroxidase. A análise da positividade do marcador foi feita de maneira semiquantitativa e a leitura das lâminas, realizada por três patologistas, de forma independente e sem prévio conhecimento dos dados clínicos e histopatológicos dos doentes. Resultados: Do total de 286 doentes analisados, o marcador foi positivo em 236 (78,8%) e negativo em 50 (21,2%). Houve diferença, estatisticamente significante (p=0.004), entre os estádios l e lV, na sobrevida global (p=0.009) e no coeficiente de mortalidade por câncer (p=0.022), porém não se identificou associação do marcador com a ocorrência de recidivas (p=0.89) e o intervalo livre de doença (p=0.91). Conclusão: O marcador tumoral c-met/HGF demonstrou significância estatística, em relação à sua expressão, nos estádios l e lV da doença, na sobrevida global e no coeficiente de mortalidade por câncer, porém não se associou de forma significante com as outras variáveis prognósticas estudadas.
Objective: To evaluate the prognostic meaning of the c-met/HGF tumoral marker, through the immunohistochemical technique, in patients with colorectal adenocarcinoma who have been subjected to surgical treatment. Methods: A retrospective descriptive study of 286 patients with colorectal adenocarcinoma, who have been seen and operated at Barretos Cancer Hospital, from 1993 to 2002. The tissular expression of the tumoral marker was evaluated using the cmet/ HGF anti-protein monoclonal antibody through the estreptavidin-biotinperoxidase technique. The positivity analysis of the marker was semiquantitative, and plate reading was independently carried out by three pathologists with no previous knowledge on clinical and histopathological data of patients. Results: Out of a total of 286 patients, the marker was positive in 236 (78.8%) and negative in 50 (21.2%). It was found statistically significant difference (p=0.004) between stages l and lV, at global life span (p=0.009), and at cancer mortality rate (p=0.022); however, there was no association between the marker and recurrence (p=0.89) or the marker and disease-free period (p=0.91). Conclusion: c-met/HGF has shown significance as a tumoral marker in stages l and lV of the disease, at global life span, and at cancer mortality rate; however, there was no significant association with the remaining prognostic variables that have been studied.
TEDE
BV UNIFESP: Teses e dissertações
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Penín, Mosquera Rosa Maria. "Factores de progresión tumoral en el sarcoma de Kaposi: estudio inmunohistoquímico." Doctoral thesis, Universitat Autònoma de Barcelona, 2003. http://hdl.handle.net/10803/4223.
Abstract:
El sarcoma de Kaposi (SK) es una enfermedad angioproliferativa con cuatro formas clínico-epidemiológicas: clásica (SK-C), africana endémica, relacionada con fármacos inmunosupresores y relacionada con el síndrome de inmunodeficiencia adquirida (SK-SIDA). La afectación del SK es generalmente cutánea, pero en los casos agresivos puede diseminarse a localizaciones extracutáneas. En la piel, las lesiones se clasifican clínicopatológicamente en máculas, placas y tumores de acuerdo con su progresión y severidad. El SK parece iniciarse como una proliferación vascular reactiva debida a una red de citocinas alterada, mientras que en estadios avanzados, se comporta como una neoplasia multifocal.El diferente comportamiento biológico del SK de acuerdo con sus presentaciones epidemiológicas y estadios puede estar relacionado con la presencia de alteraciones específicas en los mecanismos que controlan el crecimiento y desarrollo tumoral, como la sobreestimulación de citocinas y de factores de crecimiento angiogénicos o alteraciones en las oncoproteínas que controlan la proliferación celular y la apoptosis. Estas alteraciones podrían ofrecer los estímulos neoplásicos necesarios para el desarrollo, progresión y, en definitiva, un comportamiento más agresivo del SK.
El factor de crecimiento hepatocitario (HGF) es una citocina angiogénica pleiotrópica que está sobreexpresada en cánceres humanos invasivos y puede actuar como factor de progresión tumoral, estimulando la angiogénesis y la invasividad de las células tumorales. Estas respuestas son transducidas a través del receptor c-Met. El HGF estimula la proliferación de las células fusiformes cultivadas de lesiones humanas de SK, y además las células del SK sintetizan y secretan HGF y expresan c-Met, creando un rizo de retroalimentación para la proliferación tumoral y la neovascularización. Hemos estudiado la expresión del c-Met en diferentes estadios histológicos de lesiones de SK-C y SK-SIDA, observando que la intensidad de tinción de c-Met fue mayor en los tumores que en las placas, de forma que el HGF se comporta como un factor de progresión en el SK.
EL HHV-8, el factor etiológico del SK, codifica la v-ciclina, que formando complejo con la cinasa dependiente de ciclina (CDK) 6, contribuye a la fosforilación y degradación mediada por proteasoma del inhibidor de las cinasas dependientes de ciclina p27KIP1. La p27KIP1 regula negativamente la proliferación celular uniéndose e inhibiendo a los complejos ciclina-CDK de fase G1. Por otro lado, la infrarregulación de la expresión de la p27KIP1 parece facilitar el desarrollo tumoral y la diseminación metastásica; por ello la p27KIP1 ha sido considerada como un factor pronóstico independiente en una gran variedad de neoplasias humanas. Aunque la naturaleza neoplásica del SK todavía es controvertida, se ha demostrado repetidas veces que en algunos pacientes el SK puede comportarse como una neoplasia maligna y seguir un curso ominoso. Para determinar si la disminución de los niveles de la p27KIP1 está también relacionada con un comportamiento más agresivo del SK, decidimos investigar la inmunoreactividad de la p27KIP1 en biopsias de SK. De este modo, intentamos determinar si la disminución de los niveles de expresión de la p27KIP1 está relacionada con la afectación extracutánea en el SK, como ocurre en otras neoplasias cuando metastatizan. La media de porcentajes de células positivas para p27KIP1 era significativamente mayor en las biopsias de lesiones cutáneas y en las máculas-placas que en las lesiones extracutáneas y en los tumores respectivamente. Estos resultados apoyan la hipótesis de que la disminución de los niveles de la p27KIP1, que pueden ser producidos por la infección por el HHV-8, facilitan la progresión del SK a través de sus estadios histopatológicos y su eventual extensión extracutánea
Estudios recientes han demostrado que la degradación de la p27KIP1 a través de la vía ubicuitin-proteasoma está mediada por el complejo SCF/ p45SKP2 y por su receptor específico de sustrato F-box p45SKP2. La p45SKP2 está frecuentemente sobreexpresada en células transformadas, induce la fase S en células quiescentes y se sospecha que es un protooncogen en tumores humanos. De hecho, se ha determinado una asociación entre el incremento de los niveles de la p45SKP2 y la disminución de los niveles de la p27KIP1 en neoplasias epiteliales. Hemos estudiado si la expresión de la p45SKP2 está alterada en las lesiones agresivas del SK y su relación con la infrarregulación de la p27KIP1, sexo e infección por el VIH. La sobreexpresión nuclear de la p45SKP2 estaba presente en todos los estadios del SK, estando significativamente incrementada en los tumores cutáneos y en las lesiones extracutáneas en comparación con la máculas y placas. No se identificaron diferencias estadísticamente significativas en relación con el sexo y estatus VIH de los pacientes, y el análisis de regresión no mostró correlación entre la p45SKP2 y la p27KIP1. Estos hallazgos sugieren que la p45SKP2 está involucrada en el SK, no sólo promoviendo la degradación de la p27KIP1, sino también a través de otros mecanismos todavía desconocidos.
Kaposi's sarcoma (KS) is an angioproliferative disease with four clinical-epidemiological forms: classic (C-KS), African-endemic, immunosuppressive drug-related and acquired immune deficiency syndrome-related (AIDS-KS). KS involvement is usually limited to the skin, but in aggressive cases it may disseminate to extracutaneous locations. In the skin, lesions are clinicopathologically classified into macules, plaques and tumours in agreement with their progression in severity. KS seems to begin as a reactive vascular proliferation due to an unbalanced cytokine network, whereas in advanced stages, it behaves as a multifocal neoplasm.
