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DOI: 10.1055/s-2005-861232
30 Jahre dermatoonkologische Virologie - Papillomviren als Krebserreger
30 Years of Dermatooncological Virology - Papillomavirus as Cause of CancerPublikationsverlauf
Publikationsdatum:
31. Mai 2005 (online)
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Zusammenfassung
In den vergangenen 30 Jahren wurden bestimmte Typen der sehr heterogenen humanen Papillomvirus (HPV) Familie mit spezifischen Krebserkrankungen des Menschen in Zusammenhang gebracht und inzwischen für einige weit verbreitete Krebsformen als auslösende Ursache identifiziert. Hier handelt es sich vorrangig um den Gebärmutterhalskrebs, aber auch um weitere anogenitale Krebserkrankungen, sowie um etwa ein Viertel aller Mundhöhlenkarzinome. In zunehmendem Maße zeichnet sich auch eine Beteiligung bestimmter Papillomvirus-Typen für die Auslösung von Plattenepithelkarzinomen der Haut ab. Diese Typen sind in der Lage, die durch UV-Licht bedingte ausgelöste Apoptose (den programmierten Tod der geschädigten Zelle) zu unterdrücken und damit weiteres Zellwachstum mutierter Zellen zu ermöglichen. Die so genannten „Hochrisikotypen” dieser Virusfamilie, mit den Prototypen HPV 16 und 18, erweisen sich als wirksame Karzinogene, auch wenn nur ein geringer Prozentsatz der infizierten Frauen später an Gebärmutterhalskrebs erkrankt. In der großen Mehrzahl infizierter Personen wird die Infektion über Immunmechanismen erfolgreich kontrolliert. Diese Viren besitzen eigene Krebsgene (Onkogene), deren Wirkungsmechanismus heute zunehmend besser verstanden wird. Global gesehen lassen sich etwa 13 - 15 % aller bei Frauen auftretenden Krebserkrankungen ursächlich auf Papillomvirus-Infektionen zurückführen. Inzwischen wurden wirksame vorbeugende Impfstoffe gegen die bedeutsamsten pathogenen Vertreter dieser Virusfamilie entwickelt, die in den kommenden zwei Jahren allgemein verfügbar werden dürften. Deren breite Anwendung lässt auf eine wirksame Kontrolle des Gebärmutterhalskrebses und seiner Vorstufen hoffen. Bisherige Versuche, auch therapeutisch effiziente Impfstoffe zu entwickeln, erwiesen sich bisher als weniger erfolgreich.
Abstract
During the past 30 years specific types of human papillomaviruses (HPV) have been linked to certain human cancers and have been identified as causative agents of these malignant proliferations. Primarly cancer of the cervix, but also other anogenital cancers and approximately 25 % of oral cancers are etiologically related to these infections. Increasing evidence points to an indirect role of other HPV infections in squamous cell carcinomas of the skin. Some of the latter types suppress apoptosis, caused by DNA damage due to UV exposure of the skin, and enable continued proliferation of mutated cells. Anogenital high risk types like HPV16 and 18 are effective carcinogens, although only a small percentage of infected women eventually will develop cancer of the cervix. Immunological surveillance appears to result in clearance of most of these infections. These viruses express their own oncogenes. The mechanism of their oncogenic function is presently partially understood. Globally about 13 - 15 % of all cancers in women are caused by HPV infections. Effective preventive vaccinations against the most prevalent high risk HPV types are presently in clinical trials. It is anticipated that they will become available in 2006 or 2007. It is expected that they will lead to an effective control of cervical cancer and its precursor lesions, if vaccination is applied to juveniles before onset of sexual activity. Present approaches for therapeutic vaccinations have been less successful and require further studies.
Literatur
- 1 zur Hausen H. Roots and perspectives of contemporary papillomavirus research. J Cancer Res Clin Oncol. 1996; 122 3-13
- 2 Dürst M, Gissmann L, Ikenberg H, zur Hausen H. A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Nat Acad Sci US.. 1983; 80 3812-3815
- 3 Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H. A new type of papillomavirus DNA, its presence in genital cancer and in cell lines derived from genital cancer. EMBO J.. 1984; 3 1151-1157
- 4 de Villiers E-M, Fauquet C, Broker T R, Bernard H-U, zur Hausen H. Classification of papillomaviruses. Virology. 2004; 324 17-27
- 5 zurHausen H. Papillomaviruses and cancer: from basic studies to clinical application. Nature Rev Cancer. 2002; 2 342-350
- 6 Schwarz E, Freese U K, Gissmann L, Mayer W, Roggenbuck B, zur Hausen H. Structure and transcription of human papillomavirus type 18 and 16 sequences in cervical carcinoma cells. Nature. 1985; 314 111-114
