Advertisement

Molecular Pathogenesis, Detection and Clinical Management of Pre-invasive Cervical Lesions

  • Wen-Chung Chen
  • Barbara Ma
  • Chih-Ping Mao
  • T-C Wu
Chapter

Abstract

The major public health burden of cervical cancer and its associated lesions warrants the development of effective preventive measures and successful therapies. Cervical cancer is the second most common female cancer worldwide, with approximately 493,000 diagnoses and 270,000 deaths annually. The disease can be detected early by cervical cytology in the pre-malignant phase, in the form of high-grade squamous intraepithelial lesions, and treated by a variety of methods including loop electrosurgical excision procedure. As human papillomavirus (HPV) has been identified as the major causative agent of cervical dysplasia and cervical cancer, HPV DNA testing and genotyping are also valuable in enhancing the sensitivity and specificity of cervical cancer screening. Advances in the understanding of HPV pathogenesis have led to the concept that persistent infection with high-risk HPV (hrHPV) genotypes is recognized as a necessary though not sufficient step in causing cervical cancer. This has led to the identification of tumor-promoting markers that may be required in cervical carcinogenesis. Further investigation of these markers may potentially be useful for risk stratification in screening. The knowledge of HPV virology and its role in cervical carcinogenesis leads to the potential prevention and treatment of cervical cancer. The current status of HPV vaccines is also discussed.

Keywords

Cervical Cancer Cervical Intraepithelial Neoplasia Cervical Carcinogenesis Loop Electrosurgical Excision Procedure hrHPV Infection 
These keywords were added by machine and not by the authors. This process is experimental and the keywords may be updated as the learning algorithm improves.

Notes

Acknowledgements

This review is not intended to be an encyclopedic one, and the authors apologize to those not cited. This work was supported by the NCI SPORE in Cervical Cancer P50 CA098252, NCI 1RO1 CA114425-01 and 1RO1 CA118790.