The different biological behavior of KS according to its epidemiological presentations and stages might be related to the presence of specific alterations in the mechanisms controlling tumor growth and development, such as cytokine or angiogenic growth factor overstimulation or alterations of the oncoprotein networks that control cell proliferation and apoptosis. These alterations would provide neoplastic stimuli for the development, progression, and aggressive behaviour of KS.
Hepatocyte growth factor (HGF) is a pleiotropic angiogenic cytokine that is overexpressed in invasive human cancers and may function as a tumor progression factor, stimulating tumour cell invasiveness and angiogenesis. These responses are transduced through the c-Met receptor. HGF stimulates proliferation of spindle cells cultured from human KS lesions, and KS cells synthesize and secrete HGF and express c-Met, thus providing an autocrine loop for tumour proliferation and neovascularization. We have studied the expression of c-Met in different histological stages of AIDS-associated and classic KS lesions. The staining intensity of c-Met was stronger in tumours than in plaques showing that HGF would be a progression factor in KS.
HHV-8, the KS'etiologic factor, encoded v-cyclin, through its complexing with cyclin-dependent kinase (CDK) 6, contributes to the phosphorylation and proteasome-mediated degradation of p27KIP1, a cyclin-dependent kinase inhibitor. P27KIP1 regulates negatively cell proliferation by binding and inhibiting G1 cyclin-CDK complexes. On the other hand, down-regulation of p27KIP1 expression seems to facilitate tumour development and metastatic dissemination; then p27KIP1 has been considerated as an independent prognostic factor in a variety of human neoplasms. Although the neoplastic nature of KS remains controversial, it has been repeatedly demonstrated that in some patients KS may behave as a malignant neoplasm and follow an ominous course. To determine whether decreased p27KIP1 levels are also related to more aggressive behaviour in KS, it was decided to investigate p27KIP1 immunoreactivity in KS biopsy specimens. Thereby, we sought to determine whether the decrease in p27KIP1 expression levels is related to extracutaneous involvement in KS, as is the case in several other types of neoplasms when they metastasize. The mean percentages of p27KIP1-positive cells were significantly higher in biopsy specimens from skin lesions and in macules-plaques than in those from extracutaneous locations and tumours respectively. These results lend support to the hypothesis that decreased levels of p27KIP1, which may have been brought about by HHV-8 infection, play a role in KS progression through its various histopathological stages, to its eventual extracutaneous spread.
Recent studies have demonstrated that p27KIP1 degradation through the ubiquitin-proteasome pathway is mediated by the SCF/p45SKP2 complex and by the substrate-specific receptor of this complex, the F-Box protein p45SKP2. P45SKP2 is frequently over-expressed in transformed cells, induces S phase in quiescent cells and is a suspected proto-oncogene in human tumours. In fact, there are recent reports of increased levels of p45SKP2 in association with reduced p27KIP1 levels in epithelial neoplasms. We have studied of whether p45SKP2 expression is altered in aggressive lesions of KS and its relation to p27KIP1 down-regulation, gender and HIV infection. P45SKP2 nuclear over-expression was present in all KS stages, being significantly increased in skin tumours and extracutaneous lesions as compared with macules and plaques. No statistically significant differences were found in regard to patients´ sex and HIV status and regression analysis failed to show a correlation among p45SKP2 and p27KIP1. These findings suggest that p45SKP2 is involved in KS, not only by promoting the degradation of p27KIP1 but also through other mechanisms still unknown.
21
Galoul, Mohamed Chérif. "Rôle de la protéine d'échafaudage Gab1 dans le pouvoir oncogénique du récepteur Met dans les cellules épithéliales intestinales." Mémoire, Université de Sherbrooke, 2012. http://hdl.handle.net/11143/5555.
Abstract:
Plusieurs évidences indiquent que de la dérégulation des récepteurs tyrosine kinase (RTK) joue un rôle clé dans l'étiologie et la progression du cancer colorectal (CCR). Notamment, des bénéfices ont été observés en clinique avec des agents ciblant le récepteur de EGF dans le traitement des CCR métastatiques avancés. Considérant l'hétérogénéité des RTK dérégulés dans le CCR, une approche thérapeutique alternative serait de plutôt cibler les protéines effectrices engagées par plusieurs RTK, notamment celles qui régulent des processus essentiels à la progression du CCR. Toutefois, le rôle des protéines de signalisation engagées par les RTK dans le CCR reste encore très peu défini. De récents travaux menés dans notre laboratoire ont démontré que l'activation oncogénique du RTK Met, le récepteur du facteur de croissance d'hépatocyte (HGF), confère aux cellules épithéliales intestinales non cancéreuses IEC-6, des propriétés angiogéniques, tumorigéniques et métastatiques in vitro et in vivo . L'activité biologique des RTK, telle que celle du récepteur Met, s'avère étroitement liée à leur capacité d'initier une variété de voies de signalisation intracellulaire par le biais du recrutement de protéines adaptatrices, dont les protéines Gab1 et Gab2 (Grb2-associated binder). Ainsi, le but de mon projet fut de valider l'hypothèse que le pouvoir oncogénique du récepteur Met dans les cellules épithéliales intestinales serait en partie dépendant de l'engagement des voies de signalisation des protéines Gab. Pour ce faire, nous avons utilisé une approche dominante négative, soit par l'expression du domaine MBD (Met-Binding Domain) de Gab1 dans les cellules IEC-6 transformées par la forme oncogénique du récepteur Met, Tpr-Met (Tpr-Met-IEC-6). Cette stratégie repose sur le fait que la région MBD de Gab1 renferme les deux motifs de liaison, un motif riche en proline qui lie les protéines Gab aux RTK par un mécanisme indirect dépendant, de Grb2, ainsi que le motif MBM (Met-Binding Motif) qui est unique à Gab1, et qui permet une interaction directe entre Gab1 et le récepteur Met. Mes résultats montrent que l'expression du domaine MBD de Gab1 dans les cellules TprMet-IEC-6 diminue la phosphorylation de la protéine Gab1 sur tyrosine, restaure la formation de contacts cellule-cellule et une morphologie épithéliale typique ainsi qu'augmente le niveau protéique du marqueur épithéliale E-cadhérine et sa relocalisation membranaire aux zones de contact cellule-cellule. De plus, les cellules Tpr-Met-IEC-6 qui expriment le MBD de Gab1 affichent en culture une capacité réduite à proliférer au-delà de la confluence et en absence d'ancrage à la matrice extracellulaire, et de migration, ainsi qu'une diminution de leur aptitude à former des tumeurs sous-cutanées in vivo dans les souris nues. L'ensemble de mes résultats démontre pour la première fois que le pouvoir oncogénique du récepteur Met dans les cellules épithéliales intestinales dépend en partie de l'engagement des voies de signalisation de Gab1. En considérant que tous les RTK dérégulés dans le CCR peuvent se lier aux protéines Gab, ou engager leurs voies de signalisation, nos résultats identifient ces dernières comme des cibles prometteuses pour le développement de nouveaux agents thérapeutiques contre le CCR.
22
Previdi, Sara. "HGF/C-MET in breast-cancer bone metastasis : characterization and imaging analysis to evaluate the efficacy of traget therapies." Thesis, Open University, 2011. http://ethos.bl.uk/OrderDetails.do?uin=uk.bl.ethos.551620.
