Entstehung und Bedeutung von numerischen Chromosomenveränderungen bei bösartigen Tumorerkrankungen

Zusammenfassung

Genetische Veränderungen von Tumorzellen haben eine große Bedeutung für die Prognose vieler bösartiger Erkrankungen. Das Verständnis ihrer Entstehung bildet zudem die Grundlage für die Entwicklung neuer Therapiemöglichkeiten. Bei einer Vielzahl von Präkanzerosen und malignen Tumoren finden sich numerische Chromosomen-veränderungen (Aneuploidie), d. h. Zellen mit mehr oder weniger als 46 Chromosomen. Noch ist nicht abschließend geklärt, ob Aneuploidie eine kausale Bedeutung bei der Krebsentstehung hat oder ob es sich um ein Begleitphänomen handelt. Es existieren eine Reihe von Mechanismen, die die Entstehung von Aneuploidie erklären können: Diese umfassen Fehler in der Zellteilung, beispielsweise durch Chromosomenfehlverteilung infolge defekter Kontrollmechanismen oder Spindelpolabnormitäten. Zudem kann der Verlust der Telomersequenzen am Ende eines jeden Chromosoms und die defekte Reparatur von DNA-Schäden zur unkontrollierten Fusion von Chromosomen und dadurch zu abweichenden Chromosomensätzen führen. Schließlich kann ein doppelter Chromosomensatz (Tetraploidie) innerhalb nachfolgender Zellteilungen, z. B. durch Chromosomenverlust, die Entstehung aneuploider Chromosomensätze zur Folge haben. Das regelmäßige Vorkommen dieser Defekte in Präkanzerosen und Malignomen legt eine Beteiligung der Aneuploidie an der Entwicklung und dem Fortschreiten des malignen Phänotyps nahe.

Summary

Genetic aberrations of cancer cells have a profound impact for prognosis in several malignant neoplasias. The understanding of their origin is the basis for the development of new therapeutic options. Aneuploidy is observed in a large variety of premalignancies and tumors. Aneuploid cells harbor less or more than 46 chromosomes. The exact role of aneuploidy in tumorigenesis is still not clear. It has long been debated, whether aneuploidy directly contributes to tumorigenesis or reflects nonspecific changes during tumor progression. Several mechanisms are thought to be responsible for the generation of aneuploid sets of chromosomes: these comprise failure in cell division, such as defective chromosome separation caused by compromised mitotic checkpoint signaling or centrosome aberrations. Moreover, telomere shortening and defective DNA-damage signaling appear to be powerful driving forces of genomic instability. The loss of telomere sequences at the end of each chromosome and DNA double-strand breakage accompanied by compromised damage signaling favor fusion of chromosomes and generation of aneuploidy. Furthermore, aneuploidy arises to a much higher degree from a tetraploid state when compared to diploid cells. The frequent observation of the described defects in pre- and malignant cells supports the hypothesis that aneuploidy contributes to tumorigenesis.

Schlüsselwörter

Aneuploidie - Krebserkrankungen

Key words

aneuploidy - cancer

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