Untersuchung des Einflusses von CA125 auf Chemoresistenz, Sphäroidbildung und Tumorstammzellmarkerexpression in Ovarialkarzinomzellen Medizin Sphäroide CD117 CD133 CD24 CD22 Einfluss von CA125 auf Chemoresistenz, Sphäroidbildung und Tumorstammzellmarkerexpression in Ovarialkarzinomzellen Das tumorassoziierte Antigen CA125 wird häufig zur Verlaufskontrolle von Patientinnen mit Ovarialkarzinom angewendet, da es in Ovarialkarzinomzellen zumeist überexprimiert wird. Dabei ist die physiologische Funktion des Muzins bis heute weitgehend unbekannt. Ziel dieser Arbeit ist es daher, zu untersuchen, welchen Einfluss der Knockdown von CA125 in Ovarialkarzinomzellen auf die Chemosensibilität der Zellen, die Fähigkeit zu Sphäroidbildung sowie auf die Expression von Tumorstammzellmarkern besitzt. Zu diesem Zweck wurden zwei Subklone der Zelllinie OAW42 verwendet, deren CA125-Expression mittels stabiler Transfektion signifikant gehemmt wird. In dieser Arbeit konnte gezeigt werden, dass die adhärenten Zellen der Zelllinie OAWH8+ durch den CA125 Knockdown eine signifikant höhere Carboplatinresistenz besitzen, wohingegen die Paclitaxelresistenz durch die CA125 Expression unbeeinflusst bleibt. In der Zelllinie OAWB8- hingegen bewirkte der CA125 Knockdown einen gegenteiligen Effekt bezüglich der Carboplatinresistenz, so dass der CA125 Knockdown hier zu einer Erhöhung der Carboplatinsensibilität führte. Gegenüber Paclitaxel hatte CA125 wiederum keinen markanten Einfluss. Weiterhin wurde der Einfluss des CA125 Knockdowns auf die Expression von Tumorstammzellmarkern untersucht, wobei sich bei den Versuchen dieser Arbeit kein Zusammenhang nachweisen lässt. Zudem verstärkte die CA125 Expression die homotypische Interaktion der OAWB8- Zellen, sodass CA125+ Zellen eine stärkere Sphäroidbildung zeigten als die CA125- Knockdownklone. Für die Zelllinie OAWB8- zeigte hingegen nur der CA125- OAWB8- Knockdownklon die Fähigkeit zur Sphäroidbildung. Zusammenfassend konnte für beide Zelllinien beobachtet werden, dass die Zellen in Sphäroidkultur eine deutlichere Resistenz gegenüber Carboplatin und Paclitaxel aufwiesen, als die adhärenten Kontrollzellen. Besonders in der Sekundärtherapie des Ovarialkarzinoms sind Chemoresistenzen weit verbreitet. Dabei scheint CA125 eine zentrale Rolle für das Überleben von Ovarialkarzinomzellen einzunehmen. Mit welchem Mechanismus und über welche Signalmoleküle CA125 die Chemoresistenz beeinflusst, sollte daher weiter erforscht werden, um langfristig einen neuen Therapieansatz für eine kurative Therapie des Ovarialkarzinoms zu etablieren. Generell bedarf es zur Entwicklung weiterer Therapieoptionen einer umfangreichen Erforschung der physiologischen Funktion von CA125. Des Weiteren bleibt die Detektion optimaler Tumorstammzellmarker für Ovarialkarzinomzellen zu eruieren, um Tumorstammzellen effektiv identifizieren zu können. Dabei sollte in Zukunft insbesondere der Frage nachgegangen werden, ob sich im Verlauf einer Ovarialkarzinomerkrankung auch in vivo eine Veränderung der CA125 Expression sowie der Tumorstammzellanteile beobachten lässt. Hierfür würde sich besonders die Entnahme von Sphäroidzellen im Aszites von Ovarialkarzinompatientinnen nach Erstdiagnose sowie gegebenenfalls bei Auftreten eines Rezidivs eignen. 2017-05-03 Kull, Eva Kull Eva ALDH Medical sciences Medicine Medizin Ovarialkarzinom opus:7445 2017-05-09 2017-05-05 Medizin Ovarian Cancer Tumostammzellmarker ths Prof. Dr. Wagner U. Wagner, U. (Prof. Dr.) monograph application/pdf Influence of CA125 on chemosensitivity, sphere formation and cancer stem cell markers in ovarian cancer cells https://doi.org/10.17192/z2017.0295 CA125 MUC16 https://archiv.ub.uni-marburg.de/diss/z2017/0295/cover.png 2017 Chemoresistenz urn:nbn:de:hebis:04-z2017-02957 Influence of CA125 on chemosensitivity, sphere formation and cancer stem cell markers in ovarian cancer cells Since the tumor associated antigen CA125 is commonly highly expressed in ovarian cancer cells, it is frequently used to monitor patients with ovarian cancer. To this day, the physiological role of this mucin is largely unknown. Therefore it is the aim of the present study to investigate the impact of CA125 gene silencing in ovarian cancer cells on its chemosensitivity, its ability to form spheres as well as on the expression of tumor stem cell markers. For this purpose, two subclones of the OAW42 cell line were used whose CA125 expression is significantly inhibited by means of stable transfection. In the present research study it was shown that adherent cells of the OAWH8+ cell line displayed a significantly higher carboplatin resistance, whereas paclitaxel resistance was unaffected by CA125 expression. In contrast, the OAWB8- cell line showed a divergent effect on carboplatin resistance. Here, CA125 gene silencing caused an increase of carboplatin sensitivity whereas it did not show any distinctive influence on paclitaxel. Furthermore the influence of CA125 gene silencing on the expression of cancer stem cell markers was investigated, but during the present studies no prove of any correlation could be found. Moreover CA125 expression increased the interaction between OAWB8- cells so that CA125+ cells showed an enhanced sphere formation compared to CA125- clones. With regard to the OAWB8- cell line, only the CA125- clone showed the ability to form spheres. In summary, for both cell lines it was observed that sphere forming cells showed an enhanced and significant resistance to carboplatin and paclitaxel compared to adherent cells. Especially in second line treatment of ovarian cancer chemoresistance is widespread. Moreover it seems that CA125 plays a central role in the survival of ovarian cancer cells. To establish new therapeutic approaches for curative therapy of ovarian cancer it should be further explored what mechanism and via which signaling pathways CA125 affects chemoresistance. Generally, extensive research on the physiological function of CA125 is necessary to develop new therapeutic options. In order to effectively identify tumor stem cells it furthermore remains to elicit ideal tumor stem cell markers. 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