References

  1. 1.
    Parkin DM, Bray F, Ferlay J, Pisani P (2005) Global cancer statistics, 2002. CA Cancer J Clin 55(2):74–108PubMedGoogle Scholar
  2. 2.
    Broders A (1932) Carcinoma in situ contrasted with benign penetrating epithelium. JAMA 99:1670–1674Google Scholar
  3. 3.
    Richart RM (1973) Cervical intraepithelial neoplasia. Pathol Annu 8:301–328PubMedGoogle Scholar
  4. 4.
    Richart RM (1969) A theory of cervical carcinogenesis. Obstet Gynecol Surv 24(7 Pt 2):874–879PubMedGoogle Scholar
  5. 5.
    Wright TC KR, Ferenczy A (2002) Precancerous lesions of the cervix. In: Kurman R (ed) Blaustein’s pathology of the female genital tract, 5th edn. Springer-Verlag, New York, pp 253–324Google Scholar
  6. 6.
    Bergeron C, Barrasso R, Beaudenon S, Flamant P, Croissant O, Orth G (1992) Human papillomaviruses associated with cervical intraepithelial neoplasia. Great diversity and distinct distribution in low- and high-grade lesions. Am J Surg Pathol 16(7):641–649PubMedGoogle Scholar
  7. 7.
    Kalantari M, Karlsen F, Johansson B, Sigurjonsson T, Warleby B, Hagmar B (1997) Human papillomavirus findings in relation to cervical intraepithelial neoplasia grade: a study on 476 Stockholm women, using PCR for detection and typing of HPV. Hum Pathol 28(8):899–904PubMedGoogle Scholar
  8. 8.
    Lorincz AT, Reid R, Jenson AB, Greenberg MD, Lancaster W, Kurman RJ (1992) Human papillomavirus infection of the cervix: relative risk associations of 15 common anogenital types. Obstet Gynecol 79(3):328–337PubMedGoogle Scholar
  9. 9.
    Lungu O, Sun XW, Felix J, Richart RM, Silverstein S, Wright TC Jr (1992) Relationship of human papillomavirus type to grade of cervical intraepithelial neoplasia. JAMA 267(18):2493–2496PubMedGoogle Scholar
  10. 10.
    Franquemont DW, Ward BE, Andersen WA, Crum CP (1989) Prediction of ‘high-risk’ cervical papillomavirus infection by biopsy morphology. Am J Clin Pathol 92(5):577–582PubMedGoogle Scholar
  11. 11.
    (1989) The 1988 Bethesda System for reporting cervical/vaginal cytological diagnoses. National Cancer Institute Workshop. JAMA 262(7):931–934Google Scholar
  12. 12.
    Luff RD (1992) The Bethesda System for reporting cervical/vaginal cytologic diagnoses: report of the 1991 Bethesda workshop. The Bethesda System Editorial Committee. Hum Pathol 23(7):719–721PubMedGoogle Scholar
  13. 13.
    Durst M, Gissmann L, Ikenberg H, zur Hausen H (1983) A papillomavirus DNA from a cervical carcinoma and its prevalence in cancer biopsy samples from different geographic regions. Proc Natl Acad Sci U S A 80(12):3812–3815PubMedGoogle Scholar
  14. 14.
    Boshart M, Gissmann L, Ikenberg H, Kleinheinz A, Scheurlen W, zur Hausen H (1984) A new type of papillomavirus DNA, its presence in genital cancer biopsies and in cell lines derived from cervical cancer. EMBO J 3(5):1151–1157PubMedGoogle Scholar
  15. 15.
    Hoory T, Monie A, Gravitt P, Wu TC (2008) Molecular epidemiology of human papillomavirus. J Formos Med Assoc 107:198–217PubMedGoogle Scholar
  16. 16.
    Roden R, Wu TC (2006) How will HPV vaccines affect cervical cancer? Nat Rev Cancer 6(10):753–763PubMedGoogle Scholar
  17. 17.
    Munger K, Baldwin A, Edwards KM, Hayakawa H, Nguyen CL, Owens M, Grace M, Huh K (2004) Mechanisms of human papillomavirus-induced oncogenesis. J Virol 78(21):11451–11460PubMedGoogle Scholar
  18. 18.
    Kurman RJ, Malkasian GD Jr, Sedlis A, Solomon D (1991) From Papanicolaou to Bethesda: the rationale for a new cervical cytologic classification. Obstet Gynecol 77(5):779–782PubMedGoogle Scholar
  19. 19.
    Ho GY, Bierman R, Beardsley L, Chang CJ, Burk RD (1998) Natural history of cervicovaginal papillomavirus infection in young women. N Engl J Med 338(7):423–428PubMedGoogle Scholar
  20. 20.
    Trimble CL, Piantadosi S, Gravitt P et al (2005) Spontaneous regression of high-grade cervical dysplasia: effects of human papillomavirus type and HLA phenotype. Clin Cancer Res 11(13):4717–4723PubMedGoogle Scholar
  21. 21.
    Kines RC, Thompson CD, Lowy DR, Schiller JT, Day PM (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(48):20458–20463PubMedGoogle Scholar
  22. 22.
    Patterson NA, Smith JL, Ozbun MA (2005) Human papillomavirus type 31b infection of human keratinocytes does not require heparan sulfate. J Virol 79:6838–6847PubMedGoogle Scholar
  23. 23.
    Day PM, Baker CC, Lowy DR, Schiller JT (2004) Establishment of papillomavirus infection is enhanced by promyelocytic leukemia protein (PML) expression. Proc Natl Acad Sci U S A 101(39):14252–14257PubMedGoogle Scholar
  24. 24.
    Day PM, Lowy DR, Schiller JT (2003) Papillomaviruses infect cells via a clathrin-dependent pathway. Virology 307(1):1–11PubMedGoogle Scholar
  25. 25.
    Conger KL, Liu J-S, Kuo S-R, Chow LT, Wang TSF (1999) Human papillomavirus DNA replication. Interactions between the viral E1 protein and two subunits of human DNA polymerase alpha/primase. J Biol Chem 274:2696–2705PubMedGoogle Scholar
  26. 26.
    Han Y, Loo Y-M, Militello KT, Melendy T (1999) Interactions of the papovavirus DNA replication initiator proteins, bovine papillomavirus type 1 E1 and simian virus 40 large T antigen, with human replication protein A. J Virol 73:4899–4907PubMedGoogle Scholar
  27. 27.
    Loo Y-M, Melendy T (2004) Recruitment of replication protein A by the papillomavirus E1 protein and modulation by single-stranded DNA. J Virol 78:1605–1615PubMedGoogle Scholar
  28. 28.
    Masterson PJ, Stanley MA, Lewis AP, Romanos MA (1998) A C-terminal helicase domain of the human papillomavirus E1 protein binds E2 and the DNA polymerase alpha-primase p68 subunit. J Virol 72:7407–7419Google Scholar
  29. 29.
    Demeret C, Goyat S, Yaniv M, Thierry F (1998) The human papillomavirus type 18 (HPV18) replication protein E1 is a transcriptional activator when interacting with HPV18 E2. Virology 242(2):378–386PubMedGoogle Scholar
  30. 30.
    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
  31. 31.
    Doorbar J, Ely S, Sterling J, McLean C, Crawford L (1991) Specific interaction between HPV-16 E1-E4 and cytokeratins results in collapse of the epithelial cell intermediate filament network. Nature 352(6338):824–827PubMedGoogle Scholar