-
7 McDougall J K.
Immortalization and transformation of human cells by human papillomavirus. In: zur Hausen H (ed) Human Pathogenic Papillomaviruses. Berlin; Springer 1994: 101-119 - 8 IARC . Handbook on Cancer Prevention. IARC Press 2005
- 9 Guiliano A R, Harris R, Sedjo R L, Baldwin S, Roe D, Papenfuss M R, Abrahamsen M, Inserra P, Olvera S, Hatch K. Incidecne, prevalence, and clearance of type-specific human papillomavirus infections: The Young Women’s Health Study. J Infect Dis. 2002; 186 462-469
- 10 Muñoz N, Mendez F, Posso H, Molano M, van den Brule A J, Ronderos M, Meijer C MJ, Muñoz A. Incidence, duration and determinants of cervical human papillomavirus infection in a cohort of Colombian women with normal cytology results. J Infect Dis. 2004; 190 2077-2087
- 11 zur Hausen H. Papillomavirus infections - a major cause of human cancers. Biochem Biophys Acta Rev on Cancer. 1996; 1288 F55-F78
- 12 Huibregste J M, Scheffner M M, Howley P M. A cellular protein mediates association of p53 with the E6 oncoprotein of human papillomavirus typed 16 or 18. EMBO J. 1991; 10 4129-4135
- 13 Lee S S, Weiss R S, Javier E T. Binding of human virus oncoproteins to hDlg/SAP97, a mammalian homolog of the Drosophila discs large tumor suppressor protein. Proc Natl Acad Sci USA. 1997; 94 6670-6675
- 14 Lee S S, Glaunsinger B, Mantovani F, Banks L, Javier R T. Multi-PDZ domain protein MUPP1 is a cellular target for both adenovirus E4-ORF1 and high risk papillomavirus type 18 E6 proteins. J Virol. 2000; 74 9680-9693
- 15 Nguyen M L, Nguyen M M, Lee D, Griep A E, Lambert P F. The PDZ ligand domain of the human papillomavirus type 16 E6 protein is required for E6’s induction of epithelial hyperplasia in vivo. J Virol. 2003; 77 6957-6964
- 16 Dyson N, Howley P M, Münger K, Harlow E. The human papilloma virus-16 E7 oncoprotein is able to bind to the retinoblastoma gene product. Science. 1989; 243 934-937
- 17 Dyson N, Guida P, Münger K, Harlow E. Homologous sequences in adenovirus E1A and human papillomavirus E7 proteins mediate interaction with the same set of cellular proteins. J Virol. 1992; 66 6893-6902
- 18 Arroyo M, Bagchi S, Raychaudhuri P. Association of the human papillomavirus type 16 E7 protein with the S-phase-specific E2F-cyclin A complex. Mol Cell Biol. 1993; 13 6537-6546
- 19 Duensing S, Münger K. Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer. 2004; 109 157-162
- 20 Orth G. Epidermodysplasia verruciformis:a model for understanding the oncogenicity of human papillomnaviruses. CIBA Found Symp. 1986; 120 157-174
- 21 Shamanin V, Glover M, Rausch C, Proby C, Leigh I M, zur Hausen H, de Villiers E-M. Specific types of HPV found in benign proliferations and in carcinomas of the skin in immunosuppressed patients. Cancer Res. 1994; 54 4610-4613
- 22 Shamanin V, zur Hausen H, Lavergne D, Proby C, Leigh I M, Neumann C, Hamm H, Goos M, Haustein U-F, Jung E G, Plewig G, Wolff H, de Villiers E M. Human papillomavirus infections in non-melanoma skin cancers from renal transplant recipients and nonimmunosuppressed patients. J Natl Cancer Inst. 1996; 88 802-811
- 23 de Jong-Tieben L M, Berkhout R JM, Smits H L, Bouwes-Bavinck J N, Vermeer B J, van der Woude F J, ter Schegget J. High frequency of detection of epidermodysplasia verruciformis-associated human papillomavirus DNA in biopsies from malignant and premalignant skin lesions from renal transplant recipients. J Invest Dermatol. 1995; 105 367-371
- 24 Boxman I LA, Berkhout R JM, Mulder L HC, Wolkers M C, Bouwes Bavinck J N, Vermeer B J, ter Schegget J. Detection of human papillomavirus DNA in plucked hairs from renal transplant recipients and healthy volunteers. J Invest Dermatol. 1997; 108 712-715
- 25 Storey A. Papillomaviruses: death-defying acts in skin cancer. Trends Mol Med. 2002; 8 417-421
- 26 Giampieri S, Garcia-Escudero R, Green J, Storey A. Human papillomavirus type 77 E6 protein selectively inhibits p53-dependent transcription of proapoptotic genes following UV-B irradiation. Oncogene. 2004; 23 5864-5870
- 27 Fei J-W, Wei Q-X, Angel P, de Villiers E-M. Differential enhancement of a cutaneous HPV promoter by ΔNp63α, jun, and mutant p53. Cell Cycle (im Druck, 2005).
- 28 Koutsky L A, Ault K A, Wheeler C M, Brown D R, Barr E, Alvarez F B, Chiacchierine L M, Jansen K U. and investigators P.O.P.S. . A controlled trial of a human papillomavirus type 16 vaccine. New Engl J Med. 2002; 347 1645-1651
- 29 Harper D M, Franco E L, Wheeler C. et al . Efficacy of a bivalent L1 virus-like particle vaccine in prevention of infection with human papillomavirus types 16 and 18 in young women: a randomised controlled trial. Lancet. 2004; 364 1757-765
- 30 Kiyono T, Foster S A, Koop J I, McDougall J K, Galloway D A, Klingelhutz A J. Both Rb/p16INK4a inactivation and telomerase activity are required to immortalize human epithelial cells. Nature. 1998; 396 84-88
Prof. Dr. med. Dr. h.c. mult. Harald zur Hausen
Deutsches Krebsforschungszentrum
Im Neuenheimer Feld 280 · 69120 Heidelberg
eMail: zurhausen@dkfz-heidelberg.de