Dokument

Zusammenfassung:
Pdcd4 (programmed cell death 4) ist ein neuer Tumorsuppressor. In vielen Tumoren oder während maligner Transformation ließen sich supprimierte Pdcd4 Mengen nachweisen. Hohe Pdcd4 Spiegel wiederum verhinderten eine neoplastische Umwandlung. Bislang schienen aber die Wirkungen von Pdcd4 abhängig vom Zelltyp zu sein. Ang2 (Angiopoietin2), ein Wachstumsfaktor, der an der Neubildung von Gefäßen beteiligt ist, könnte ein zelltypübergreifendes Zielgen von Pdcd4 darstellen. Eine gezielte Suppression von Pdcd4 mittels siRNA (siPdcd4) in verschiedenen Tumorzelllinien der Mamma, der Leber, des pankreatiko-gastro-intestinalen Traktes sowie in Endothelzellen bestätigte in Western Blots eine Steigerung von Ang2 Protein. Zusätzlich zeigte sich in semiquantitativen RT- und RTD-PCRs eine Regulierung auf transkriptionaler Ebene. Damit ist Ang2 tatsächlich ein in mehreren Tumorzelltypen reguliertes Zielgen von Pdcd4. Nachdem eine erhöhte Ang2 Proteinexpression unter Pdcd4 Suppression in Western Blot Untersuchungen belegt werden konnte, ließen sich auch in Mediumüberständen von stabil (shPdcd4) oder transient (siPdcd4) transfizierten Zelllinien erhöhte Ang2 Mengen im Vergleich zur Kontrolle nachweisen. Dies sprach für eine gesteigerte Sekretion von Ang2 Protein. Die funktionelle Bedeutung der erhöhten Ang2 Spiegel wurde in Tube Formation- und Boyden Chamber Assays untersucht und dabei die immortalisierte humane mikrovaskuläre endotheliale Zelllinie HMEC-1 verwendet. Die im konditionierten Medium von stabil shPdcd4 transfizierten BON-1- und HCT116-Zellen erhöhten Ang2 Spiegel führten in Tube Formation Assays, im Vergleich zum Kontrollmedium, zu einer gesteigerten Gefäßneubildung. Anhand von Verzweigungen und Länge der Tubes erfolgte eine Software-basierte Auswertung. Bestätigt wurden diese Ergebnisse in Tube Formation Assays mit rekombinanten Ang2. Dabei ließen sich im Einklang mit der bestehenden Literatur zwei Auswirkungen nachweisen. Zum einen zeigten sich proangiogenetische Effekte von Ang2 in Verbindung mit Medium mit 10% FBS, zum anderen gefäßregressive Wirkungen von Ang2 in Medium mit 1% FBS. Vermutlich liegt das an den unterschiedlichen VEGF Konzentrationen, die mit steigendem FBS Gehalt des Mediums auch zunehmen. Zusätzlich ließ sich die Fähigkeit von Ang2, Migration von endothelialen Zellen zu fördern, in Boyden Chamber Assays nachweisen. Hierbei zeigten die gesteigerten Ang2 Konzentrationen im konditionierten Medium der stabil transfizierten BON-1- und HCT116 Zellen mit 1% und 10% FBS promigratorische Effekte auf die HMEC-1 Zellen im Vergleich zur Kontrolle. Im Rahmen dieser Arbeit konnte gezeigt werden, dass Ang2 in diversen Tumorzelllinien ein Zielgen des Tumorsuppressors Pdcd4 ist. Durch Verringerung von Pdcd4 mittels siRNA wurde Ang2 vermehrt transkribiert, translatiert und sezerniert. Die funktionelle Bedeutung der gesteigerten Ang2 Sekretion ließ sich in Tube Formation Assays (angiogenetische Wirkung) und Boyden Chamber Assays (promigratorische Wirkung) nachweisen. Mit der Steuerung von Ang2 durch Pdcd4 bindet sich der Tumorsuppressor direkt in die Neoangiogenese von Tumoren ein und unterstreicht damit seine Bedeutung in der Entwicklung maligner Neoplasien. Insgesamt gesehen ist eine Wiederherstellung der Pdcd4 Expression in Tumoren und die damit verbundene Überführung in die aktive Rolle als Tumorsuppressor ein Hauptanliegen möglicher therapeutischer Ansätze.

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