  32. 32.
    Hwang ES, Nottoli T, Dimaio D (1995) The HPV16 E5 protein: expression, detection, and stable complex formation with transmembrane proteins in COS cells. Virology 211(1):227–233PubMedGoogle Scholar
  33. 33.
    Crusius K, Rodriguez I, Alonso A (2000) The human papillomavirus type 16 E5 protein modulates ERK1/2 and p38 MAP kinase activation by an EGFR-independent process in stressed human keratinocytes. Virus genes 20(1):65–69PubMedGoogle Scholar
  34. 34.
    Disbrow GL, Hanover JA, Schlegel R (2005) Endoplasmic reticulum-localized human papillomavirus type 16 E5 protein alters endosomal pH but not trans-Golgi pH. J Virol 79:5839–5846PubMedGoogle Scholar
  35. 35.
    Straight SW, Herman B, McCance DJ (1995) The E5 oncoprotein of human papillomavirus type 16 inhibits the acidification of endosomes in human keratinocytes. J Virol 69:3185–3192PubMedGoogle Scholar
  36. 36.
    Oh ST, Longworth MS, Laimins LA (2004) Roles of the E6 and E7 proteins in the life cycle of low-risk human papillomavirus type 11. J Virol 78(5):2620–2626PubMedGoogle Scholar
  37. 37.
    Thomas JT, Hubert WG, Ruesch MN, Laimins LA (1999) Human papillomavirus type 31 oncoproteins E6 and E7 are required for the maintenance of episomes during the viral life cycle in normal human keratinocytes. Proc Natl Acad Sci U S A 96(15):8449–8454PubMedGoogle Scholar
  38. 38.
    Stoler MH, Rhodes CR, Whitbeck A, Wolinsky SM, Chow LT, Broker TR (1992) Human papillomavirus type 16 and 18 gene expression in cervical neoplasias. Hum Pathol 23(2):117–128PubMedGoogle Scholar
  39. 39.
    Durst M, Glitz D, Schneider A, zur Hausen H (1992) Human papillomavirus type 16 (HPV 16) gene expression and DNA replication in cervical neoplasia: analysis by in situ hybridization. Virology 189(1):132–140PubMedGoogle Scholar
  40. 40.
    Oh JM, Kim SH, Cho EA, Song YS, Kim WH, Juhnn YS (2010) Human papillomavirus type 16 E5 protein inhibits hydrogen peroxide-induced apoptosis by stimulating ubiquitin/proteasome-mediated degradation of Bax in human cervical cancer cells. Carcinogenesis 31(3):402–410PubMedGoogle Scholar
  41. 41.
    Oh JM, Kim SH, Lee YI, Seo M, Kim SY, Song YS, Kim WH, Juhnn YS (2009) Human papillomavirus E5 protein induces expression of the EP4 subtype of prostaglandin E2 receptor in cyclic AMP response element-dependent pathways in cervical cancer cells. Carcinogenesis 30(1):141–149PubMedGoogle Scholar
  42. 42.
    Kim SH, Oh JM, No JH, Bang YJ, Juhnn YS, Song YS (2009) Involvement of NF-kappaB and AP-1 in COX-2 upregulation by human papillomavirus 16 E5 oncoprotein. Carcinogenesis 30(5):753–757PubMedGoogle Scholar
  43. 43.
    Stoppler MC, Straight SW, Tsao G, Schlegel R, McCance DJ (1996) The E5 gene of HPV-16 enhances keratinocyte immortalization by full-length DNA. Virology 223(1):251–254PubMedGoogle Scholar
  44. 44.
    zur Hausen H (2002) Papillomaviruses and cancer: from basic studies to clinical application. Nat Rev Cancer 2(5):342–350PubMedGoogle Scholar
  45. 45.
    Duensing S, Munger K (2004) Mechanisms of genomic instability in human cancer: insights from studies with human papillomavirus oncoproteins. Int J Cancer 109(2):157–162PubMedGoogle Scholar
  46. 46.
    Horner SM, DeFilippis RA, Manuelidis L, DiMaio D (2004) Repression of the human papillomavirus E6 gene initiates p53-dependent, telomerase-independent senescence and apoptosis in HeLa cervical carcinoma cells. J Virol 78(8):4063–4073PubMedGoogle Scholar
  47. 47.
    Plug-DeMaggio AW, Sundsvold T, Wurscher MA, Koop JI, Klingelhutz AJ, McDougall JK (2004) Telomere erosion and chromosomal instability in cells expressing the HPV oncogene 16E6. Oncogene 23(20):3561–3571PubMedGoogle Scholar
  48. 48.
    Jackson S, Harwood C, Thomas M, Banks L, Storey A (2000) Role of Bak in UV-induced apoptosis in skin cancer and abrogation by HPV E6 proteins. Genes Dev 14(23):3065–3073PubMedGoogle Scholar
  49. 49.
    Oda H, Kumar S, Howley PM (1999) Regulation of the Src family tyrosine kinase Blk through E6AP-mediated ubiquitination. Proc Natl Acad Sci U S A 96(17):9557–9562PubMedGoogle Scholar
  50. 50.
    Li X, Coffino P (1996) High-risk human papillomavirus E6 protein has two distinct binding sites within p53, of which only one determines degradation. J Virol 70(7):4509–4516PubMedGoogle Scholar
  51. 51.
    Crook T, Tidy JA, Vousden KH (1991) Degradation of p53 can be targeted by HPV E6 sequences distinct from those required for p53 binding and trans-activation. Cell 67(3):547–556PubMedGoogle Scholar
  52. 52.
    Werness BA, Levine AJ, Howley PM (1990) Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science 248(4951):76–79PubMedGoogle Scholar
  53. 53.
    Scheffner M, Werness BA, Huibregtse JM, Levine AJ, Howley PM (1990) The E6 oncoprotein encoded by human papillomavirus types 16 and 18 promotes the degradation of p53. Cell 63(6):1129–1136PubMedGoogle Scholar
  54. 54.
    Klingelhutz AJ, Foster SA, McDougall JK (1996) Telomerase activation by the E6 gene product of human papillomavirus type 16. Nature 380(6569):79–82PubMedGoogle Scholar
  55. 55.
    Rincon-Orozco B, Halec G, Rosenberger S et al (2009) Epigenetic silencing of interferon-kappa in human papillomavirus type 16-positive cells. Cancer Res 69(22):8718–8725PubMedGoogle Scholar
  56. 56.
    Cheng S, Schmidt-Grimminger DC, Murant T, Broker TR, Chow LT (1995) Differentiation-dependent up-regulation of the human papillomavirus E7 gene reactivates cellular DNA replication in suprabasal differentiated keratinocytes. Genes Dev 9(19):2335–2349PubMedGoogle Scholar
  57. 57.
    Heck DV, Yee CL, Howley PM, Munger K (1992) Efficiency of binding the retinoblastoma protein correlates with the transforming capacity of the E7 oncoproteins of the human papillomaviruses. Proc Natl Acad Sci U S A 89(10):4442–4446PubMedGoogle Scholar
  58. 58.
    Gage JR, Meyers C, Wettstein FO (1990) The E7 proteins of the nononcogenic human papillomavirus type 6b (HPV-6b) and of the oncogenic HPV-16 differ in retinoblastoma protein binding and other properties. J Virol 64(2):723–730PubMedGoogle Scholar
  59. 59.
    Munger K, Werness BA, Dyson N, Phelps WC, Harlow E, Howley PM (1989) Complex formation of human papillomavirus E7 proteins with the retinoblastoma tumor suppressor gene product. EMBO J 8(13):4099–4105PubMedGoogle Scholar
