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Titel:Rolle des Nerve Growth Factor (NGF) im Modell der pulmonalen Metastasierung
Autor:Seidler, Katrin Michaela
Weitere Beteiligte: Nockher, Andreas (PD Dr.)
Veröffentlicht:2013
URI:https://archiv.ub.uni-marburg.de/diss/z2013/0740
DOI: https://doi.org/10.17192/z2013.0740
URN: urn:nbn:de:hebis:04-z2013-07402
DDC:610 Medizin
Titel (trans.):Role of nerve growth factor (NGF) in a model of pulmonary metastasis
Publikationsdatum:2013-12-18
Lizenz:https://rightsstatements.org/vocab/InC-NC/1.0/

Dokument

Schlagwörter:
inflammation, Nervenwachstumsfaktor (NGF), pulmonale Metastasierung, Lunge, extravasation, nerve growth factor (NGF), pulmonary metastasis, Entzündung, Extravasation

Zusammenfassung:
Die Metastasierung sekundärer Organe ist die Haupttodesursache vieler Krebspatienten. Ein häufig von Metastasen befallenes Organ ist die Lunge, da sie ein sehr dichtes Kapillarbett aufweist und bei der systemischen venösen sowie der lymphatischen Drainage als eines der ersten Organe durchlaufen wird. Die pathologischen Mechanismen, die der pulmonalen Metastasierung zu Grunde liegen, sind jedoch noch wenig verstanden. Einen Mediator der Metastasierung und des Tumorwachstums stellt das Neurotrophin nerve growth factor (NGF) dar. NGF wurde ursprünglich im ZNS identifiziert, wo es die Entwicklung und den Erhalt neuronaler Zellen fördert. Inzwischen ist belegt, dass NGF auch in anderen Organen und Zellen eine Vielzahl biologischer Funktionen steuert. Bei Lungenkarzinomen wird die Rolle von NGF jedoch kontrovers diskutiert. Einerseits fördert NGF die Proliferation von isolierten Lungenkarzinomzellen über autokrine Mechanismen. Andererseits wird die Proliferation von kleinzelligen Lungenkarzinomzellen (small cell lung cancer, SCLC) durch NGF in vitro sowie deren tumorigene Eigenschaften in vivo inhibiert. Daten der eigenen Arbeitsgruppe belegen, dass NGF einen Wachstumsfaktor für Epithelzellen darstellt sowie die Atemwegsentzündung im Mausmodell des experimentellen Asthmas fördert. Da sowohl die gesteigerte Proliferation von Tumorzellen als auch ein pro-tumorigenes Entzündungsmilieu die Metastasierung vorantreiben, wurde die Hypothese abgeleitet, dass NGF auch am Prozess der Metastasierung der Lunge beteiligt ist. Dies sollte anhand eines Mausmodells der pulmonalen Metastasierung nachgewiesen werden. Dazu wurde die Anzahl der Oberflächenmetastasen sowie das Metastasenvolumen in der Lunge von Wildtyp- (WT) und NGF-Tg Mäusen quantifiziert, die NGF im Atemwegsepithels überexprimieren. Dabei ergab sich eine signifikante Reduktion der gemessenen Parameter in NGF-Tg Tieren. Diese wurden von einer geringen lokalen Entzündungsreaktion begleitet. Obwohl kein direkter Effekt von NGF auf die Funktionalität der Tumorzellen ersichtlich war, konnte die Wirkung von NGF auf das Gefäßsystem der Lunge nachgewiesen werden. Dabei zeigte sich, dass die Permeabilität pulmonaler Blutgefäße von NGF-Tg Tieren im ex vivo Modell reduziert ist und die Tiere vor der damit einhergehenden Ödembildung geschützt sind. Damit übereinstimmend konnte eine verringerte Extravasation metastasierender Tumorzellen in die Lunge NGF-Tg Mäuse nachgewiesen werden. In dieser Arbeit konnte somit erstmals gezeigt werden, dass die lokale NGF-Überexpression in der Lunge die Funktion pulmonaler Blutgefäße verändert, was zu einer geringeren vaskulären Permeabilität und zur Retention von Tumorzellen im Gefäßsystem führt. Dies belegt die Tumor-supprimierende Wirkung von NGF, die in der verringerten Metastasierung der Lunge resultiert.

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