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Zentralbl Gynakol 2002; 124(11): 511-524
DOI: 10.1055/s-2002-39579
Review

© Georg Thieme Verlag Stuttgart · New York

HPV induced cervical carcinogenesis: molecular basis and vaccine development

HPV induzierte Karzinogenese der cervix uteri: molekulare Mechanismen und ImpfstoffentwicklungA. M. Kaufmann1 , C. Backsch1 , A. Schneider1 , M. Dürst1
  • 1Gynäkologische Molekularbiologie, Frauenklinik, Friedrich-Schiller-Universität Jena
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Publication History

Publication Date:
10 June 2003 (online)

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Zusammenfassung

Prädisponierend für die Entstehung eines Zervixkarzinoms ist die Infektion mit humanen „high-risk” Papillomviren (HPV). Es gibt nur wenige Zervixkarzinome, bei denen keine HPV DNA nachweisbar ist. Mechanismen der Immortalisierung von Epithelzellen durch Interaktion mit Tumorsuppressorgenen p53 und pRB durch virale Onkogene E6 und E7 wurden definiert. Die Progression einer HPV-infizierten Zelle zu einem malignen Phänotyp erfordert weitere genetische Veränderungen des Wirtszellgenoms. Mit dem Auftreten von chromosomalen Aberrationen kann es zur Mutation oder dem Verlust von Tumorsuppressorgenen (TSG) und zur Aktivierung und Amplifikation von Onkogenen kommen, die im Prozess der Tumorgenese involviert sind. Die Onkogenamplifikation scheint mit Ausnahme weniger Berichte allerdings in der Zervixkarzinogenese nicht bedeutsam zu sein. Demgegenüber zeigen zytogenetische und „loss of heterozygosity” LOH-Untersuchungen an CIN-Läsionen und an invasiven Zervixkarzinomen den häufigen Verlust von spezifischen chromosomalen Regionen, die auf die Lokalisation von TSG hinweisen. Genetische Veränderungen der Chromosomen 3p, 6p und 11q wurden häufig in der frühen Tumorentwicklung gefunden. Primäre invasive Karzinome zeigten zusätzliche Allelverluste an Chromosomenbereichen 6q, 17p und 18q. Als biologische Marker für die diagnostische und prognostische Einschätzung von „high-risk” HPV Infektionen und maligne Progression sind für bestimmte Fragestellungen p16INK4, p27Kip1, und NET-I/C4.8 zu nennen. Putative Seneszenzgenloci mit Relevanz für HPV-induzierte Karzinogenese sind auf Chromosomen 2, 4 und 10 lokalisiert. Gene für Telomerasesuppression werden auf den Chromosomen 3, 4, und 6 vermutet. Natürliche Immunität gegen HPV Infektionen existieren. Daher sind Immuntherapien eine attraktive Möglichkeit für die Prävention und Therapie von HPV Infektionen. Derzeit hat die Vakzinentwicklung das Stadium der klinischen Prüfung erreicht. Prophylaxe zielt auf die Induktion virus-neutralisierender Antikörper gegen Kapsidproteine. Auf Virus-ähnliche Partikel basierende Impfstoffe werden in klinischen Versuchen geprüft. Wegen der langen Verzögerungsperiode zwischen Infektion und klinischer Manifestation werden klinische Untersuchungen einer langen Zeit bedürfen, bis schlüssige Ergebnisse vorliegen. Die grundsätzliche Expression viraler und vielleicht zellulärer Gene in infizierten Epithelien und Tumorzellen bietet Zielstrukturen für therapeutische Vorgehensweisen. Dass die meisten Dysplasien spontan regredieren zeigt, dass die Virusinfektion immunogen ist. In einigen Patientinnen muss die Immunantwort durch Impfungen verstärkt werden, um effektiv zu sein. Verschiedene Strategien werden in klinischen Versuchen getestet und andere sind in präklinischer Entwicklung. Die Aufgabe wird sein, die Immunsuppression von HPV-Infizierten zu umgehen.

Schlüsselwörter

Humane Papillomaviren (HPV) - Progression - Genomveränderungen - Prophylaxe - Immuntherapie - Klinische Studien

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Dr. Andreas M. Kaufmann

Gynäkologische Molekularbiologie · Frauenklinik · FSU Jena

Bachstrasse 18

07743 Jena

Germany

Phone: +49/36 41/93 42 73

Fax: +49/36 41/93 42 16

Email: andreas.kaufmann@med.uni-jena.de

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