title: HPV-mediated cervical carcinogenesis: concepts and clinical implications.
abstract: Persistent infection with a high-risk human papillomavirus (hrHPV) is generally accepted as a necessary cause of cervical cancer. However, cervical cancer is a rare complication of an hrHPV infection since most such infections are transient, not even giving rise to cervical lesions. On average, it takes 12-15 years before a persistent hrHPV infection may ultimately, via consecutive premalignant stages (ie CIN lesions), lead to an overt cervical carcinoma. This argues that HPV-induced cervical carcinogenesis is multi-step in nature. In this review, the data from hrHPV-mediated in vitro transformation studies and those obtained from analysis of clinical specimens have been merged into a cervical cancer progression model. According to this model, a crucial decision maker in the early stages following infection involves individual susceptibility for certain HPV types depending on the genetic make-up of immune surveillance determinants. Once a CIN lesion has developed, altered transcriptional regulation of the viral E6/E7 oncogenes, resulting in genomic instability and distinguishing the process of cell transformation from a productive viral infection, probably provides the subsequent important step towards malignancy. The additional (epi)genetic alterations that subsequently accumulate in high-grade CIN lesions may result in overt malignancy via immortality and growth conditions that gradually become less sensitive to growth-modulating influences mediated by cytokines and cell-cell and cell-matrix adhesions. The potential implications of hrHPV testing and some other biomarkers deduced from this model for cervical screening and the clinical management of CIN disease are also discussed.
authors.affiliation: Department of Pathology, VU University Medical Center, Amsterdam, The Netherlands.
authors.forename: Peter J F
authors.initials: PJ
authors.lastname: Snijders
authors.forename: Renske D M
authors.initials: RD
authors.lastname: Steenbergen
authors.forename: Daniëlle A M
authors.initials: DA
authors.lastname: Heideman
authors.forename: Chris J L M
authors.initials: CJ
authors.lastname: Meijer
mesh_terms: D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D002470:Cell Survival / Q000502:physiology; D002471:Cell Transformation, Neoplastic; D004273:DNA, Neoplasm / Q000032:analysis; D005260:Female; D016147:Genes, Tumor Suppressor; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics; D008565:Membrane Proteins / Q000235:genetics; D008954:Models, Biological; D030361:Papillomavirus Infections / Q000150:complications*; D012307:Risk Factors; D025521:Tumor Suppressor Proteins / Q000235:genetics; D002583:Uterine Cervical Neoplasms / Q000235:genetics / Q000503:physiopathology / Q000821:virology*; D002578:Uterine Cervical Dysplasia / Q000821:virology
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D004273:DNA, Neoplasm; D007136:Immunoglobulins; D008565:Membrane Proteins; D025521:Tumor Suppressor Proteins