Abstract:
cancer exhibits a propensity to metastatize to bone, resulting in debilitating skeletal complications associated with significant morbidity and poor prognosis. The interactions between metastatic cells and bone are critical to the development and progression of bone metastases and their unravelling could lead to novel therapeutic approaches. This PhD thesis intended to investigate the contribution of the HGH/c-Met pathway to the pathogenesis of bone metastasis. An experimental breast cancer bone metastatic model were used, in combination with in vivo imaging techniques, to demonstrate the involvement of HGF/c-Met system in tumor-bone interaction contributing to bone metastatisation. Moreover, the efficacy of three therapeutic approaches able to interfere with the HGC/c-Met pathway has been investigated. Firstly, I demonstrated that NK4, an HGF antagonist, induces a delay in the progression of bone metastasis probably via its bifunctional properties to act as an HGF antagonist and an angiogenesis inhibitor. Secondly, the efficacy of strategies directed against c-Met receptor, including both a c-Met inhibitor, ARQ197, and a specific shRNA, has been evaluated. Dual c-Met inhibition induces a pronounced tumor growth suppression with concomitant marked decreases of lytic lesions and prolongation of survival. Finally, the effect of targeting PLCyl, one of the c-Met downstream effectors, has been explored. Surprisingly, PLCyl silencing by shRNA significantly accelerates the formation and progression of bone metastases. Overall, these findings highlighted the efficacy of HGF/c- Met inhibition in delaying the onset and progression of bone metastases and strongly suggested that targeting the HGF ligand or the c-Met receptor may have promising therapeutic value in the treatment of breast cancer bone metastases. Despite that, special attention should be paid to block PLCyl since its inhibition could potentiate the aggressive phenotype of breast cancer cells stimulating bone metastatic disease. Therefore, PLCyl should not be considered as a therapeutic candidate for the management of bone metastasis.
23
Naim, Ramin. "Koexpression von VEGF (Vascular endothelial growth factor), c-Met-Rezeptor und HGF/SF (Hepatocyte growth factor, scatter factor) in Pleurametastasen." [S.l.] : [s.n.], 2000. http://deposit.ddb.de/cgi-bin/dokserv?idn=962323403.
24
Klenk, Nicola Anna [Verfasser], Alexander [Gutachter] Kübler, and Uwe [Gutachter] Gbureck. "Einfluss von HGF/c-Met auf das Tumormikromilieu in Kopf-Hals-Karzinomen / Nicola Anna Klenk ; Gutachter: Alexander Kübler, Uwe Gbureck." Würzburg : Universität Würzburg, 2019. http://d-nb.info/1192216539/34.
25
Al-Waleedi, Saeed A. "The roles of hepatocyte growth factor family members in androgen-regulation of human hair growth : a comparison of the expression of hepatocyte growth factor family members, HGF and MSP, and their receptors, c-Met and RON, in isolated hair follicles from normal and androgenetic alopecia (balding) scalp." Thesis, University of Bradford, 2010. http://hdl.handle.net/10454/5271.
Abstract:
Androgens are the main regulators of human hair growth stimulating larger, terminal hair development e.g. beard and causing scalp balding, androgenetic alopecia. Hair disorders cause psychological distress but are poorly controlled. Androgens probably act by altering regulatory paracrine factors produced by the mesenchyme-derived dermal papilla. This study aimed to investigate paracrine factors involved in androgen-regulated alopecia, particularly hepatocyte growth factor (HGF) family members, by investigating their in vivo status. Balding and non-balding scalp hair follicles and their component tissues were isolated and analysed by molecular biological methods (reverse transcriptase-polymerase chain reaction (RT-PCR), quantitative PCR and DNA microarray analysis), cell culture and immunohistochemistry. Scalp follicles expressed a range of paracrine messenger genes. The dermal papilla, cultured dermal papilla cells and dermal sheath expressed several HGF family genes, while matrix cells only produced the receptor RON suggesting autocrine roles for HGF and MSP, but a paracrine route only for MSP. Comparing balding and non-balding follicles from the same individuals revealed the expected reduction in several keratin and keratin-related protein genes supporting this approach's validity. There were also significant differences in paracrine factors previously implicated in androgen action by in vitro studies. Several factors believed to increase during androgen stimulation of larger, darker follicles, e.g. IGF-I and SCF, were lowered in balding follicles, while putative inhibitory factors, e.g. TGFß-1, were increased. HGF and MSP and their receptors, c-Met and RON, were significantly reduced. These results increase our understanding of androgen action in human hair follicles; this could lead to better treatments for hair disorders.
26
Naim, Ramin [Verfasser]. "Koexpression von VEGF (Vascular Endothelial Growth Factor), c-Met - Rezeptor und HGF/SF (Hepatocyte Growth Factor/ Scatter Factor) in Pleurametastasen / Ramin Naim." München : GRIN Verlag, 2007. http://d-nb.info/1181005078/34.
27
Langford, Peter R. "c-Met Initiates Epithelial Scattering through Transient Calcium Influxes and NFAT-Dependent Gene Transcription." BYU ScholarsArchive, 2011. https://scholarsarchive.byu.edu/etd/3186.
Abstract:
Hepatocyte growth factor (HGF) signaling drives epithelial cells to scatter by breaking cell-cell adhesions and migrating as solitary cells, a process that parallels epithelial-mesenchymal transition. HGF binds and activates the c-Met receptor tyrosine kinase, but downstream signaling required for scattering remains poorly defined. This study addresses this shortcoming in a number of ways.A high-throughput in vitro drug screen was employed to identify proteins necessary in this HGF-induced signaling. Cells were tested for reactivity to HGF stimulation in a Boyden chamber assay. This tactic yielded several small molecules that block HGF-induced scattering, including a calcium channel blocker. Patch clamping was used to determine the precise effect of HGF stimulation on Ca2+ signaling in MDCK II cells. Cell-attached patch clamping was employed to detect Ca2+ signaling patterns, and channel blockers were used in various combinations to deduce the identity of Ca2+ channels involved in EMT. The results of these experiments show that HGF stimulation results in sudden and transient increases in calcium channel influxes. These increases occur at predictable intervals and rely on proper tubulin polymerization to appear, as determined through the use of a tubulin polymerization inhibitor. Though multiple channels occur in the membranes of MDCK II cells, noticeably TRPV4 and TrpC6, it is TrpC6 that is specifically required for HGF-induced scattering. These HGF-induced calcium influxes through TrpC6 channels drive a transient increase in NFAT-dependent gene transcription which is required for HGF-induced EMT. This was determined through the use of luciferase-based NFAT reporter assays and confirmed through confocal immunofluorescence. Using a small-molecule inhibitor of WNK kinase, it was determined that loss of WNK kinase function is sufficient to prevent HGF-induced EMT. Furthermore, patch-clamp analysis demonstrated that WNK kinase significantly increases channel opening at the surface of MDCK cells, indicating a possible mechanism of action for c-Met inhibition, but leaving doubt as to whether WNK kinase is in fact normally involved in c-Met signaling, or whether it is simply permissive.
28
Berger, Evelin [Verfasser], and Lothar [Akademischer Betreuer] Jänsch. "Time-resolved characterization of the HGF/Met response and the influence of L. monocytogenes InlB on the physiological phosphoproteome / Evelin Berger ; Betreuer: Lothar Jänsch." Braunschweig : Technische Universität Braunschweig, 2013. http://d-nb.info/1175822671/34.
29
Giebeler, Arne [Verfasser]. "HGF/c-Met and IL-6/gp130 mediated signalling pathways in a model of acute and chronic cholestatic liver injury in mice / Arne Giebeler." Aachen : Hochschulbibliothek der Rheinisch-Westfälischen Technischen Hochschule Aachen, 2011. http://d-nb.info/1016243774/34.
30
Fan, Yannan. "Tissue-specific gain of wild-type RTK levels combined with screen strategies identify new mechanisms of cell vulnerability in developmental and tumorigenic programs." Thesis, Aix-Marseille, 2016. http://www.theses.fr/2016AIXM4071.
