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Molekulare Pathogenese des Zervixkarzinoms und seiner Vorstufen

Molecular pathogenesis of cervical cancer

Zusammenfassung

Bestimmte Typen der humanen Papillomviren (so genannte humane Papillomviren vom Hochrisikotyp: HR-HPV). spielen eine zentrale Rolle bei der Entstehung des Zervixkarzinoms. Zwar sind diese Viren in der Bevölkerung sehr weit verbreitet, jedoch entwickelt sich nach einer HPV-Infektion eher selten eine klinisch relevante Läsion. Für die Entstehung einer Dysplasie ist die deregulierte Expression der viralen Onkoproteine E6 und E7 in epithelialen Stammzellen erforderlich. Im Verlauf einer akuten Infektion werden diese Gene aber normalerweise nur in differenzierten und zellzyklusarretierten Zellen der oberen Schichten des Epithels exprimiert. Kommt es dagegen zur Aktivierung dieser Gene in den proliferierenden Basal- und Parabasalzellen, kann es durch Beeinträchtigung der Zellzyklusregulation, des mitotischen Spindelapparats und der Zentrosomenfunktionen zur Störung der Chromosomenverteilung und -struktur während der Mitose kommen. Dies führt zur chromosomalen Instabilität und bereitet den Boden für die anschließende Karzinogenese. Die Expression des HPV-E7-Onkoproteins bewirkt eine massive Überexpression des zellulären p16INK4a-Proteins, das sich daher zunehmend als geeigneter Surrogatmarker für die Diagnostik in Zytologie und Histologie erweist. Diese Übersicht fasst die Mechanismen der HPV-assoziierten Transformation zusammen und legt die sich daraus ergebende Möglichkeiten für die Diagnostik des Zerivxkarzinoms dar.

Abstract

Specific types of the human papillomaviruses (high risk human papillomaviruses) play an essential role in the pathogenesis of cervical cancer. Although infections by these viruses are very common in the general population, only few result in clinically relevant lesions. Continuous and deregulated expression of two viral oncoproteins E6 and E7 in basal or parabasal cells are required to induce and maintain neoplastic growth. In the course of an acute HPV-infection these genes are exclusively expressed in cell cycle arrested, terminally differentiated cells in the intermediate or superficial layers of the epithelium. Accidental activation of these genes in proliferating cells in the basal or parabasal cell layers results in interference with the cell cycle regulation, disturbances of the mitotic spindle apparatus and centrosome functions. This results in numerical and structural chromosome aberrations, chromosomal instability, increasing aneuploidy and initiates cervical carcinogenesis. The deregulated expression of the viral oncogene E7 is indicated by strong over-expression of the cellular p16INK4a gene product. This finding may have significant influence on novel strategies in cervical cancer diagnosis and screening. This review summarizes the basic molecular mechanisms of how papillomaviruses contribute to cellular transformation and how this can influence future diagnostic applications.

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Interessenkonflikt:

Der korrespondierende Autor weist auf eine Verbindung mit folgender Firma/Firmen hin: M. J. Trunk ist Angestellter der Firma mtm Laboratories AG, die diagnostische Tests (p16INK4a) entwickelt und vermarktet.

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Correspondence to M. von Knebel Doeberitz.

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Trunk, M.J., Wentzensen, N. & von Knebel Doeberitz, M. Molekulare Pathogenese des Zervixkarzinoms und seiner Vorstufen. Pathologe 26, 283–290 (2005). https://doi.org/10.1007/s00292-005-0763-4

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Schlüsselwörter

  • Zervixkarzinom
  • Humanes Papillomvirus
  • Zervikale intraepitheliale Neoplasie
  • Onkogene
  • p16INK4a

Keywords

  • Cervical carcinoma
  • Human papillomavirus
  • Cervical intraepithelial neoplasia
  • Oncogenes
  • p16INK4a