Publikationsserver der Universitätsbibliothek Marburg
Titel:Expression und Funktion der Toll-Like Rezeptoren TLR-4 und TLR-9 an Zelllinien des Harnblasenkarzinoms
Autor:Kesch, Claudia Verena
Weitere Beteiligte: Olbert, P. (PD Dr.)
Veröffentlicht:2015
URI:https://archiv.ub.uni-marburg.de/diss/z2015/0148
DOI: https://doi.org/10.17192/z2015.0148
URN: urn:nbn:de:hebis:04-z2015-01489
DDC: Medizin
Titel (trans.):Expression and function of toll-like receptors TLR-4 and TLR-9 on bladder cancer cell lines
Publikationsdatum:2015-02-26
Lizenz:https://creativecommons.org/licenses/by-nc-sa/4.0

Dokument

Schlagwörter:
Toll-like receptors, BCG, Blasenkrebs, Toll-like-Rezeptoren, Bladder cancer, BCG

Zusammenfassung:
Das Harnblasenkarzinom ist eine der häufigsten malignen Tumorerkrankungen weltweit. 75%-85% der Patienten werden noch in nicht-muskelinvasiven Stadien diagnostiziert. Für einen Teil dieser Patienten stellt die Dispositionsprophylaxe mittels BCG-Instillation nach TUR eine effektive Therapie dar und wird empfohlen. Bis heute ist der Wirkungsmechanismus von BCG nicht vollständig geklärt, aber es ist bekannt, dass Bestandteile von BCG mit Toll-like Rezeptoren, unter ihnen TLR-4 und TLR-9, interagieren und dass CpG-ODN, ein TLR-9-Agonist, in vitro und in Tierversuchen dem BCG sogar überlegen ist. Trotzdem gibt es bisher nur wenige Untersuchungen zur Existenz und Funktionalität von Toll-like Rezeptoren auf Harnblasenkarzinomzellen selbst. Ziel dieser Arbeit war es daher, die Expression von TLR-4 und TLR-9 an verschiedenen Zelllinien des Harnblasenkarzinoms zu untersuchen und zu überprüfen, ob eine Stimulation dieser Rezeptoren durch ihren spezifischen Liganden zu Veränderungen im Zytokinexperssionsmuster, in der Zellproliferation und in der Zellinvasion führt. Alle untersuchten Harnblasenkarzinomzelllinien exprimierten TLR-9 mRNA und zumeist auch TLR-4 mRNA. Exemplarisch wurden für alle weiteren Untersuchungen vier Zelllinien gewählt. An ihnen wurde zunächst die TLR-4- und TLR-9- Proteinexpression mittels Immunzytologie bzw. Western Blot untersucht. Diese zeigte übereinstimmende Ergebnisse mit der mRNA-Expression. Zur Untersuchung der LPS-Effekte wurden T24 als Zelllinie mit starker TLR-4- Expression und BFTC als Zelllinie ohne TLR-4-Expression gewählt. LPS induziert eine signifikante IL-6- und TNFα-Antwort in der Zelllinie T24, nicht aber in BFTC. LPS hatte keinen Einfluss auf die Zellproliferation. Zur Untersuchung der CpG-ODN-Effekte wurden UMUC3 als Zelllinie mit starker TLR-9-Expression und RT112 als Zelllinie mit schwacher TLR-9-Expression gewählt. Es konnte gezeigt werden, dass INTERFERin® die Aufnahme von CpG-ODN in das Zellinnere, also den Ort der TLR-9-Expression, verstärkt. Daher wurde teilweise mit INTERFERin® gearbeitet, um minimale CpG-ODN-Effekte besser charakterisieren zu können. In der Zelllinie UMUC3 verstärkte CpG-A + INTERFERin® die Expression von IL-8, TNFα, INFß, VEGF-A und PlGF signifikant. CpG-B + INTERFERin® verstärkte nur die Expression von IL-8 und INFß. In der Zelllinie RT112 hatte CpG-A + INTERFERin® hingegen keine Effekte. CpG-B + INTERFERin® verstärkte die IL-8- und TNFα-Expression signifikant. Die Zellproliferation der Zelllinie UMUC3 wurde sowohl durch CpG-B alleine, als auch durch CpG-B + INTERFERin®, sowie durch CpG-A +INTERFERin® signifikant vermindert. Die Zellproliferation der Zelllinie RT112 wurde durch CpG-B und durch CpG-B + INTERFERin® signifikant vermindert. Beide CpG-Motive verstärkten in beiden Zelllinien die Zellinvasion signifikant, CpG-B hatte hierbei einen noch ausgeprägteren Effekt, als CpG-A. Dies zeigt, dass BCG und potentiell zukünftige Immunotherapeutika des nicht-muskelinvasiven Harnblasenkarzinoms, die ihre Wirkung über Toll-like Rezeptoren entfalten, immer auch Einfluss auf die Tumorzellen direkt nehmen, da diese selbst auch funktionelle Toll-like Rezeptoren exprimieren. Die Untersuchungen zu Zytokinexpression, Zellproliferation und Invasion verdeutlichen, dass dies, therapeutisch gesehen, sowohl positive, als aber auch negative Folgen haben kann. Diese Mechanismen und vor allem ihre Signalwege sollten noch genauer untersucht werden, um die Wirkung von Immunotherapeutika zu optimieren und einen Therapieerfolg vorhersehbarer zu machen.

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