  60. 60.
    Gonzalez SL, Stremlau M, He X, Basile JR, Munger K (2001) Degradation of the retinoblastoma tumor suppressor by the human papillomavirus type 16 E7 oncoprotein is important for functional inactivation and is separable from proteasomal degradation of E7. J Virol 75(16):7583–7591PubMedGoogle Scholar
  61. 61.
    Munger K, Basile JR, Duensing S, Eichten A, Gonzalez SL, Grace M, Zacny VL (2001) Biological activities and molecular targets of the human papillomavirus E7 oncoprotein. Oncogene 20(54):7888–7898PubMedGoogle Scholar
  62. 62.
    Zerfass K, Schulze A, Spitkovsky D, Friedman V, Henglein B, Jansen-Durr P (1995) Sequential activation of cyclin E and cyclin A gene expression by human papillomavirus type 16 E7 through sequences necessary for transformation. J Virol 69(10):6389–6399PubMedGoogle Scholar
  63. 63.
    Jones DL, Alani RM, Munger K (1997) The human papillomavirus E7 oncoprotein can uncouple cellular differentiation and proliferation in human keratinocytes by abrogating p21Cip1-mediated inhibition of cdk2. Genes Dev 11(16):2101–2111PubMedGoogle Scholar
  64. 64.
    Funk JO, Waga S, Harry JB, Espling E, Stillman B, Galloway DA (1997) Inhibition of CDK activity and PCNA-dependent DNA replication by p21 is blocked by interaction with the HPV-16 E7 oncoprotein. Genes Dev 11:2090–2100PubMedGoogle Scholar
  65. 65.
    Zerfass-Thome K, Zwerschke W, Mannhardt B, Tindle R, Botz JW, Jansen-Durr P (1996) Inactivation of the cdk inhibitor p27KIP1 by the human papillomavirus type 16 E7 oncoprotein. Oncogene 13(11):2323–2330PubMedGoogle Scholar
  66. 66.
    Martin LG, Demers GW, Galloway DA (1998) Disruption of the G1/S transition in human papillomavirus type 16 E7-expressing human cells is associated with altered regulation of cyclin E. J Virol 72(2):975–985PubMedGoogle Scholar
  67. 67.
    Menges CW, Baglia LA, Lapoint R, McCance DJ (2006) Human papillomavirus type 16 E7 up-regulates AKT activity through the retinoblastoma protein. Cancer Res 66(11):5555–5559PubMedGoogle Scholar
  68. 68.
    McDougall JK (1994) Immortalization and transformation of human cells by human papillomavirus. Curr Top Microbiol Immunol 186:101–119PubMedGoogle Scholar
  69. 69.
    Thomas JT, Laimins LA (1998) Human papillomavirus oncoproteins E6 and E7 independently abrogate the mitotic spindle checkpoint. J Virol 72(2):1131–1137PubMedGoogle Scholar
  70. 70.
    Zhao W, Noya F, Chen WY, Townes TM, Chow LT, Broker TR (1999) Trichostatin A up-regulates human papillomavirus type 11 upstream regulatory region-E6 promoter activity in undifferentiated primary human keratinocytes. J Virol 73(6):5026–5033PubMedGoogle Scholar
  71. 71.
    Kalantari M, Calleja-Macias IE, Tewari D, Hagmar B, Lie K, Barrera-Saldana HA, Wiley DJ, Bernard HU (2004) Conserved methylation patterns of human papillomavirus type 16 DNA in asymptomatic infection and cervical neoplasia. J Virol 78(23):12762–12772PubMedGoogle Scholar
  72. 72.
    Turan T, Kalantari M, Calleja-Macias IE et al (2006) Methylation of the human papillomavirus-18 L1 gene: a biomarker of neoplastic progression? Virology 349(1):175–183PubMedGoogle Scholar
  73. 73.
    Turan T, Kalantari M, Cuschieri K, Cubie HA, Skomedal H, Bernard HU (2007) High-throughput detection of human papillomavirus-18 L1 gene methylation, a candidate biomarker for the progression of cervical neoplasia. Virology 361(1):185–193PubMedGoogle Scholar
  74. 74.
    Durst M, Dzarlieva-Petrusevska RT, Boukamp P, Fusenig NE, Gissmann L (1987) Molecular and cytogenetic analysis of immortalized human primary keratinocytes obtained after transfection with human papillomavirus type 16 DNA. Oncogene 1(3):251–256PubMedGoogle Scholar
  75. 75.
    Pirisi L, Yasumoto S, Feller M, Doniger J, DiPaolo JA (1987) Transformation of human fibroblasts and keratinocytes with human papillomavirus type 16 DNA. J Virol 61(4):1061–1066PubMedGoogle Scholar
  76. 76.
    Munger K, Phelps WC, Bubb V, Howley PM, Schlegel R (1989) The E6 and E7 genes of the human papillomavirus type 16 together are necessary and sufficient for transformation of primary human keratinocytes. J Virol 63(10):4417–4421PubMedGoogle Scholar
  77. 77.
    Hawley-Nelson P, Vousden KH, Hubbert NL, Lowy DR, Schiller JT (1989) HPV16 E6 and E7 proteins cooperate to immortalize human foreskin keratinocytes. EMBO J 8(12):3905–3910PubMedGoogle Scholar
  78. 78.
    Chen TM, Pecoraro G, Defendi V (1993) Genetic analysis of in vitro progression of human papillomavirus-transfected human cervical cells. Cancer Res 53(5):1167–1171PubMedGoogle Scholar
  79. 79.
    Seagon S, Durst M (1994) Genetic analysis of an in vitro model system for human papillomavirus type 16-associated tumorigenesis. Cancer Res 54(21):5593–5598PubMedGoogle Scholar
  80. 80.
    Psyrri A, DeFilippis RA, Edwards AP, Yates KE, Manuelidis L, DiMaio D (2004) Role of the retinoblastoma pathway in senescence triggered by repression of the human papillomavirus E7 protein in cervical carcinoma cells. Cancer Res 64(9):3079–3086PubMedGoogle Scholar
  81. 81.
    Steenbergen RD, Walboomers JM, Meijer CJ, van der Raaij-Helmer EM, Parker JN, Chow LT, Broker TR, Snijders PJ (1996) Transition of human papillomavirus type 16 and 18 transfected human foreskin keratinocytes towards immortality: activation of telomerase and allele losses at 3p, 10p, 11q and/or 18q. Oncogene 13(6):1249–1257PubMedGoogle Scholar
  82. 82.
    Klingelhutz AJ, Barber SA, Smith PP, Dyer K, McDougall JK (1994) Restoration of telomeres in human papillomavirus-immortalized human anogenital epithelial cells. Mol Cell Biol 14(2):961–969PubMedGoogle Scholar
  83. 83.
    Kim NW, Piatyszek MA, Prowse KR et al (1994) Specific association of human telomerase activity with immortal cells and cancer. Science 266(5193):2011–2015PubMedGoogle Scholar
  84. 84.
    Meyerson M, Counter CM, Eaton EN et al (1997) hEST2, the putative human telomerase catalytic subunit gene, is up-regulated in tumor cells and during immortalization. Cell 90(4):785–795PubMedGoogle Scholar
  85. 85.