Abstract:
Pour étudier la capacité cellulaire à s’adapter aux changements de signalisation dépendante des RTKs, nous utilisons un modèle de souris où l’expression du RTK Met sauvage peut être accrue dans un tissu spécifique. La plupart des tissus se protègent contre cette expression anormale des RTK. Mais certains types cellulaires sont sensibles aux altérations des RTKs, c’est le cas du mésenchyme du membre pendant l’embryogenèse. En effet, l’expression de certains gènes du mésenchyme est modifiée et celui-ci n’est plus accessible aux myoblastes qui le colonisent, conduisant à des déficits des muscles du membre. Chez l’adulte une augmentation de l’expression de Met dans le foie (Alb-R26Met) perturbe l’homéostasie tissulaire, conduisant à la tumorigenèse. Pour identifier des gènes qui coopèrent avec les RTKs pendant l’initiation de la tumorigenèse, nous avons combiné les souris Alb-R26Met avec le système de mutagenèse Sleeping Beauty (SB) transposon. 285 gènes putatifs liés au cancer ont été identifiés. Certains sont des proto-oncogènes ou suppresseurs de tumeurs déjà connus, validant le système. D’autres gènes n’avaient, jusqu’à présent, jamais été associés à ce processus. 9 candidats ont été fonctionnellement validés. Pour identifier des signaux assurant le maintien de la tumeur, nous avons analysé le phosphokinome, testé l’efficacité de composés et identifié de nouvelles combinaisons de drogues qui agissent en synergie pour tuer les cellules cancéreuses dérivées de Alb-R26Met. En conclusion, ces travaux montrent qu’une approche génétique non-biaisée combinée à une approche génomique permet d’identifier de nouveaux mécanismes pertinents pour la biologie du cancerWe explore the cell competence to deal with slight changes in RTK inputs during embryogenesis and tissue homeostasis using a mouse model in which wild-type RTK Met levels can be moderately enhanced in a tissue specific manner. Most tissues buffer enhanced RTK levels thus avoiding perturbation of developmental programs and tissue homeostasis. Nevertheless, certain cell types are vulnerable to RTK levels. During embryogenesis, the limb mesenchyme is sensitive to alterations of the spatial distribution of RTKs, as illustrated by gene expression changes and by loss of accessibility to incoming myoblasts, which lead to limb muscle defects. At adulthood, liver enhanced Met levels (Alb-R26Met) perturbs tissue homeostasis, leading to tumorigenesis. To uncover new genes that cooperate with RTKs during tumour initiation, we combined Alb-R26Met mice with the Sleeping Beauty (SB) transposon mutagenesis system. 285 putative cancer-related genes have been identified. Some correspond to known proto-oncogenes or tumour suppressors, thus validating the overall strategy we employed for cancer gene discovery. Others have not been previously linked to cancer. 9 new tumour suppressors have been functionally validated, demonstrating the validity of our screen strategy. To identify signals involved in tumour maintenance, we employed a phosphokinome-guided drug screen and identified new synergistic drugs deleterious for cancer cells modelled by the Alb-R26Met genetic setting. The overall strategy and outcomes strengthen the value of combining unbiased genetic and genomic approaches to identify new mechanisms relevant for cancer biology and new therapeutic interventions
31
川口, 晃司, 秀樹 村上, 裕太郎 鈴木, 哲郎 谷口, 香平 横井, and 好孝 関戸. "P-211 悪性胸膜中皮腫におけるHGF/METの発現と活性化の解析." 日本肺癌学会, 2007. http://hdl.handle.net/2237/10958.
32
Villalobos, Hernandez Alberto. "Role of suppressor of cytokine signalling 1 (SOCS1) in the pathogenesis of prostate cancer." Mémoire, Université de Sherbrooke, 2016. http://hdl.handle.net/11143/11618.
Abstract:
Le cancer de la prostate (PCa) est le deuxième cancer le plus courant chez les hommes au niveau mondial. Le suppresseur de la signalisation des cytokines 1 (SOCS1) est considéré comme un suppresseur de tumeur en raison de la fréquente répression épigénétique de ce gène dans de nombreux cancers. Il a été reporté que SOCS1 inhibait l’activation de STAT3 induite par l’IL-6, ainsi que les cyclines et les kinases dépendantes des cyclines dans les cellules malignes de la prostate. D’autre part, il a été montré que SOCS1 n’était pas essentiel lors du contrôle de la signalisation de l’IL-6 dans les hépatocytes dépourvus de cette protéine, cependant elle est essentielle pour atténuer la signalisation du facteur de croissance des hépatocytes (HGF) via son récepteur MET. MET est un récepteur de tyrosine kinases qui est surexprimé dans le PCa agressif et métastatique. Notre hypothèse de recherche propose que la répression de SOCS1 par méthylation du promoteur et la dérégulation de l’expression de MET et de sa signalisation, sont des mécanismes pathogéniques liés au développement et à la progression du PCa. Nous avons généré des lignées de cellules PC3 et DU145 stables exprimant SOCS1. Les cellules ont été stimulées avec HGF et l’activation des voies de signalisation a été évaluée par immunobuvardage. Des essais in vitro de migration, de prolifération et d’invasion ont été effectués en présence de HGF. Des gènes de transition épithélio-mésenchymateuse ont été évalués par PCR quantitatif en présence ou non du facteur de croissance. Les cellules du PCa transfectées ou pas avec SOCS1 ont été inoculées dans des souris NOD SCID gamma de façon sous-cutanée ou orthoptique afin d’évaluer respectivement la croissance tumorale et la formation de métastases. Les tumeurs reséquées ont été analysées histologiquement et biochimiquement. Nos résultats montrent que SOCS1 atténue l'activation de MET induite par HGF et la phosphorylation d’ERK dans les cellules PC3, ainsi que la phosphorylation d’ERK et d’AKT dans les cellules DU145. SOCS1 inhibe également la prolifération cellulaire induite par HGF, ainsi que la migration et l’invasion in vitro. De plus, SOCS1 réduit l’expression des gènes de transition épithélio-mésenchymateuse impliqués dans la dégradation des composants de la matrice extracellulaire dans les cellules DU145 mais pas dans les cellules PC3. La surexpression de SOCS1 a stimulé l’augmentation de déposition de collagène, in vivo. Les tumeurs formées par les cellules exprimant SOCS1 étaient de taille significativement plus petites avec une réduction de la prolifération comparé aux tumeurs provenant des cellules contrôles. En outre, SOCS1 a inhibé la formation de métastases à distance dans un modèle orthotopique. En conclusion, nous suggérons que SOCS1 est un suppresseur de tumeur indispensable de la prostate, et qu’au moins une partie de sa fonction a lieu via la régulation négative de la signalisation du récepteur MET.Abstract : Prostate cancer (PCa) is the second most common cancer among men worldwide. Suppressor of cytokine signaling 1 (SOCS1) is considered a tumor suppressor due to frequent epigenetic repression of the SOCS1 gene in several human malignancies. Inactivation of SOCS1 also occurs in PCa by gene methylation and micro-RNA-mediated repression. SOCS1 has been reported to inhibit IL-6-induced STAT3 activation and down-regulates cyclins and cyclin-dependent kinases in PCa cells. It has been shown that SOCS1 is not required to control IL-6 signaling in SOCS1-deficient hepatocytes, but is essential to attenuate hepatocyte growth factor (HGF) signaling via its receptor MET. This protein is a receptor tyrosine kinase (RTK), overexpressed in aggressive and metastatic PCa. Thus we hypothesized that the repression of SOCS1 via promoter methylation and deregulated MET expression and signaling are inter-related pathogenic mechanisms in PCa development and progression. We generated stable SOCS1-expressing PCa cell lines (PC3 and DU145) using lentiviral transduction followed by clonal selection via limiting dilution. Cells were stimulated with HGF and downstream signaling events were assessed by Western blot. Proliferation, migration and invasion assays were also conducted in the presence of HGF in vitro. Epithelial mesenchymal transition genes were evaluated by qPCR in the presence or absence of the growth factor. The PCa cells transfected with SOCS1 and non-transfected controls were inoculated into NOD SCID gamma mice as xenografts or as orthotopic tumors to assess tumor growth and metastasis formation, respectively. Resected tumors were further analyzed histologically and biochemically. Our results showed that SOCS1 attenuates HGF-induced MET activation and ERK phosphorylation in PC3 and DU145 PCa cell lines. SOCS1 inhibited HGF induced cell proliferation, migration and invasion in vitro. Additionally, SOCS1 decreased epithelial mesenchymal transition genes involved in the degradation of extracellular matrix components in DU145 cells but not in PC3. In vivo, SOCS1 overexpression leads to an increase of collagen deposition. Tumors formed by SOCS1 expressing cells were significantly smaller in size with reduced cell proliferation compared to tumors arising from control cells. Furthermore, SOCS1 inhibited distant metastasis formation in the orthotopic model. Overall our results suggest that SOCS1 has a tumor suppressor role in PCa evolution and part of this function is mediated by the negative regulation of MET receptor signalling and down-regulation of genes supporting migration and invasion processes such as matrix metalloproteinases.
