Advertisement

Der Pathologe

, 32:451 | Cite as

HPV-assoziiertes Karzinom des weiblichen Genitaltrakts

Molekulare Mechanismen der Entstehung
  • M. ReuschenbachEmail author
  • S. Vinokurova
  • M. von Knebel Doeberitz
Schwerpunkt

Zusammenfassung

Infektionen mit humanen Papillomaviren (HPV) sind bei Frauen und Männern ein häufiges Ereignis. Dagegen kommen HPV-assoziierte Neoplasien verhältnismäßig selten und auch nur an ganz bestimmten Körperstellen vor. Das Virus hat offensichtlich effiziente Mechanismen entwickelt, wie es persistieren kann, ohne dem Wirt allzu großen Schaden zuzufügen. Die Entstehung einer Neoplasie scheint eher die Ausnahme zu sein. Für die Regulierung der viralen Genexpression spielen epigenetische Mechanismen eine wichtige Rolle. Untersuchungen deuten darauf hin, dass gerade der Übergang vom permissiven Infektionsstadium in ein transformierendes Stadium, in dem es durch die Expression der viralen Onkogene zu neoplastischen Veränderungen kommen kann, mit bestimmten Methylierungsmustern des viralen Genoms assoziiert ist, die die Expression der Onkogene E6 und E7 fördern. Das transformierende Stadium wird als das eigentliche karzinogene Ereignis angesehen und kann durch den Biomarker p16INK4a immunhistochemisch nachgewiesen werden.

Schlüsselwörter

Zervilale intraepitheliale Neoplasie Zelldifferenzierung Epigenetik Methylierung Onkogenproteine, viral 

HPV-associated carcinomas of the female genital tract

Molecular mechanisms of development

Abstract

Infections with human papillomaviruses (HPV) are a common occurrence in both men and women. In contrast HPV-associated neoplasias are relatively rare and occur only in certain areas of the body. The virus has obviously developed efficient mechanisms for its persistence without inducing too much damage to the host. The formation of neoplasia seems to be more an exception. Epigenetic mechanisms play an important role in the regulation of viral gene expression. Investigations have indicated that exactly the transition from the permissive infection stage to a transformation stage, where neoplastic alterations can occur due to expression of the viral oncogenes, is associated with certain methylation patterns of the viral genome which promote the expression of the oncogenes E6 and E7. The transforming stage is seen as the actual carcinogenic event and can be immunohistochemically detected by the biomarker p16INK4a.

Keywords

Cervical intraepithelial neoplasia Cell differentiation Epigenetics Methylation Oncogene proteins, viral 

Notes

Interessenkonflikt

Die korrespondierenden Autoren geben an, dass kein Interessenkonflikt besteht.