    Steenbergen RD, Kramer D, Meijer CJ et al (2001) Telomerase suppression by chromosome 6 in a human papillomavirus type 16-immortalized keratinocyte cell line and in a cervical cancer cell line. J Natl Cancer Inst 93(11):865–872PubMedGoogle Scholar
  86. 86.
    Sprague DL, Phillips SL, Mitchell CJ, Berger KL, Lace M, Turek LP, Klingelhutz AJ (2002) Telomerase activation in cervical keratinocytes containing stably replicating human papillomavirus type 16 episomes. Virology 301(2):247–254PubMedGoogle Scholar
  87. 87.
    Backsch C, Wagenbach N, Nonn M, Leistritz S, Stanbridge E, Schneider A, Durst M (2001) Microcell-mediated transfer of chromosome 4 into HeLa cells suppresses telomerase activity. Genes Chromosomes Cancer 31(2):196–198PubMedGoogle Scholar
  88. 88.
    Backsch C, Rudolph B, Kuhne-Heid R et al (2005) A region on human chromosome 4 (q35.1→qter) induces senescence in cell hybrids and is involved in cervical carcinogenesis. Genes Chromosomes Cancer 43(3):260–272PubMedGoogle Scholar
  89. 89.
    Poignee M, Backsch C, Beer K et al (2001) Evidence for a putative senescence gene locus within the chromosomal region 10p14-p15. Cancer Res 61(19):7118–7121PubMedGoogle Scholar
  90. 90.
    Uejima H, Mitsuya K, Kugoh H, Horikawa I, Oshimura M (1995) Normal human chromosome 2 induces cellular senescence in the human cervical carcinoma cell line SiHa. Genes Chromosomes Cancer 14(2):120–127PubMedGoogle Scholar
  91. 91.
    Snijders PJ, van Duin M, Walboomers JM, Steenbergen RD, Risse EK, Helmerhorst TJ, Verheijen RH, Meijer CJ (1998) Telomerase activity exclusively in cervical carcinomas and a subset of cervical intraepithelial neoplasia grade III lesions: strong association with elevated messenger RNA levels of its catalytic subunit and high-risk human papillomavirus DNA. Cancer Res 58(17):3812–3818PubMedGoogle Scholar
  92. 92.
    van Duin M, Steenbergen RD, de Wilde J, Helmerhorst TJ, Verheijen RH, Risse EK, Meijer CJ, Snijders PJ (2003) Telomerase activity in high-grade cervical lesions is associated with allelic imbalance at 6Q14-22. Int J Cancer 105(5):577–582PubMedGoogle Scholar
  93. 93.
    Koi M, Morita H, Yamada H, Satoh H, Barrett JC, Oshimura M (1989) Normal human chromosome 11 suppresses tumorigenicity of human cervical tumor cell line SiHa. Mol Carcinog 2(1):12–21PubMedGoogle Scholar
  94. 94.
    Hampton GM, Penny LA, Baergen RN et al (1994) Loss of heterozygosity in cervical carcinoma: subchromosomal localization of a putative tumor-suppressor gene to chromosome 11q22-q24. Proc Natl Acad Sci U S A 91(15):6953–6957PubMedGoogle Scholar
  95. 95.
    Steenbergen RD, Kramer D, Braakhuis BJ, Stern PL, Verheijen RH, Meijer CJ, Snijders PJ (2004) TSLC1 gene silencing in cervical cancer cell lines and cervical neoplasia. J Natl Cancer Inst 96(4):294–305PubMedGoogle Scholar
  96. 96.
    Shingai T, Ikeda W, Kakunaga S et al (2003) Implications of nectin-like molecule-2/IGSF4/RA175/SgIGSF/TSLC1/SynCAM1 in cell-cell adhesion and transmembrane protein localization in epithelial cells. J Biol Chem 278(37):35421–35427PubMedGoogle Scholar
  97. 97.
    Boles KS, Barchet W, Diacovo T, Cella M, Colonna M (2005) The tumor suppressor TSLC1/NECL-2 triggers NK-cell and CD8+ T-cell responses through the cell-surface receptor CRTAM. Blood 106(3):779–786PubMedGoogle Scholar
  98. 98.
    Soto U, Das BC, Lengert M, Finzer P, zur Hausen H, Rosl F (1999) Conversion of HPV 18 positive non-tumorigenic HeLa-fibroblast hybrids to invasive growth involves loss of TNF-alpha mediated repression of viral transcription and modification of the AP-1 transcription complex. Oncogene 18(21):3187–3198PubMedGoogle Scholar
  99. 99.
    Soto U, Denk C, Finzer P, Hutter KJ, zur Hausen H, Rosl F (2000) Genetic complementation to non-tumorigenicity in cervical-carcinoma cells correlates with alterations in AP-1 composition. Int J Cancer 86(6):811–817PubMedGoogle Scholar
  100. 100.
    Finzer P, Soto U, Delius H, Patzelt A, Coy JF, Poustka A, zur Hausen H, Rosl F (2000) Differential transcriptional regulation of the monocyte-chemoattractant protein-1 (MCP-1) gene in tumorigenic and non-tumorigenic HPV 18 positive cells: the role of the chromatin structure and AP-1 composition. Oncogene 19(29):3235–3244PubMedGoogle Scholar
  101. 101.
    Cheung TH, Leung JO, Chung TK, Lam SK, To KF, Wong YF (1997) c-fos overexpression is associated with the pathoneogenesis of invasive cervical cancer. Gynecol Obstet Invest 43(3):200–203PubMedGoogle Scholar
  102. 102.
    Heselmeyer K, Schrock E, du Manoir S, Blegen H, Shah K, Steinbeck R, Auer G, Ried T (1996) Gain of chromosome 3q defines the transition from severe dysplasia to invasive carcinoma of the uterine cervix. Proc Natl Acad Sci U S A 93(1):479–484PubMedGoogle Scholar
  103. 103.
    Papanicolaou GN, Traut HF (1941) The diagnostic value of vaginal smears in carcinoma of the uterus. Am J Obstet Gynecol 42:193–206Google Scholar
  104. 104.
    Parkin DM (1991) Screening for cervix cancer in developing countries. In: Miller AB (ed) Cancer screening. Cambridge University Press, Cambridge, pp 184–198Google Scholar
  105. 105.
    Cibas ES, Alonzo TA, Austin RM et al (2008) The MonoPrep Pap test for the detection of cervical cancer and its precursors. Part I: results of a multicenter clinical trial. Am J Clin Pathol 129(2):193–201PubMedGoogle Scholar
  106. 106.
    ACOG (2009 Dec) ACOG Education Pamphlet AP085 – The Pap TestGoogle Scholar
  107. 107.
    (1989) The 1988 Bethesda System for reporting cervical/vaginal cytologic diagnoses. Developed and approved at a National Cancer Institute Workshop, Bethesda, Maryland, U.S.A., December 12–13, 1988. Anal Quant Cytol Histol 11(5):291–297Google Scholar
  108. 108.
    Solomon D, Davey D, Kurman R et al (2002) The 2001 Bethesda System: terminology for reporting results of cervical cytology. JAMA 287(16):2114–2119PubMedGoogle Scholar
  109. 109.
    Zappacosta R, Rosini S (2008) Cervical cancer screening: from molecular basis to diagnostic practice, going through new technologies. Technol Cancer Res Treat 7(3):161–174PubMedGoogle Scholar
  110. 110.
  111. 111.
    ThinPrep Pap Test. 2009 [cited 2010 Jan 2]; Available from: http://www.thinprep.com/index.html
  112. 112.