33
Segarra, Joseph. "Le système HGF/Met au cours du développement du système nerveux : réseau de signalisation impliqué dans la migration des neurones corticaux et caractérisation de nouvelles cibles géniques." Aix-Marseille 2, 2005. http://theses.univ-amu.fr.lama.univ-amu.fr/2005AIX22034.pdf.
34
KERMORGANT, STEPHANIE. "Hepatocyte growth factor (hgf) et son recepteur c-met dans les tissus digestifs. Ontogenie, role dans la differenciation et la migration cellulaire, association avec les proteases dans les processus d'invasiontumorale." Paris 7, 1999. http://www.theses.fr/1999PA077122.
Abstract:
Le but de cette these etait, d'une part, d'etudier l'expression et d'aborder le role morphogene de l'hepatocyte growth factor (hgf) et de son recepteur c-met dans les tissus digestifs humains adultes et ftaux et deux lignees cellulaires coliques et, d'autre part, d'analyser leur implication ainsi que celle des metalloproteases matricielles (mmps) dans les processus d'invasion tumorale in vitro et/ou in vivo. 1 l'hgf et le c-met, exprimes des 7-8 semaines de gestation dans les tissus digestifs humains, semblent fortement impliques dans sa morphogenese (dynamique de localisation au cours du developpement, capacite du c-met a se phosphoryler) et ceci selon un mode autocrine. 2, nous avons etudie l'effet morphogene de l'hgf sur les cellules cancereuses coliques humaines caco-2 au cours du temps de culture. L'hgf stimule des evenements associes a la differenciation enterocytaire des cellules caco-2, comme l'activite de la phosphatase alcaline et l'expression de la villine et de la cadherine e. Les proteines gab-1 et pkc semblent etre impliquees dans ce signal. 3, nous avons etudie l'effet d'un inhibiteur general synthetique des mmps, le batimastat, sur l'invasivite in vitro et in vivo des cellules cancereuses coliques de rat dhd/k12. Ces cellules secretent les mmp-1, -2 et -9. Le batimastat diminue faiblement leur invasivite in vitro. Il inhibe tres significativement leur invasivite in vivo et augmente la survie. L'inhibition des mmps est donc une approche therapeutique prometteuse dans le traitement des cancers coliques. 4, nous avons etudie le role motogene de l'hgf sur les cellules caco-2. L'hgf stimule l'invasivite des cellules caco-2 selon les mecanismes suivants : 1) il stimule la motilite des cellules, 2) il active les voies de la pi3k et de la pkc qui 3) sont responsables au moins en partie de l'augmentation de l'expression des mmps -1, -2, -9 et de l'upa qui a leur tour, 4) en degradant le matrigel, favorisent la migration des cellules a travers le matrigel.
35
Simonneau, Claire. "Mécanismes d'activation du récepteur tyrosine kinase MET par son ligand l'HGF/SF : rôles des domaines N et K1." Thesis, Lille 2, 2015. http://www.theses.fr/2015LIL2S071.
Abstract:
L’HGF/SF (Hepatocyte Growth Factor/Scatter Factor) est le ligand du Récepteur Tyrosine Kinase (RTK) MET. Ce couple ligand-récepteur joue un rôle essentiel dans de nombreux processus biologiques tels que l’embryogenèse, la régénération tissulaire et l’angiogenèse. Comme pour de nombreux RTK, la dérégulation de l’activité de MET est associée à la progression et l’invasion tumorales. Bien que le récepteur MET ait été intensivement étudié au cours de ces dernières décennies, les processus moléculaires conduisant à son activation par l’HGF/SF restent encore mal connus et controversés.NK1, un variant naturel de l’HGF/SF, comprenant la partie N-terminale (N) et le premier domaine kringle (K1) de l’HGF/SF, possède une activité agoniste. En effet, NK1 dimérise spontanément en position « tête-bêche » et est considéré aujourd’hui comme la structure minimale permettant la dimérisation de MET et son activation. Afin de déterminer leur contribution respective, les domaines N et K1 isolés ont été produits par voie recombinante et ne montrent aucune ou qu’une très faible activité agoniste respectivement. Une présentation monovalente de ces domaines au récepteur MET ne semble donc pas pertinente pour déterminer leur fonction.Par conséquent, nous avons souhaité générer des complexes multivalents mimant le positionnement des domaines N et K1 au sein du dimère naturel. En tirant partie de la « One-Pot SEA ligation » développée au laboratoire, ces domaines ont été synthétisés par voie chimique et fonctionnalisés avec une extrémité C-terminale biotinylée (NB et K1B). En utilisant la streptavidine (S) comme plateforme de multimérisation, nous avons généré des complexes semi-synthétiques NB/S et K1B/S et déterminé les propriétés biologiques de ces nouvelles constructions multivalentes.L’ensemble des analyses de signalisations cellulaires et phénotypiques démontre sans équivoque que le complexe K1B/S est capable de mimer les réponses biologiques induites par l’HGF/SF et son variant NK1. De plus, le complexe K1B/S, injecté dans la circulation systémique, déclenche la signalisation de MET dans le foie. L’utilisation de ce complexe K1B/S nous a permis de démontrer que deux domaines K1, correctement assemblés et orientés, constituent l'interface minimale et suffisante requise pour déclencher une pleine activation de MET. A l’inverse, les premières données fonctionnelles ont démontré que le complexe NB/S ne lie pas directement MET mais utilise les héparanes sulfates comme pont moléculaire.Ces études utilisant de nouvelles configurations structurales pourraient donc servir de modèle de base au développement de nouveaux agonistes de MET dans le cadre de thérapies régénératives ou préservatrices, mais aussi d’antagonistes dans le cadre de thérapies anticancéreuses cibléesHepatocyte Growth Factor/Scatter Factor (HGF/SF) and its receptor tyrosine kinase (RTK) MET play an essential role in embryogenesis, tissue regeneration and angiogenesis. As observed for many others RTK, MET is also strongly involved in tumor progression and invasion mechanisms. Although numerous biological and structural approaches have been focused on the molecular processes leading to MET activation by HGF/SF, the HGF/SF-MET interaction framework remains only partially understood due to the complexity of the multivalent ligand-receptor binding events.NK1, a naturally occurring splice variant of HGF/SF, comprising the N-terminal part and the first kringle domain (K1) of HGF/SF, exhibits a partial agonistic activity toward MET. Indeed, in presence of heparan sulfates, NK1 self-associates into a “head-to-tail” dimer and is considered as the minimal structural module able to trigger MET dimerization and activation. Nevertheless, the individual role of N and K1 domains in the dimerization/activation of MET remain elusive.Stimulated by the conviction that monomeric N and K1 domains are not suitable for studying the functioning of HGF/SF-MET, we produced, by total chemical synthesis, biotinylated analogs of the N and K1 domains (NB and K1B). By combining with streptavidin (S), we engineered the semisynthetic constructs NB/S and K1B/S in order to determine the biological properties of these new multivalent architectures of N and K1 domains.In vitro, as observed with HGF/SF or NK1, we show that the K1B/S complex is able to fully activate MET signaling cascades to promote scattering, morphogenesis and survival phenotypes in various cell types. Even more, the K1B/S complex stimulates angiogenesis in vivo and, when injected systemically, triggers MET signaling in the liver. The use of this K1B/S complex allows us to demonstrate that two K1 domains, correctly assembled and oriented, constitute the minimal unit for sufficient MET activation. In contrast, first in vitro data have demonstrated that NB/S complex does not bind directly MET as previously thought, but rather, uses heparan sulfates as a molecular bridge.We envision these new structural configurations serving as a template for both the rational design of potent MET agonists (e.g. using K1B/S for regenerative therapies) and antagonists (e.g. using NB/S for targeted cancer therapies)
36
Liu, Lei [Verfasser], Sunami [Akademischer Betreuer] Yoshiaki, Norbert [Akademischer Betreuer] Hüser, and Helmut [Akademischer Betreuer] Friess. "Peroxisome Proliferator-Activated Receptor gamma negatively regulates liver regeneration after partial hepatectomy via the HGF/c-met/ERK1/2 pathway : PPAR gamma in liver regeneration / Lei Liu. Gutachter: Helmut Friess ; Norbert Hüser. Betreuer: Sunami Yoshiaki ; Norbert Hüser." München : Universitätsbibliothek der TU München, 2015. http://d-nb.info/1076866328/34.
