HPV-mediated cervical carcinogenesis: concepts and clinical implications

J Pathol. 2006 Jan;208(2):152-64. doi: 10.1002/path.1866.

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.

Publication types

  • Research Support, Non-U.S. Gov't
  • Review

MeSH terms

  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • Cell Survival / physiology
  • Cell Transformation, Neoplastic
  • Cervical Intraepithelial Neoplasia / virology
  • DNA, Neoplasm / analysis
  • Female
  • Genes, Tumor Suppressor
  • Humans
  • Immunoglobulins / genetics
  • Membrane Proteins / genetics
  • Models, Biological
  • Papillomavirus Infections / complications*
  • Risk Factors
  • Tumor Suppressor Proteins / genetics
  • Uterine Cervical Neoplasms / genetics
  • Uterine Cervical Neoplasms / physiopathology
  • Uterine Cervical Neoplasms / virology*

Substances

  • CADM1 protein, human
  • Cell Adhesion Molecule-1
  • Cell Adhesion Molecules
  • DNA, Neoplasm
  • Immunoglobulins
  • Membrane Proteins
  • Tumor Suppressor Proteins