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The American Journal of Pathology logoLink to The American Journal of Pathology
. 1991 Jan;138(1):1–8.

Evolution of in vitro transformation and tumorigenesis of HPV16 and HPV18 immortalized primary cervical epithelial cells.

G Pecoraro 1, M Lee 1, D Morgan 1, V Defendi 1
PMCID: PMC1886048  PMID: 1846261

Abstract

Cervical carcinoma develops through a progressive spectrum of premalignant intraepithelial lesions (CIN I-III), the majority of which are associated with human papillomavirus (HPV) types 16 and 18. We established HPV16 and HPV18 immortalized human cervical epithelial cell lines and used them as a model to investigate the genesis and progression of cervical malignancy. The cell lines when cultured in vitro in a system mimicking their in vivo environment exhibit cytologic atypia and a variety of defects in morphologic differentiation at early passage compared to their normal counterparts. With increased passage, these alterations progress to more severe grades, histologically similar to CIN III; however only a limited number of the cell lines are tumorigenic, mimicking the epidemiologic evidence on the rate of conversion from premalignant to invasive carcinoma. The observed changes are not associated with alterations of viral DNA integration or expression and may reflect specific cellular events or changes in virus-host interactions associated with malignant progression.

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Selected References

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  1. Asselineau D., Bernard B. A., Bailly C., Darmon M., Pruniéras M. Human epidermis reconstructed by culture: is it "normal"? J Invest Dermatol. 1986 Feb;86(2):181–186. doi: 10.1111/1523-1747.ep12284237. [DOI] [PubMed] [Google Scholar]
  2. Barron B. A., Cahill M. C., Richart R. M. A statistical model of the natural history of cervical neoplastic disease: the duration of carcinoma in situ. Gynecol Oncol. 1978 Apr;6(2):196–205. doi: 10.1016/0090-8258(78)90022-7. [DOI] [PubMed] [Google Scholar]
  3. Bedell M. A., Jones K. H., Grossman S. R., Laimins L. A. Identification of human papillomavirus type 18 transforming genes in immortalized and primary cells. J Virol. 1989 Mar;63(3):1247–1255. doi: 10.1128/jvi.63.3.1247-1255.1989. [DOI] [PMC free article] [PubMed] [Google Scholar]
  4. Camps J. L., Chang S. M., Hsu T. C., Freeman M. R., Hong S. J., Zhau H. E., von Eschenbach A. C., Chung L. W. Fibroblast-mediated acceleration of human epithelial tumor growth in vivo. Proc Natl Acad Sci U S A. 1990 Jan;87(1):75–79. doi: 10.1073/pnas.87.1.75. [DOI] [PMC free article] [PubMed] [Google Scholar]
  5. Chen P. L., Scully P., Shew J. Y., Wang J. Y., Lee W. H. Phosphorylation of the retinoblastoma gene product is modulated during the cell cycle and cellular differentiation. Cell. 1989 Sep 22;58(6):1193–1198. doi: 10.1016/0092-8674(89)90517-5. [DOI] [PubMed] [Google Scholar]
  6. Chen S. L., Mounts P. Transforming activity of E5a protein of human papillomavirus type 6 in NIH 3T3 and C127 cells. J Virol. 1990 Jul;64(7):3226–3233. doi: 10.1128/jvi.64.7.3226-3233.1990. [DOI] [PMC free article] [PubMed] [Google Scholar]
  7. Chomczynski P., Sacchi N. Single-step method of RNA isolation by acid guanidinium thiocyanate-phenol-chloroform extraction. Anal Biochem. 1987 Apr;162(1):156–159. doi: 10.1006/abio.1987.9999. [DOI] [PubMed] [Google Scholar]
  8. DiPaolo J. A., Woodworth C. D., Popescu N. C., Notario V., Doniger J. Induction of human cervical squamous cell carcinoma by sequential transfection with human papillomavirus 16 DNA and viral Harvey ras. Oncogene. 1989 Apr;4(4):395–399. [PubMed] [Google Scholar]
  9. 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 Feb 17;243(4893):934–937. doi: 10.1126/science.2537532. [DOI] [PubMed] [Google Scholar]