37
Guérin, Célia. "Caractérisation de nouvelles mutations activatrices dépendantes de l'HGF dans le lobe N-terminal du domaine kinase du récepteur MET dans le cancer du rein héréditaire." Electronic Thesis or Diss., Université de Lille (2022-....), 2023. https://pepite-depot.univ-lille.fr/ToutIDP/EDBSL/2023/2023ULILS074.pdf.
Abstract:
Les thérapies ciblées révolutionnent actuellement la prise en charge des patients atteints de cancer, à la condition qu’ils présentent une altération moléculaire ciblable responsable de la progression tumorale. Les récepteurs à activité tyrosine kinase (RTK) présentant des mutations activatrices sont les cibles majeures des thérapies ciblées avec, comme exemple représentatif, l’EGFR dont les mutations conduisent à son activation constitutive le rendant indépendant d’une stimulation par son ligand.Le récepteur MET, un autre RTK de cette famille, présente des mutations activatrices dans le cancer du rein et le cancer du poumon. En effet, le carcinome rénal papillaire de type I (HPRC), un cancer héréditaire peu fréquent, a la particularité de présenter dans plus de 80 % des cas des mutations activatrices de MET. En revanche, dans le cancer du poumon non à petites cellules (CBNPC), les mutations de MET conduisent au saut de l’exon 14 codant pour le domaine juxtamembranaire (mutations MET ex14). Ce saut d’exon conduit à la perte du domaine juxtamembranaire, un domaine régulateur impliqué dans la régulation négative du récepteur. De façon originale par rapport à d’autres mutations de RTK, ces mutations nécessitent toujours une stimulation par l’HGF, le ligand de MET, plaçant la production d’HGF comme un paramètre à considérer dans la stratification des patients pouvant bénéficier de thérapies ciblées.Des inhibiteurs de tyrosine kinase (TKI) dirigés contre MET ont été approuvés très récemment pour une utilisation en clinique, offrant un véritable espoir pour les patients présentant ces mutations.Grâce au développement du séquençage haut-débit pour le diagnostic et l’émergence de nouvelles mutations de résistance suite aux traitements par les thérapies ciblées, le spectre des mutations affectant les RTK s’élargit considérablement. L’enjeu actuel n’est plus la détection de ces mutations mais leur interprétation fonctionnelle, pouvant démontrer leur caractère activateur ou leur ciblage par des TKI.Dans ce contexte, mon objectif de thèse a été d’exploiter les données de séquençage de patients souffrant d’un HPRC ou d’un CBNPC afin d’identifier de nouvelles mutations activatrices de MET et de caractériser leurs mécanismes d’activation afin de déterminer leur éligibilité pour un traitement potentiel par des TKI.Grâce à une collaboration avec l'Institut Gustave Roussy qui centralise les données de séquençage des patients atteints d’HPRC, nous avons identifié dans une cohorte de 158 patients, 8 mutations non décrites jusqu'à présent, touchant le domaine extracellulaire (V37A et R426P), le domaine juxtamembranaire (S1018P et G1086E) et le lobe N-terminal de la kinase de MET (H1086L, I1102T, C1125G et L1130S). En parallèle, grâce à notre collaboration avec le CHU de Lille, qui centralise les données de 2808 patients atteint d’un CBNPC, nous avons identifié 2 mutations du domaine kinase non décrites.Dans un premier temps, nous avons démontré dans un modèle de transformation de fibroblastes que les quatre mutations du lobe N-terminal, répertoriées dans les HPRC, sont potentiellement des mutations activatrices de MET. De façon intéressante, bien qu’elles soient localisées dans la kinase, ces mutations conservent une dépendance à l’HGF pour induire la transformation cellulaire. De plus, ces quatre mutations sont sensibles aux TKI dirigés contre MET.Dans un second temps, afin de mieux caractériser ces nouvelles mutations activatrices, nous avons établis des lignées cellulaires épithéliales T47D exprimant deux des nouvelles mutations activatrices (H1086L et I1102T) que nous avons comparé à MET sauvage et MET ex14, connue pour conserver sa dépendance à l’HGF. Nos résultats confirment que ces deux mutations nécessitent une activation par l’HGF pour l’activation des voies de signalisation en aval et l’induction de réponse comme la mobilité cellulaire [...]Targeted therapies are currently revolutionizing the management of cancer patients, provided they present a targetable molecular alteration responsible for tumor progression. Receptor tyrosine kinases (RTKs) with activating mutations are major targets of targeted therapies, with EGFR as a representative example, whose mutations lead to its constitutive activation, making it independent of stimulation by its ligand.The MET receptor, another RTK in this family, has activating mutations in kidney and lung cancer. Indeed, type I papillary renal cell carcinoma (HPRC), an uncommon hereditary cancer, is unique in that over 80% of cases have MET activating mutations. In contrast, in non-small cell lung cancer (NSCLC), MET mutations lead to skipping of exon 14 encoding the juxtamembrane domain (MET ex14 mutations). This exon skipping leads to the loss of the juxtamembrane domain, a regulatory domain involved in the negative regulation of the receptor. In an original way from other RTK mutations, these mutations always require stimulation by HGF, the ligand of MET, making HGF production a parameter to be considered in the stratification of patients eligible for targeted therapies.Tyrosine kinase inhibitors (TKIs) directed against MET have very recently been approved for clinical use, offering real hope for patients with these mutations.Thanks to the development of high-throughput sequencing for diagnosis and the emergence of new resistance mutations following treatment with targeted therapies, the spectrum of mutations affecting TKIs is expanding considerably. The current challenge is no longer the detection of these mutations, but their functional interpretation, which can demonstrate their activating character or their targeting by TKIs.In this context, my thesis objective was to exploit sequencing data from patients suffering from HPRC or NSCLC to identify new MET activating mutations and characterize their activation mechanisms in order to determine their eligibility for potential treatment by TKIs.Thanks to a collaboration with the Institute Gustave Roussy, which centralizes sequencing data from HPRC patients, we have identified 8 previously undescribed mutations in a cohort of 158 patients, affecting the extracellular domain (V37A and R426P), the juxtamembrane domain (S1018P and G1086E) and the N-terminal lobe of MET kinase (H1086L, I1102T, C1125G and L1130S). In parallel, thanks to our collaboration with the Lille University Hospital, which centralizes data on 2808 NSCLC patients, we have identified 2 undescribed kinase domain mutations.First, we demonstrated in a fibroblast transformation model that the four N-terminal lobe mutations identified in HPRC are potential MET-activating mutations. Interestingly, although localized to the kinase, these mutations retain a dependence on HGF to induce cell transformation. Moreover, all four mutations are sensitive to TKIs directed against MET.In a second step, to better characterize these new activating mutations, we established T47D epithelial cell lines expressing two of the new activating mutations (H1086L and I1102T), which we compared with wild-type MET and MET ex14, known to retain its dependence on HGF. Our results confirm that both mutations require activation by HGF for activation of downstream signaling pathways and induction of responses such as cell motility. Transcriptomic analysis reveals significant similarities between the transcriptional programs of the MET I1102T, H1086L and MET exon14 mutations, highlighting their involvement in extracellular matrix remodeling and invasion. Xenografts of cells expressing these new mutations in mouse models demonstrate their ability to promote tumor growth [...]
38
Alami, Jennifer. "The role of HGF and met in Wilms tumour." 2004. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=80291&T=F.
