Journal Article

Malignant transformation of human ectocervical cells immortalized by HPV 18: <i>in vitro</i> model of carcinogenesis by cigarette smoke

Yoshifumi Nakao, Xiaolong Yang, Masatoshi Yokoyama, Mary M. Pater and Alan Pater

in Carcinogenesis

Volume 17, issue 3, pages 577-583
Published in print March 1996 | ISSN: 0143-3334
e-ISSN: 1460-2180 | DOI: http://dx.doi.org/10.1093/carcin/17.3.577
Malignant transformation of human ectocervical cells immortalized by HPV 18: in vitro model of carcinogenesis by cigarette smoke

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In addition to the established role of human papilloma-viruses (HPVs) in cervical cancer, smoking has been suggested to be an important cofactor. Previously, primary human ectocervical cells immortalized by HPV types 16 and 18 DNA did not form tumors on nude mice. Here, we derived a new line of HPV 18-immortalized ectocervical cells (HEC-18-1), which was also non-tumorigenic. To examine the role of cigarette smoking in the progression of cervical cancer initiated by HPV 18, we adapted these cells to growth in serum and high calcium and treated the cells with cigarette smoke condensate until tumorigenic cells (HEC-18-1C) were produced. Moderate and late passage serum-adapted untreated HEC-18-1 (HEC-18-1S) remained non-tumorigenic. A typical HEC-18-1C tumor was an invasive squamous cell carcinoma, from which we established a clonal line of cells (HEC-18-1CT). Although the physical state of HPV 18 was not affected by malignant transformation and the gene expression of HPV 18 was affected little, the differentiation of the epithelium derived in organotypic (raft) culture from HEC-18-1CT was altered dramatically. Moderate and late passage HEC-18-1 and HEC-18-1S were reconstructed into mild dysplasia in organotypic (raft) culture. On the other hand, the moderate passage malignantly transformed HEC-18-1CT displayed severe dysplasia/carcinoma in situ in raft culture. We describe here the first direct evidence of the role of cigarette smoke in the progression of HPV-initiated carcinogenesis using an in vitro model system.

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Subjects: Clinical Cytogenetics and Molecular Genetics

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