Literatur

  1. 1.
    Cameron JE, Hagensee ME (2007) Human papillomavirus infection and disease in the HIV +  individual. Cancer Treat Res 133:185–213PubMedCrossRefGoogle Scholar
  2. 2.
    Cheng S, Schmidt-Grimminger DC, Murant T et al (1995) Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 9:2335–2349PubMedCrossRefGoogle Scholar
  3. 3.
    Day PM, Lowy DR, Schiller JT (2003) Papillomaviruses infect cells via a clathrin-dependent pathway. Virology 307:1–11PubMedCrossRefGoogle Scholar
  4. 4.
    von Knebel Doeberitz M, Vinokurova S (2009) Host factors in HPV-related carcinogenesis: cellular mechanisms controlling HPV infections. Arch Med Res 40:435–442. doi 10.1016/j.arcmedCrossRefGoogle Scholar
  5. 5.
    Doerfler W (2008) In pursuit of the first recognized epigenetic signal-DNA methylation: a 1976 to 2008 synopsis. Epigenetics 3:125–133 (6249 [pii])PubMedCrossRefGoogle Scholar
  6. 6.
    Doorbar J (2006) Molecular biology of human papillomavirus infection and cervical cancer. Clin Sci (Lond) 110:525–541. doi 10.1042/CS 20050369Google Scholar
  7. 7.
    Feinberg AP (2007) Phenotypic plasticity and the epigenetics of human disease. Nature 447:433–440. doi 10.1038/nature05919PubMedCrossRefGoogle Scholar
  8. 8.
    Fernandez AF, Rosales C, Lopez-Nieva P et al (2009) The dynamic DNA methylomes of double-stranded DNA viruses associated with human cancer. Genome Res 19:438–451. doi 10.1101/gr.083550.108PubMedCrossRefGoogle Scholar
  9. 9.
    Kines RC, Thompson CD, Lowy DR et al (2009) The initial steps leading to papillomavirus infection occur on the basement membrane prior to cell surface binding. Proc Natl Acad Sci U S A 106:20458–20463. doi 10.1073/pnas.0908502106PubMedCrossRefGoogle Scholar
  10. 10.
    Klaes R, Woerner SM, Ridder R et al (1999) Detection of high-risk cervical intraepithelial neoplasia and cervical cancer by amplification of transcripts derived from integrated papillomavirus oncogenes. Cancer Res 59:6132–6136PubMedGoogle Scholar
  11. 11.
    Klose RJ, Bird AP (2006) Genomic DNA methylation: the mark and its mediators. Trends Biochem Sci 31:89–97 (S 0968-0004(05)00352-X [pii]; doi 10.1016/j.tibs.2005.12.008)PubMedCrossRefGoogle Scholar
  12. 12.
    McLaughlin-Drubin ME, Crum CP, Munger K (2011) Human papillomavirus E7 oncoprotein induces KDM 6 A and KDM 6B histone demethylase expression and causes epigenetic reprogramming. Proc Natl Acad Sci U S A 108:2130–2135 (1009933108 [pii]; doi 10.1073/pnas.1009933108)PubMedCrossRefGoogle Scholar
  13. 13.
    Munger K (2002) The role of human papillomaviruses in human cancers. Front Biosci 7:d641-d649PubMedCrossRefGoogle Scholar
  14. 14.
    Orth G, Favre M, Majewski S, Jablonska S (2001) Epidermodysplasia verruciformis defines a subset of cutaneous human papillomaviruses. J Virol 75:4952–4953PubMedCrossRefGoogle Scholar
  15. 15.
    Pett M, Coleman N (2007) Integration of high-risk human papillomavirus: a key event in cervical carcinogenesis? J Pathol 212:356–367 (doi 10.1002/path.2192)PubMedCrossRefGoogle Scholar
  16. 16.
    Schelhaas M, Ewers H, Rajamaki ML (2008) Human papillomavirus type 16 entry: retrograde cell surface transport along actin-rich protrusions. PLoS Pathog 4:e1000148 (doi 10.1371/journal.ppat.1000148)PubMedCrossRefGoogle Scholar
  17. 17.
    Schiffman M, Castle PE, Jeronimo J et al (2007) Human papillomavirus and cervical cancer. Lancet 370:890–907 (S 0140-6736(07)61416-0 [pii]; doi 10.1016/S 0140-6736(07)61416-0)PubMedCrossRefGoogle Scholar
  18. 18.