    BD SurePath Liquid-based Pap Test. 2010. [cited 2010 Jan 3]; Available from: http://www.bd.com/tripath/products/surepath/index.asp
  113. 113.
    Bernstein SJ, Sanchez-Ramos L, Ndubisi B (2001) Liquid-based cervical cytologic smear study and conventional Papanicolaou smears: a metaanalysis of prospective studies comparing cytologic diagnosis and sample adequacy. Am J Obstet Gynecol 185(2):308–317PubMedGoogle Scholar
  114. 114.
    Davey E, D’Assuncao J, Irwig L, Macaskill P, Chan SF, Richards A, Farnsworth A (2007) Accuracy of reading liquid based cytology slides using the ThinPrep Imager compared with conventional cytology: prospective study. BMJ 335(7609):31PubMedGoogle Scholar
  115. 115.
    Nance KV (2007) Evolution of Pap testing at a community hospital: a ten year experience. Diagn Cytopathol 35(3):148–153PubMedGoogle Scholar
  116. 116.
    Papillo JL, St John TL, Leiman G (2008) Effectiveness of the ThinPrep Imaging System: clinical experience in a low risk screening population. Diagn Cytopathol 36(3):155–160PubMedGoogle Scholar
  117. 117.
    Schiffman M, Adrianza ME (2000) ASCUS-LSIL Triage Study. Design, methods and characteristics of trial participants. Acta Cytol 44(5):726–742PubMedGoogle Scholar
  118. 118.
    Manos MM, Kinney WK, Hurley LB et al (1999) Identifying women with cervical neoplasia: using human papillomavirus DNA testing for equivocal Papanicolaou results. JAMA 281(17):1605–1610PubMedGoogle Scholar
  119. 119.
    Cox JT (2009) History of the use of HPV testing in cervical screening and in the management of abnormal cervical screening results. J Clin Virol 45(Suppl 1):S3–S12PubMedGoogle Scholar
  120. 120.
    Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D (2007) 2006 consensus guidelines for the management of women with abnormal cervical screening tests. J Low Genit Tract Dis 11(4):201–222PubMedGoogle Scholar
  121. 121.
    Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D (2007) 2006 consensus guidelines for the management of women with abnormal cervical cancer screening tests. Am J Obstet Gynecol 197(4):346–355PubMedGoogle Scholar
  122. 122.
    Arbyn M, Buntinx F, Van Ranst M, Paraskevaidis E, Martin-Hirsch P, Dillner J (2004) Virologic versus cytologic triage of women with equivocal Pap smears: a meta-analysis of the accuracy to detect high-grade intraepithelial neoplasia. J Natl Cancer Inst 96(4):280–293PubMedGoogle Scholar
  123. 123.
    Wright TC Jr, Lorincz A, Ferris DG, Richart RM, Ferenczy A, Mielzynska I, Borgatta L (1998) Reflex human papillomavirus deoxyribonucleic acid testing in women with abnormal Papanicolaou smears. Am J Obstet Gynecol 178(5):962–966PubMedGoogle Scholar
  124. 124.
    Caussy D, Orr W, Daya AD, Roth P, Reeves W, Rawls W (1988) Evaluation of methods for detecting human papillomavirus deoxyribonucleotide sequences in clinical specimens. J Clin Microbiol 26(2):236–243PubMedGoogle Scholar
  125. 125.
    The digene HPV Test. 2009. [cited 2010 Jan 4]; Available from: http://www.thehpvtest.com/default.html
  126. 126.
    Sandri MT, Lentati P, Benini E et al (2006) Comparison of the Digene HC2 assay and the Roche AMPLICOR human papillomavirus (HPV) test for detection of high-risk HPV genotypes in cervical samples. J Clin Microbiol 44(6):2141–2146PubMedGoogle Scholar
  127. 127.
    Roche Molecular Diagnostics Amplicor HPV Test. 2009 [cited 2010 Jan 4]; Available from: http://molecular.roche.com/diagnostics/hpv_ctng/hpv_test_1.html
  128. 128.
    Day SP, Hudson A, Mast A et al (2009) Analytical performance of the Investigational Use Only Cervista HPV HR test as determined by a multi-center study. J Clin Virol 45(Suppl 1):S63–S72PubMedGoogle Scholar
  129. 129.
    FDA Approves Two Hologic HPV Tests. 2009 March 13 [cited 2010 Jan 4]; Available from: http://www.hologic.com/news-releases/view/173-year.2009_173-id.234881444.html
  130. 130.
    Cervista HPV. 2009. [cited 2010 Jan 4]; Available from: http://www.cervistahpv.com/index.html
  131. 131.
    Qiao YL, Sellors JW, Eder PS et al (2008) A new HPV-DNA test for cervical-cancer screening in developing regions: a cross-sectional study of clinical accuracy in rural China. Lancet Oncol 9(10):929–936PubMedGoogle Scholar
  132. 132.
    Cuschieri K, Wentzensen N (2008) Human papillomavirus mRNA and p16 detection as biomarkers for the improved diagnosis of cervical neoplasia. Cancer Epidemiol Biomarkers Prev 17(10):2536–2545PubMedGoogle Scholar
  133. 133.
    Villa LL (2008) Assessment of new technologies for cervical cancer screening. Lancet Oncol 9(10):910–911PubMedGoogle Scholar
  134. 134.
    Lambert AP, Anschau F, Schmitt VM (2006) p16INK4A expression in cervical premalignant and malignant lesions. Exp Mol Pathol 80(2):192–196PubMedGoogle Scholar
  135. 135.
    Horn LC, Reichert A, Oster A et al (2008) Immunostaining for p16INK4a used as a conjunctive tool improves interobserver agreement of the histologic diagnosis of cervical intraepithelial neoplasia. Am J Surg Pathol 32(4):502–512PubMedGoogle Scholar
  136. 136.
    Carozzi F, Confortini M, Dalla Palma P et al (2008) Use of p16-INK4A overexpression to increase the specificity of human papillomavirus testing: a nested substudy of the NTCC randomised controlled trial. Lancet Oncol 9(10):937–945PubMedGoogle Scholar
  137. 137.
    Eleuterio J Jr, Giraldo PC, Goncalves AK, Cavalcante DI, de Almeida Ferreira FV, Mesquita SM, Morais SS (2007) Prognostic markers of high-grade squamous intraepithelial lesions: the role of p16INK4a and high-risk human papillomavirus. Acta Obstet Gynecol Scand 86(1):94–98PubMedGoogle Scholar
  138. 138.
    Asadurian Y, Kurilin H, Lichtig H, Jackman A, Gonen P, Tommasino M, Zehbe I, Sherman L (2007) Activities of human papillomavirus 16 E6 natural variants in human keratinocytes. J Med Virol 79(11):1751–1760PubMedGoogle Scholar
  139. 139.
    Wise-Draper TM, Wells SI (2008) Papillomavirus E6 and E7 proteins and their cellular targets. Front Biosci 13:1003–1017PubMedGoogle Scholar
  140. 140.
    Dixon EP, King LM, Adams MD et al (2008) Isolation of RNA from residual BD SurePath liquid-based cytology specimens and detection of HPV E6/E7 mRNA using the PreTectt HPV-Proofer assay. J Virol Methods 154(1–2):220–222PubMedGoogle Scholar
  141. 141.