39
LEONETTI, ERICA. "c-MET activated pathways and their implication in TGCTs oncogenesis." Doctoral thesis, 2020. http://hdl.handle.net/11573/1442833.
Abstract:
HGF/C-MET system has a very intricate signalling whose importance is well known during embryogenesis. c-MET de-regulation is widely described in several human cancers, and for this purpose, it is used as a target in several personalized therapies (www.vai.org/met). Though, few data are present in literature about this system in TGCTs. c-MET is encoded on chromosome 7, region 7q31. A duplication of this chromosome was described in TGCT patients. Noteworthy, high levels of HGF in serum plasma of patients affected by TGCT were found.
TGCTs are a group of pathologies that arise from altered testicular niche during embryogenesis. This alteration is responsible for a block of gonocyte differentiation, which can give rise to all type II TGCTs. TGCTs are mostly curable, but there is still a little percentage of patients who develop drug resistance, radio-resistance, or long-term toxicity due to the used chemo- and radio-therapy. For these reasons, as well as for the young age of the patients and the increasing incidence in recent years, it is a paramount to have a better understanding on the onset and progression of TGCTs.
In a previous work we demonstrated that c-MET is expressed by several cell lines derived from type II TGCTs and that HGF administration determines strong biological responses, especially in non-seminoma cell lines. In line with these results, we also observed that c-MET was present in human biopsies derived from patients affected by all type II TGCTs (102). In order to better characterize onset and progression of TGCTs, we decided to investigate:
1) The specific role of the c-MET receptor in chemotaxis and collective migration (continuing the previous work).
2) The signalling pathways triggered by HGF and mediated by c-MET activation, by identifying the main adaptor proteins related to it in NT2D1 cells and their role.
3) The synergic relationship among different activated adaptors in NT2D1 cells.
4) The differential HGF expression in biopsies derived from patients affected by type II TGCTs with specific concern on SE and EC.
40
Onvani, Sara. "Effects of Aberrant HGF/MET Signalling on Cerebellar Development and Medulloblastoma Pathogenesis." Thesis, 2012. http://hdl.handle.net/1807/33766.
Abstract:
Medulloblastoma is the most common malignant paediatric brain tumour. Similar to other tumours, medulloblastoma pathogenesis involves abnormal regulation of several developmental growth pathways. As my thesis project, I studied the effects of aberrant HGF/MET signalling on medulloblastoma formation in two ways. In my first objective, I investigated the role that mutations play in activated HGF/MET signalling in medulloblastoma by searching for mutations in HGF/MET pathway genes, SPINT1, SPINT2, and MET, within primary medulloblastoma specimens. This screen identified several single nucleotide polymorphisms (SNPs) and two novel variations, one in each SPINT1 and SPINT2 genes.
In my second objective, I generated a transgenic mouse model with cerebellar-specific aberrant MET signalling. These mice developed extensive cerebellar abnormalities but formed no tumours. These results indicate that mutations in the HGF/MET pathway components alone are not sufficient to initiate medulloblastoma formation and must coincide with additional genetic insults to promote tumour formation, maintenance, and progression.
41
Klenk, Nicola Anna. "Einfluss von HGF/c-Met auf das Tumormikromilieu in Kopf-Hals-Karzinomen." Doctoral thesis, 2019. https://nbn-resolving.org/urn:nbn:de:bvb:20-opus-184916.
Abstract:
Der HGF/c-Met-Signalweg wurde bereits seit vielen Jahren als ein wesentlicher Faktor in der Tumorgenese von Kopf-Hals-Karzinomen diskutiert. Allerdings lag der Fokus bisher nur auf den Tumorzellen selbst. In letzter Zeit wurde jedoch mehr über das umgebende Tumormikromilieu und seine bedeutende Rolle in der Tumorprogression bekannt. In anderen Tumormodellen wurde bereits gezeigt, dass der HGF/c-Met-Signalweg eine immunologische und metabolische Wirkung auf das Tumormikromilieu hat. Eine Signal-Aktivierung führte zu einer Zunahme des Immun-Checkpoint-Proteins PD-L1 auf der Tumorzelloberfläche. PD-L1 bewirkt wiederum eine Hemmung des Immunsystems, indem es die T-Zell-Aktivierung im Mikromilieu verhindert und somit die Tumorzellen nicht vom Immunsystem erkannt und beseitigt werden können. Außerdem wurde gezeigt, dass HGF/c-Met eine Glykolyse-steigernde Wirkung auf Tumorzellen hat und durch die Energiezufuhr indirekt zu einer hohen Proliferationsrate beiträgt. Ein Nebeneffekt ist hier, dass das durch die hochregulierte Glykolyse anfallende Laktat im Tumormikromilieu akkumuliert und dadurch die T-Zellen der Immunabwehr zusätzlich schädigt. Um auch den Einfluss von HGF/c-Met auf das Tumormikromilieu von Kopf-Hals-Karzinomen zu prüfen, wurden zwei etablierte Zelllinien (Detroit562 und FaDu), aus humanen Plattenepithelkarzinomen der Kopf-Hals-Region, für die Versuchsreihen in der vorliegenden Arbeit herangezogen. Die Durchflusszytometrie ergab, dass nach HGF-Stimulation die Menge an PD-L1 auf der Zelloberfläche beider Tumorzelllinien im Vergleich zur unbehandelten Probe zunahm. Bei Detroit562 war die Zunahme signifikant. Als Kontrolle wurde zusätzlich mit zwei verschiedenen Hemmprinzipien (PHA-665752 und c-Met-siRNA) das HGF-Signal unterbunden. Zusammen konnte damit bestätigt werden, dass die Zunahme von PD-L1 durch die Zugabe von HGF ausgelöst wurde. Mit Hilfe eines Verfahrens zur Messung des Glykolyse-bedingten Protonenausstroms, konnte festgestellt werden, dass eine Behandlung mit HGF in Detroit562 und FaDu zu einer gesteigerten Glykolyse führt. Auffällig war, dass sowohl beim durchflusszytometrischen Nachweis von PD-L1, als auch bei der Messung der Glykolyse, nach HGF-Stimulation bei Detroit562 im Vergleich zu FaDu ein deutlich größerer Effekt zu sehen war. Ein Zusammenhang könnte darin bestehen, dass die Detroit562-Tumorzellen aus Metastasen stammen. Aus anderen Vorarbeiten ist bekannt, dass Metastasen eine höhere Expression des HGF-Rezeptors c-Met zeigen. Eine im Vergleich zu FaDu höhere c-Met-Expression in Detroit562 kann zu einem stärkeren HGF-Signal und damit zu einem stärkeren Effekt auf nachfolgende Prozesse führen. Die Ergebnisse der vorliegenden Arbeit erweitern unser Verständnis bezüglich des HGF/c-Met-Signalwegs und zeigen, dass eine simultane Hemmung der PD-1/PD-L1-Achse und des HGF/c-Met-Signalwegs synergistische Effekte haben könnteThe HGF/c-Met signalling pathway has been discussed for many years as an essential factor in the tumorgenesis of head and neck cancer. However, the focus has so far only been on the tumor cells themselves. Recently, there is more knowledge about the surrounding tumor microenvironment and its important role in tumor progression. Other tumor models have already shown that the HGF/c-Met signalling pathway has an immunological and metabolic effect on the tumor micromilieu. Signal activation led to an increase in the immune checkpoint protein PD-L1 on the tumor cell surface. PD-L1 inhibits the immune system by preventing T-cell activation in the micromilieu and thus prevents tumor cells from being recognized and eliminated by the immune system. It has also been shown that HGF/c-Met has a glycolysis-increasing effect on tumor cells and indirectly contributes to a high rate of proliferation through the supply of energy. A side effect here is that the lactate produced by the highly regulated glycolysis accumulates in the tumor microenvironment and thus additionally damages the T-cells of the immune system. In order to examine the influence of HGF/c-Met on the tumor micromilieu of head and neck carcinomas, two established cell lines (Detroit562 and FaDu), from human squamous cell carcinomas of the head and neck region, were used for the test series in this paper. Flow cytometry showed that after HGF stimulation the amount of PD-L1 on the cell surface of both tumor cell lines compared to the untreated sample. Detroit562 showed a significant increase. As a control, two different inhibitors (PHA-665752 and c-Met-siRNA) were used to inhibit the HGF signal. Together they confirmed that the increase of PD-L1 was caused by the addition of HGF. Using a method to measure the glycolysis-related proton outflow, it was found that treatment with HGF in Detroit562 and FaDu leads to increased glycolysis. It was noticeable that both the flow cytometric detection of PD-L1 and glycolysis showed a greater effect after HGF stimulation in Detroit562 compared to FaDu. The reason could be that the Detroit562 tumor cells originate from metastases. From other preliminary work it is known that metastases show a higher expression of the HGF receptor c-Met. A higher c-Met expression in Detroit562 compared to FaDu can lead to a stronger HGF signal and thus to a stronger effect on subsequent processes. The results of the present work broaden our understanding of the HGF/c-Met signaling pathway and show that simultaneous inhibition of the PD-1/PD-L1 axis and the HGF/c-Met signaling pathway could have synergistic effects
42
Hung, Shin-Huei, and 洪馨徽. "The Role Of PKC-Mediated C-Met Endocytosis In HGF-Induced Fluctuant Signaling." Thesis, 2014. http://ndltd.ncl.edu.tw/handle/ckvm59.
