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DOI: 10.1055/s-2006-944821
© Georg Thieme Verlag KG Stuttgart · New York
Epigenetik in der Entstehung von Plattenenepithelkarzinomen des Kopf-Halses - mögliche neue Therapieoption?
Role of Epigenetics in the Carcinogenesis of Head and Neck Carcinomas - Possible New Targeted Therapy?Publication History
Publication Date:
17 January 2007 (online)
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Zusammenfassung
Auf der Suche nach innovativen, individualisierten Therapien von Plattenepithelkarzinomen des Kopf-Halses ist ein besseres Verständnis der Karzinogenese unabdingbar. Entgegen der bisherigen Vorstellung, dass allein genetische Veränderungen den schrittweisen Prozess der Karzinogenese initiieren und perpetuieren, belegen neuere Studien, dass auch epigenetische Phänomene wesentlich zur Tumorentstehung beitragen. Bei epigenetischen Veränderungen kommt es zu Genexpressionsveränderungen ohne Genalterationen. Das am besten untersuchte epigenetische Phänomen ist die Hypermethylierung der Promotorregion eines Gens. Durch die Bindung der Methylgruppen an die DNA wird die Anlagerung des Promotors verhindert und somit die Transkription unterbunden. Bei Hypermethylierung von Tumorsuppressorgenen kommt es somit z. B. zu ungehemmter Proliferation und fehlender Apoptose.
Eine Hypermethylierung von Tumorsuppressorgenen konnte bereits in Vorstufen der Plattenepithelkarzinome nachgewiesen werden. Daher bietet sich Epigenetik oder DNA-Methylierung möglicherweise als „Biomarker” zur Frühentdeckung von Kopf-Hals-Karzinomen an.
Die durch Methyltransferasen vermittelte Methylgruppenbindung ist mit Hilfe von DNA Demethylierungsagenzien reversibel. In mehreren Studien konnte eine Verminderung der Proliferationsrate sowie Steigerung der Apoptose in Tumorzellkulturen nach Behandlung mit Demethylierungsagenzien erreicht werden. Diese Ergebnisse bieten einen interessanten Ansatzpunkt für neue, zielgerichtete Therapien.
Abstract
In search of new targeted therapies for squamous cell carcinoma of the head neck (HNSCC), a better understanding of the carcinogenesis is of outmost importance. Recent studies show that not only genetic but also epigenetic alterations initiate the multistep process of tumordevelopment. Epigenetic changes lead to altered gene expression without alterations of the DNA sequence. The best characterized epigenetic change is the methylation of the promoter region of genes, especially of tumorsuppressor genes. The methylation of the promoter region blocks the promoter and therefore represses transcription. The loss of the gene products of tumorsuppressor genes leads to increased proliferation and decreased apoptosis.
Methylation of tumorsuppressor genes was shown in precancerous lesions of HNSCC, which emphasizes the importance of methylation as an early biomarker.
Several studies of tumor cell cultures show reactivated expression of proteins and as a result reduction of proliferation and induction of apoptosis after treatment with demethylating agentens. This presents a very promising new option for a targeted therapy.
Schlüsselwörter
Kopf-Hals-Karzinome - Epigenetik - Hypermethylierung
Key words
head neck carcinoma - Epigenetics - Hypermethylation
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Priv.-Doz. Dr. med. Anette Weber
Klinik und Poliklinik für Hals-Nasen-Ohrenheilkunde, Plastische Operationen
Universitätsklinikum Leipzig
Liebigstraße 10 - 14
04103 Leipzig
Email: Anette.Weber@medizin.uni-leipzig.de