    Selinka HC, Florin L, Patel HD et al (2007) Inhibition of transfer to secondary receptors by heparan sulfate-binding drug or antibody induces noninfectious uptake of human papillomavirus. J Virol 81:10970–10980 (JVI.00998–07 [pii]; doi 10.1128/JVI.00998–07)PubMedCrossRefGoogle Scholar
  19. 19.
    Smith JL, Campos SK, Ozbun MA (2007) Human papillomavirus type 31 uses a caveolin 1- and dynamin 2-mediated entry pathway for infection of human keratinocytes. J Virol 81:9922–9931 (JVI.00988–07 [pii]; doi 10.1128/JVI.00988–07)PubMedCrossRefGoogle Scholar
  20. 20.
    Smith JL, Campos SK, Wandinger-Ness A, Ozbun MA (2008) Caveolin-1-dependent infectious entry of human papillomavirus type 31 in human keratinocytes proceeds to the endosomal pathway for pH-dependent uncoating. J Virol 82:9505–95120 (JVI.01014–08 [pii];10.1128/JVI.01014–08 [doi])PubMedCrossRefGoogle Scholar
  21. 21.
    Stanley MA (2001) Immunobiology of papillomavirus infections. J Reprod Immunol 52:45–59 (S 0165037801001139 [pii])PubMedCrossRefGoogle Scholar
  22. 22.
    Steger G, Corbach S (1997) Dose-dependent regulation of the early promoter of human papillomavirus type 18 by the viral E2 protein. J Virol 71:50–58PubMedGoogle Scholar
  23. 23.
    Stoler MH, Broker TR (1986) In situ hybridization detection of human papillomavirus DNAs and messenger RNAs in genital condylomas and a cervical carcinoma. Hum Pathol 17:1250–1258PubMedCrossRefGoogle Scholar
  24. 24.
    Stoler MH, Wolinsky SM, Whitbeck A et al (1989) Differentiation-linked human papillomavirus types 6 and 11 transcription in genital condylomata revealed by in situ hybridization with message-specific RNA probes. Virology 172:331–340PubMedCrossRefGoogle Scholar
  25. 25.
    Strickler HD, Burk RD, Fazzari M et al (2005) Natural history and possible reactivation of human papillomavirus in human immunodeficiency virus-positive women. J Natl Cancer Inst 97:577–586 (97/8/577 [pii];10.1093/jnci/dji073 [doi])PubMedCrossRefGoogle Scholar
  26. 26.
    Thierry F (2009) Transcriptional regulation of the papillomavirus oncogenes by cellular and viral transcription factors in cervical carcinoma. Virology 384:375–379 (S 0042–6822(08)00728–9 [pii];10.1016/j.virol.2008.11.014 [doi])PubMedCrossRefGoogle Scholar
  27. 27.
    Vinokurova S, Knebel Doeberitz M von (2011) Differential methylation of the HPV16 upstream regulatory region during epithelial differentiation and neoplastic transformation. PLoS One 6:e24451PubMedCrossRefGoogle Scholar
  28. 28.
    Weissenborn S, Neale RE, Waterboer T et al (2011) Beta-papillomavirus DNA loads in hair follicles of immunocompetent people and organ transplant recipients. Med Microbiol Immunol (10.1007/s00430–011-0212–3 [doi])Google Scholar
  29. 29.
    You J, Croyle JL, Nishimura A et al (2004) Interaction of the bovine papillomavirus E2 protein with Brd4 tethers the viral DNA to host mitotic chromosomes. Cell 117:349–360 (S 0092867404004027 [pii])PubMedCrossRefGoogle Scholar
  30. 30.
    zur Hausen H (2000) Papillomaviruses causing cancer: evasion from host-cell control in early events in carcinogenesis. J Natl Cancer Inst 92:690–698CrossRefGoogle Scholar
  31. 31.
    zur Hausen H (2009) Papillomaviruses in the causation of human cancers – a brief historical account. Virology 384:260–265 (S 0042-6822(08)00772-1 [pii];10.1016/j.virol.2008.11.046 [doi])CrossRefGoogle Scholar

Copyright information

© Springer-Verlag 2011

Authors and Affiliations

  • M. Reuschenbach
    • 1
    Email author
  • S. Vinokurova
    • 1
  • M. von Knebel Doeberitz
    • 1
  1. 1.Abteilung für Angewandte Tumorbiologie, Institut für PathologieUniversitätsklinikum HeidelbergHeidelbergDeutschland

Personalised recommendations