Abstract:
碩士慈濟大學
醫學檢驗生物技術學系醫學生物技術碩士班
102
Hepatocyte growth factor (HGF) is one of the essential metastatic factors capable of triggering tumor progression of hepatocellular carcinoma cell (HCC). c-Met, the receptor tyrosine kinase (RTK) of HGF was regarded as a potential therapeutic target for treatment of hepatocellular carcinoma. It is urgent to explore the detailed mechanisms of HGF/c-Met signaling for devising more effective targeting strategy. Our recent study demonstrated that HGF-induced fluctuant ERK-paxillin signaling for cell migration of HepG2. We further found HGF-induced phosphorylations of c-Met, JNK and paxillin (Ser178) shared a common fluctuant pattern characterized by an initial peak at 0.5h, a middle drop at 4h and a later peak at 10 h. Such signaling fluctuation was reminiscent of c-Met endocytosis, which control signal transduction in a temporal and spatial manner. After HGF-induced RTK endocytosis, signal transduction can be sustained within early endosome which may recycle back to the plasma membrane or subject to ubiquitin - directed lysosomal degradation. Here, we demonstrated that endosome formation is required for initial enhancement of JNK/Paxillin (S178) phosphorylations at 0.5 h. On the other hand, blockade of early endosome formation by dynasor may suppress HGF-induced cell migration of HepG2 and suppress HGF- induced fluctuant JNK-paxillin signaling. Our recent study demonstrated that protein kinase C (PKC) mediated HGF-induced fluctuant ERK/JNK-paxillin signaling for cell migration of HepG2. We further proposed that HGF-induced fluctuant signaling is well correlated with endocytosis of c-Met, mediated by PKC. Subsequently, PKC mediates endosomal c-Met degradation for subsequent signal declination until 4h. At 10 h, the phosphorylations of JNK/ Paxillin (S178) rised again via Golgi-localized, gamma – ear – containing , Arf -binding proteins 3 (GGA3)-mediated endosomal recycling. Finally, HGF-induced cell migration and metastasis of HepG2 can be prevented by inhibitors of endocytosis, implicating that critical endosomal components are promising therapeutic targets for preventing HGF-induced tumor progression of HCC.
43
Daher, Zeinab. "Identification des métalloprotéases de la matrice extracellulaire synthétisées et sécrétées par des cellules dérivées de la lignée MDCK, les cellules MSV-MDCK-INV aux propriétés tumorales et invasives." Thèse, 2004. http://hdl.handle.net/1866/15189.
44
Ugur, Hafize [Verfasser]. "Untersuchungen zum c-met, HGF-System an humanen Mesothelzellen in vitro / Hafize Ugur geb. Atakul." 2007. http://d-nb.info/987525611/34.
45
Stefan, Monica [Verfasser]. "Identifizierung eines neuen Interaktionspartners des HGF-Rezeptors c-Met : SHIP-1 spielt eine Schlüsselrolle bei der Vermittlung der HGF-induzierten Tubulogenese von Epithelzellen / von Monica Stefan." 2001. http://d-nb.info/961707232/34.
46
Starova, BLERTA. "ROLE OF CELL ADHESION MICROENVIRONMENT AND THE SRC/STAT3 AXIS IN AUTOCRINE HGF SIGNALING DURING BREAST TUMOURIGENESIS." Thesis, 2008. http://hdl.handle.net/1974/1455.
Abstract:
Over-expression of both hepatocyte growth factor (HGF) and its receptor Met
frequently occurs in invasive human breast cancer, suggesting that the establishment of an HGF “autocrine loop” may be linked to breast tumour progression. We have recently
shown a novel activating function of two signaling molecules, Src tyrosine kinase and the signal transducer and activator of transcription-3 factor (Stat3), on HGF expression in breast epithelial cells. Interestingly, Stat3 is also important in normal breast development,but this function does not require Src. In addition, β1-integrin adhesion occurs minimally in differentiated breast epithelium, but is upregulated during oncogenic progression and is required for transformation by Src. We therefore hypothesize that β1-integrin engagement is necessary for Src/Stat3-dependent activation of HGF transcription and breast tumourigensis. Using specific inhibitors of Src (Dasatinib) and Stat3 (CPA7) we demonstrated that autocrine HGF expression is linked to activation of Src/Stat3 in a malignant breast cell line. Phenotypic reversion (e.g., cell rounding and loss of filopodial extensions) and inhibition of pY705Stat3, HGF and pYMet expression as determined by immunofluorescence was achieved with both inhibitor treatments separately, and a
synergistic effect was observed with combined treatment. Furthermore, β-catenin
localization was nuclear in malignant cells, but shifted to cortical cytoplasmic following
inhibitor treatment, similar to non-malignant mouse breast epithelial cells (EPH4). We are currently extrapolating these findings to a 3D Matrigel culture model in which EPH4 cells form acini-like spheroids with hollow lumen surrounded by a well-polarized outer layer of cells. Under these conditions, Stat3 levels are decreased followed by a reduction in cyclin D1 expression, while Src activation remains at a low baseline level. Interestingly,expression of Stat5, which has a reciprocal relationship with Stat3 in breast development and involution, is increased concomitant with elevated β-casein expression. Moreover, Fibronectin and HGF in combination stimulate tubular outgrowths with lumen filling.
These findings suggest that aberrant changes in extracellular matrix milieu may stimulate
integrin cross talk resulting in a switch of HGF/Met signaling to a transformation
phenotype. Information from this study may lead to novel cancer therapies through
targeting the HGF/Met and integrin signaling cascades.Thesis (Master, Pathology & Molecular Medicine) -- Queen's University, 2008-09-19 18:19:22.744
47
Seiden, Long Isolde Marie. "Functional relationships between hepatocyte growth factor receptor (HGF)/Met signaling and Ki-ras oncogenic mutation in colon carcinoma cells." 2005. http://link.library.utoronto.ca/eir/EIRdetail.cfm?Resources__ID=232774&T=F.
48
Yi-TszLin and 林憶慈. "The role of HGF/c-Met signaling in ultrafine carbon particles-induced proliferation of human pulmonary adenocarcinoma H441 cells." Thesis, 2012. http://ndltd.ncl.edu.tw/handle/32910678695346823512.
49
Giannini, Giuseppe. "A tumoral and invasive phenotype independent of c-Met mutation." Thèse, 2003. http://hdl.handle.net/1866/14926.
50
Goupil, Eugénie. "Rôles de Gab 1/2 et de Shp2 dans l'établissement du phénotype transformé et invasif de cellules MDCK infectées par le virus du sarcome de Moloney." Thèse, 2006. http://hdl.handle.net/1866/15232.