    Jeantet D, Schwarzmann F, Tromp J, Melchers WJ, van der Wurff AA, Oosterlaken T, Jacobs M, Troesch A (2009) NucliSENS EasyQ HPV v1 test - Testing for oncogenic activity of human papillomaviruses. J Clin Virol 45(Suppl 1):S29–S37PubMedGoogle Scholar
  142. 142.
    Szarewski A, Ambroisine L, Cadman L et al (2008) Comparison of predictors for high-grade cervical intraepithelial neoplasia in women with abnormal smears. Cancer Epidemiol Biomarkers Prev 17(11):3033–3042PubMedGoogle Scholar
  143. 143.
    Dockter J, Schroder A, Hill C, Guzenski L, Monsonego J, Giachetti C (2009) Clinical performance of the APTIMA HPV Assay for the detection of high-risk HPV and high-grade cervical lesions. J Clin Virol 45(Suppl 1):S55–S61PubMedGoogle Scholar
  144. 144.
    Wright TC Jr, Massad LS, Dunton CJ, Spitzer M, Wilkinson EJ, Solomon D (2007) 2006 consensus guidelines for the management of women with cervical intraepithelial neoplasia or adenocarcinoma in situ. J Low Genit Tract Dis 11(4):223–239PubMedGoogle Scholar
  145. 145.
    Helmerhorst TJ (1992) Clinical significance of endocervical curettage as part of colposcopic evaluation. A review. Int J Gynecol Cancer 2(5):256–262PubMedGoogle Scholar
  146. 146.
    Hoffman MS, Sterghos S Jr, Gordy LW, Gunasekaran S, Cavanagh D (1993) Evaluation of the cervical canal with the endocervical brush. Obstet Gynecol 82(4 Pt 1):573–577PubMedGoogle Scholar
  147. 147.
    Klam S, Arseneau J, Mansour N, Franco E, Ferenczy A (2000) Comparison of endocervical curettage and endocervical brushing. Obstet Gynecol 96(1):90–94PubMedGoogle Scholar
  148. 148.
    Mitchell MF, Tortolero-Luna G, Cook E, Whittaker L, Rhodes-Morris H, Silva E (1998) A randomized clinical trial of cryotherapy, laser vaporization, and loop electrosurgical excision for treatment of squamous intraepithelial lesions of the cervix. Obstet Gynecol 92(5):737–744PubMedGoogle Scholar
  149. 149.
    Townsend DE, Richart RM (1983) Cryotherapy and carbon dioxide laser management of cervical intraepithelial neoplasia: a controlled comparison. Obstet Gynecol 61(1):75–78PubMedGoogle Scholar
  150. 150.
    Stafl A, Wilkinson EJ, Mattingly RF (1977) Laser treatment of cervical and vaginal neoplasia. Am J Obstet Gynecol 128(2):128–136PubMedGoogle Scholar
  151. 151.
    Zhou J, Sun XY, Davies H, Crawford L, Park D, Frazer IH (1992) Definition of linear antigenic regions of the HPV16 L1 capsid protein using synthetic virion-like particles. Virology 189(2):592–599PubMedGoogle Scholar
  152. 152.
    Breitburd F, Kirnbauer R, Hubbert NL, Nonnenmacher B, Trin-Dinh-Desmarquet C, Orth G, Schiller JT, Lowy DR (1995) Immunization with viruslike particles from cottontail rabbit papillomavirus (CRPV) can protect against experimental CRPV infection. J Virol 69(6):3959–3963PubMedGoogle Scholar
  153. 153.
    Lin YL, Borenstein LA, Ahmed R, Wettstein FO (1993) Cottontail rabbit papillomavirus L1 protein-based vaccines: protection is achieved only with a full-length, nondenatured product. J Virol 67(7):4154–4162PubMedGoogle Scholar
  154. 154.
    Hagensee ME, Yaegashi N, Galloway DA (1993) Self-assembly of human papillomavirus type 1 capsids by expression of the L1 protein alone or by coexpression of the L1 and L2 capsid proteins. J Virol 67(1):315–322PubMedGoogle Scholar
  155. 155.
    Heino P, Dillner J, Schwartz S (1995) Human papillomavirus type 16 capsid proteins produced from recombinant Semliki Forest virus assemble into virus-like particles. Virology 214(2):349–359PubMedGoogle Scholar
  156. 156.
    Kirnbauer R, Booy F, Cheng N, Lowy DR, Schiller JT (1992) Papillomavirus L1 major capsid protein self-assembles into virus-like particles that are highly immunogenic. Proc Natl Acad Sci U S A 89(24):12180–12184PubMedGoogle Scholar
  157. 157.
    Rose RC, Reichman RC, Bonnez W (1994) Human papillomavirus (HPV) type 11 recombinant virus-like particles induce the formation of neutralizing antibodies and detect HPV-specific antibodies in human sera. J Gen Virol 75(Pt 8):2075–2079PubMedGoogle Scholar
  158. 158.
    Sasagawa T, Pushko P, Steers G, Gschmeissner SE, Hajibagheri MA, Finch J, Crawford L, Tommasino M (1995) Synthesis and assembly of virus-like particles of human papillomaviruses type 6 and type 16 in fission yeast Schizosaccharomyces pombe. Virology 206(1):126–135PubMedGoogle Scholar
  159. 159.
    Nardelli-Haefliger D, Roden RB, Benyacoub J et al (1997) Human papillomavirus type 16 virus-like particles expressed in attenuated Salmonella typhimurium elicit mucosal and systemic neutralizing antibodies in mice. Infect Immun 65(8):3328–3336PubMedGoogle Scholar
  160. 160.
    Ghim SJ, Jenson AB, Schlegel R (1992) HPV-1 L1 protein expressed in cos cells displays conformational epitopes found on intact virions. Virology 190(1):548–552PubMedGoogle Scholar
  161. 161.
    Koutsky LA, Ault KA, Wheeler CM, Brown DR, Barr E, Alvarez FB, Chiacchierini LM, Jansen KU (2002) A controlled trial of a human papillomavirus type 16 vaccine. N Engl J Med 347(21):1645–1651PubMedGoogle Scholar
  162. 162.
    Evans TG, Bonnez W, Rose RC et al (2001) A Phase 1 study of a recombinant viruslike particle vaccine against human papillomavirus type 11 in healthy adult volunteers. J Infect Dis 183(10):1485–1493PubMedGoogle Scholar
  163. 163.
    Harro CD, Pang YY, Roden RB et al (2001) Safety and immunogenicity trial in adult volunteers of a human papillomavirus 16 L1 virus-like particle vaccine. J Natl Cancer Inst 93(4):284–292PubMedGoogle Scholar
  164. 164.
    Harper DM (2009) Currently approved prophylactic HPV vaccines. Expert Rev Vaccines 8(12):1663–1679PubMedGoogle Scholar
  165. 165.
    FDA Approves New Vaccine for Prevention of Cervical Cancer. 2009 Oct 16 [cited 2009 Dec 29]; Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm187048.htm
  166. 166.
    FDA Approves New Indication for Gardasil to Prevent Genital Warts in Men and Boys. 2009 Oct 16 Dec 29 2009 [cited 2009 Dec 29]; Available from: http://www.fda.gov/NewsEvents/Newsroom/PressAnnouncements/ucm187003.htm
  167. 167.
    Einstein MH, Baron M, Levin MJ et al (2009) Comparison of the immunogenicity and safety of Cervarix() and Gardasil((R)) human papillomavirus (HPV) cervical cancer vaccines in healthy women aged 18-45 years. Hum Vaccin 5(10):705–719PubMedGoogle Scholar
