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Cooperation of genes in HPV16 E6/E7-dependent cervicovaginal carcinogenesis trackable by endoscopy and independent of exogenous estrogens or carcinogens.

  • Böttinger, Paula1
  • Schreiber, Karin1
  • Hyjek, Elizabeth2
  • Krausz, Thomas2
  • Spiotto, Michael T2
  • Steiner, Madeline1
  • Idel, Christian1
  • Booras, Heather1
  • Beck-Engeser, Gabriele1
  • Riederer, Jessie1
  • Willimsky, Gerald3, 4, 5
  • Wolf, Steven P1, 3
  • Karrison, Theodore6
  • Jensen, Elizabeth1
  • Weichselbaum, Ralph R2
  • Nakamura, Yusuke7
  • Yew, Poh Yin8
  • Lambert, Paul F9
  • Kurita, Takeshi10
  • Kiyotani, Kazuma7
  • And 2 more
  • 1 Department of Pathology, The University of Chicago, Chicago, IL, USA.
  • 2 Department of Radiation and Cellular Oncology, The University of Chicago, Chicago, IL, USA.
  • 3 Institute of Immunology, Charité-Universitätsmedizin Berlin, Campus Buch, Berlin, Germany. , (Germany)
  • 4 German Cancer Research Center, Heidelberg, Germany. , (Germany)
  • 5 German Cancer Consortium, Partner site Berlin, Berlin, Germany. , (Germany)
  • 6 Department of Public Health Sciences, The University of Chicago, Chicago, IL, USA.
  • 7 Project for Immunogenomics, Cancer Precision Medicine Center, Japanese Foundation for Cancer Research, Tokyo, Japan. , (Japan)
  • 8 Department of Medicine, The University of Chicago, Chicago, IL, USA.
  • 9 McArdle Laboratory for Cancer Research/Department of Oncology, University of Wisconsin, Madison, WI, USA.
  • 10 Department of Cancer Biology and Genetics, Ohio State University, Columbus, OH, USA.
Published Article
Oxford University Press
Publication Date
Nov 13, 2020
DOI: 10.1093/carcin/bgaa027
PMID: 32221533


Human papillomavirus (HPV) infection is necessary but insufficient for progression of epithelial cells from dysplasia to carcinoma-in situ (CIS) to invasive cancer. The combination of mutant cellular and viral oncogenes that regulate progression of cervical cancer (CC) remains unclear. Using combinations of HPV16 E6/E7 (E+), mutant Kras (mKras) (K+) and/or loss of Pten (P-/-), we generated autochthonous models of CC without exogenous estrogen, carcinogen or promoters. Furthermore, intravaginal instillation of adenoCre virus enabled focal activation of the oncogenes/inactivation of the tumor suppressor gene. In P+/+ mice, E6/E7 alone (P+/+E+K-) failed to cause premalignant changes, while mKras alone (P+/+E-K+) caused persistent mucosal abnormalities in about one-third of mice, but no cancers. To develop cancer, P+/+ mice needed both E6/E7 and mKras expression. Longitudinal endoscopies of P+/+E+K+ mice predicted carcinoma development by detection of mucosal lesions, found on an average of 23 weeks prior to death, unlike longitudinal quantitative PCRs of vaginal lavage samples from the same mice. Endoscopy revealed that individual mice differed widely in the time required for mucosal lesions to appear after adenoCre and in the time required for these lesions to progress to cancer. These cancers developed in the transition zone that extends, unlike in women, from the murine cervix to the distal vagina. The P-/-E+K+ genotype led to precipitous cancer development within a few weeks and E6/E7-independent cancer development occurred in the P-/-E-K+ genotype. In the P-/-E+K- genotype, mice only developed CIS. Thus, distinct combinations of viral and cellular oncogenes are involved in distinct steps in cervical carcinogenesis. © The Author(s) 2020. Published by Oxford University Press. All rights reserved. For Permissions, please email: [email protected]

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