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Characterization of Normal Human Exocervical Epithelial Cells Immortalized in Vitro by Papillomavirus Types 16 and 18 DNA¹

Laboratory of Biology, Division of Cancer Etiology, National Cancer Institute, Bethesda, Maryland 20892 [C. D. W., P. E. B., J. D., L. P., J. A. D.], and Department of Obstetrics and Gynecology, Georgetown University Medical Center, Washington, DC 20007 [W. B., W. D. L.]

An in vitro system for studying the interaction between human papillomavirus (HPV) 16 and 18 recombinant DNA and normal human exocervical epithelial cells is described. Eight HPV-immortalized human exocervical epithelial cell lines were established; all the lines contained either integrated HPV16 or 18 sequences and expressed HPV mRNAs. Thus, integration and expression appear to be required for immortalization. Immortalized cells (>200 population doublings to date) divided rapidly (doubling time of 30 to 46 h) and morphologically resembled primary cultures of normal human exocervical epithelial cells. They expressed a keratin pattern consistent with their origin from exocervical epithelium. When cultured at high density or in the presence of serum they terminally differentiated. Sublines resistant to terminal differentiation were selected by growth in serum-supplemented medium. Keratin pattern changes suggest they have some properties in common with cervical squamous carcinoma cells. However, HPV-immortalized cell lines were not tumorgenic in nude mice. Thus, HPV16/18 is not carcinogenic by itself. These cell lines represent an appropriate model for studying factors that regulate HPV gene expression in normal cervical epithelial cells and examining the influence of cocarcinogens on neoplastic progression.

¹ The investigation was supported in part by Grant CA32638 awarded to W. D. L. by the National Cancer Institute, Department of Health and Human Services, Bethesda, MD 20892.

² To whom requests for reprints should be addressed, at the National Cancer Institute, Laboratory of Biology, Division of Cancer Etiology, Building 37, Room 2A19, Bethesda, MD 20892.

³ Present address: Department of Chemistry, University of South Carolina, Columbia, SC 29208.

Received 12/16/87. Revised 4/12/88. Revised 5/13/88. Accepted 5/19/88.

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