  168. 168.
    Munoz N, Manalastas R Jr, Pitisuttithum P et al (2009) Safety, immunogenicity, and efficacy of quadrivalent human papillomavirus (types 6, 11, 16, 18) recombinant vaccine in women aged 24-45 years: a randomised, double-blind trial. Lancet 373(9679):1949–1957PubMedGoogle Scholar
  169. 169.
    Kjaer SK, Sigurdsson K, Iversen OE et al (2009) A pooled analysis of continued prophylactic efficacy of quadrivalent human papillomavirus (Types 6/11/16/18) vaccine against high-grade cervical and external genital lesions. Cancer Prev Res (Phila Pa) 2(10):868–878Google Scholar
  170. 170.
    Paavonen J, Naud P, Salmeron J et al (2009) Efficacy of human papillomavirus (HPV)-16/18 AS04-adjuvanted vaccine against cervical infection and precancer caused by oncogenic HPV types (PATRICIA): final analysis of a double-blind, randomised study in young women. Lancet 374(9686):301–314PubMedGoogle Scholar
  171. 171.
    David MP, Van Herck K, Hardt K, Tibaldi F, Dubin G, Descamps D, Van Damme P (2009) Long-term persistence of anti-HPV-16 and -18 antibodies induced by vaccination with the AS04-adjuvanted cervical cancer vaccine: modeling of sustained antibody responses. Gynecol Oncol 2009 Dec; 115 (3 Suppl):51–56Google Scholar
  172. 172.
    Rowhani-Rahbar A, Mao C, Hughes JP, Alvarez FB, Bryan JT, Hawes SE, Weiss NS, Koutsky LA (2009) Longer term efficacy of a prophylactic monovalent human papillomavirus type 16 vaccine. Vaccine 27(41):5612–5619PubMedGoogle Scholar
  173. 173.
    Garland SM, Hernandez-Avila M, Wheeler CM et al (2007) Quadrivalent vaccine against human papillomavirus to prevent anogenital diseases. N Engl J Med 356(19):1928–1943PubMedGoogle Scholar
  174. 174.
    Paavonen J, Jenkins D, Bosch FX et al (2007) Efficacy of a prophylactic adjuvanted bivalent L1 virus-like-particle vaccine against infection with human papillomavirus types 16 and 18 in young women: an interim analysis of a phase III double-blind, randomised controlled trial. Lancet 369(9580):2161–2170PubMedGoogle Scholar
  175. 175.
    Reisinger KS, Block SL, Lazcano-Ponce E et al (2007) Safety and persistent immunogenicity of a quadrivalent human papillomavirus types 6, 11, 16, 18 L1 virus-like particle vaccine in preadolescents and adolescents: a randomized controlled trial. Pediatr Infect Dis J 26(3):201–209PubMedGoogle Scholar
  176. 176.
    Mao C, Koutsky LA, Ault KA et al (2006) Efficacy of human papillomavirus-16 vaccine to prevent cervical intraepithelial neoplasia: a randomized controlled trial. Obstet Gynecol 107(1):18–27PubMedGoogle Scholar
  177. 177.
    Block SL, Nolan T, Sattler C et al (2006) Comparison of the immunogenicity and reactogenicity of a prophylactic quadrivalent human papillomavirus (types 6, 11, 16, and 18) L1 virus-like particle vaccine in male and female adolescents and young adult women. Pediatrics 118(5):2135–2145PubMedGoogle Scholar
  178. 178.
    Harper DM, Franco EL, Wheeler CM et al (2006) Sustained efficacy up to 4.5 years of a bivalent L1 virus-like particle vaccine against human papillomavirus types 16 and 18: follow-up from a randomised control trial. Lancet 367(9518):1247–1255PubMedGoogle Scholar
  179. 179.
    Munoz N, Bosch FX, Castellsague X, Diaz M, de Sanjose S, Hammouda D, Shah KV, Meijer CJ (2004) Against which human papillomavirus types shall we vaccinate and screen? The international perspective. Int J Cancer 111(2):278–285PubMedGoogle Scholar
  180. 180.
    Chen XS, Garcea RL, Goldberg I, Casini G, Harrison SC (2000) Structure of small virus-like particles assembled from the L1 protein of human papillomavirus 16. Mol Cell 5(3):557–567PubMedGoogle Scholar
  181. 181.
    Rose RC, White WI, Li M, Suzich JA, Lane C, Garcea RL (1998) Human papillomavirus type 11 recombinant L1 capsomeres induce virus-neutralizing antibodies. J Virol 72(7):6151–6154PubMedGoogle Scholar
  182. 182.
    Li M, Cripe TP, Estes PA, Lyon MK, Rose RC, Garcea RL (1997) Expression of the human papillomavirus type 11 L1 capsid protein in Escherichia coli: characterization of protein domains involved in DNA binding and capsid assembly. J Virol 71(4):2988–2995PubMedGoogle Scholar
  183. 183.
    Rechtsteiner G, Warger T, Osterloh P, Schild H, Radsak MP (2005) Cutting edge: priming of CTL by transcutaneous peptide immunization with imiquimod. J Immunol 174(5):2476–2480PubMedGoogle Scholar
  184. 184.
    Nardelli-Haefliger D, Lurati F, Wirthner D, Spertini F, Schiller JT, Lowy DR, Ponci F, De Grandi P (2005) Immune responses induced by lower airway mucosal immunisation with a human papillomavirus type 16 virus-like particle vaccine. Vaccine 23(28):3634–3641PubMedGoogle Scholar
  185. 185.
    Merck. A study of V503 in Preadolescents and Adolescents. 2009 [cited 2009 Dec 20]; Available from: http://clinicaltrials.gov/ct2/show/NCT00943722
  186. 186.
    Roden RB, Gravitt P, Wu TC (2008) Towards global prevention of human papillomavirus-induced cancer. Eur J Immunol 38(2):323–326PubMedGoogle Scholar
  187. 187.
    Roden R, Monie A, Wu TC (2006) The impact of preventive HPV vaccination. Discov Med 6(35):175–181PubMedGoogle Scholar
  188. 188.
    Schiller JT, Castellsague X, Villa LL, Hildesheim A (2008) An update of prophylactic human papillomavirus L1 virus-like particle vaccine clinical trial results. Vaccine 26(Suppl 10):K53–K61PubMedGoogle Scholar
  189. 189.
    Hung CF, Ma B, Monie A, Tsen SW, Wu TC (2008) Therapeutic human papillomavirus vaccines: current clinical trials and future directions. Expert Opin Biol Ther 8(4):421–439PubMedGoogle Scholar

Copyright information

© Springer Science+Business Media, LLC 2011

Authors and Affiliations

  • Wen-Chung Chen
  • Barbara Ma
  • Chih-Ping Mao
  • T-C Wu
    • 1
    • 2
    • 3
    • 4
  1. 1.Department of PathologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  2. 2.Department of Obstetrics and GynecologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  3. 3.Department of Molecular Microbiology and ImmunologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA
  4. 4.Department of oncologyThe Johns Hopkins Medical InstitutionsBaltimoreUSA

Personalised recommendations