  10. Gustafsson L., Adami H. O. Natural history of cervical neoplasia: consistent results obtained by an identification technique. Br J Cancer. 1989 Jul;60(1):132–141. doi: 10.1038/bjc.1989.236. [DOI] [PMC free article] [PubMed] [Google Scholar]
  11. Horwitz B. H., Burkhardt A. L., Schlegel R., DiMaio D. 44-amino-acid E5 transforming protein of bovine papillomavirus requires a hydrophobic core and specific carboxyl-terminal amino acids. Mol Cell Biol. 1988 Oct;8(10):4071–4078. doi: 10.1128/mcb.8.10.4071. [DOI] [PMC free article] [PubMed] [Google Scholar]
  12. Klein G., Klein E. Evolution of tumours and the impact of molecular oncology. Nature. 1985 May 16;315(6016):190–195. doi: 10.1038/315190a0. [DOI] [PubMed] [Google Scholar]
  13. Koss L. G. Pathogenesis of carcinoma of the uterine cervix. Curr Top Pathol. 1981;70:111–142. doi: 10.1007/978-3-642-68185-1_5. [DOI] [PubMed] [Google Scholar]
  14. Martin P., Vass W. C., Schiller J. T., Lowy D. R., Velu T. J. The bovine papillomavirus E5 transforming protein can stimulate the transforming activity of EGF and CSF-1 receptors. Cell. 1989 Oct 6;59(1):21–32. doi: 10.1016/0092-8674(89)90866-0. [DOI] [PubMed] [Google Scholar]
  15. McAlpine P. J., Shows T. B., Boucheix C., Stranc L. C., Berent T. G., Pakstis A. J., Douté R. C. Report of the nomenclature committee and the 1989 catalog of mapped genes. Cytogenet Cell Genet. 1989;51(1-4):13–66. doi: 10.1159/000132780. [DOI] [PubMed] [Google Scholar]
  16. Nelson J. H., Jr, Averette H. E., Richart R. M. Dysplasia, carcinoma in situ, and early invasive cervical carcinoma. CA Cancer J Clin. 1984 Nov-Dec;34(6):306–327. doi: 10.3322/canjclin.34.6.306. [DOI] [PubMed] [Google Scholar]
  17. Pecoraro G., Morgan D., Defendi V. Differential effects of human papillomavirus type 6, 16, and 18 DNAs on immortalization and transformation of human cervical epithelial cells. Proc Natl Acad Sci U S A. 1989 Jan;86(2):563–567. doi: 10.1073/pnas.86.2.563. [DOI] [PMC free article] [PubMed] [Google Scholar]
  18. Peehl D. M., Stanbridge E. J. Anchorage-independent growth of normal human fibroblasts. Proc Natl Acad Sci U S A. 1981 May;78(5):3053–3057. doi: 10.1073/pnas.78.5.3053. [DOI] [PMC free article] [PubMed] [Google Scholar]
  19. Schiller J. T., Vass W. C., Vousden K. H., Lowy D. R. E5 open reading frame of bovine papillomavirus type 1 encodes a transforming gene. J Virol. 1986 Jan;57(1):1–6. doi: 10.1128/jvi.57.1.1-6.1986. [DOI] [PMC free article] [PubMed] [Google Scholar]
  20. Uldbjerg N., Ulmsten U., Ekman G. The ripening of the human uterine cervix in terms of connective tissue biochemistry. Clin Obstet Gynecol. 1983 Mar;26(1):14–26. doi: 10.1097/00003081-198303000-00006. [DOI] [PubMed] [Google Scholar]
  21. Werness B. A., Levine A. J., Howley P. M. Association of human papillomavirus types 16 and 18 E6 proteins with p53. Science. 1990 Apr 6;248(4951):76–79. doi: 10.1126/science.2157286. [DOI] [PubMed] [Google Scholar]
  22. Woodworth C. D., Bowden P. E., Doniger J., Pirisi L., Barnes W., Lancaster W. D., DiPaolo J. A. Characterization of normal human exocervical epithelial cells immortalized in vitro by papillomavirus types 16 and 18 DNA. Cancer Res. 1988 Aug 15;48(16):4620–4628. [PubMed] [Google Scholar]
  23. Woodworth C. D., Waggoner S., Barnes W., Stoler M. H., DiPaolo J. A. Human cervical and foreskin epithelial cells immortalized by human papillomavirus DNAs exhibit dysplastic differentiation in vivo. Cancer Res. 1990 Jun 15;50(12):3709–3715. [PubMed] [Google Scholar]
  24. Yang Y. C., Spalholz B. A., Rabson M. S., Howley P. M. Dissociation of transforming and trans-activation functions for bovine papillomavirus type 1. Nature. 1985 Dec 12;318(6046):575–577. doi: 10.1038/318575a0. [DOI] [PubMed] [Google Scholar]

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