Differential Response of Cervical Intraepithelial and Cervical Carcinoma Cell Lines to Transforming Growth Factor-β1

Abstract

Transforming growth factor-β1 (TGF-β1) is a potent inhibitor of epithelial cell proliferation. It has been proposed that loss of sensitivity to growth inhibition by TGF-β1 may be an important step in the development of cervical carcinoma, but it remains unclear whether this represents an early or a late event. We compared the sensitivity to TGF-β1 of nontumorigenic human papillomavirus deoxyribonucleic acid (HPV DNA)-positive cell lines derived from cervical intraepithelial neoplasia (CIN), of newly established cervical carcinoma cell lines, of nontumorigenic HPV DNA-transfected cervical cell lines, and of normal ectocervical cells. There is a dose-dependent inhibition of DNA synthesis by TGF-β1 in the CIN cell lines and the HPV DNA-transfected cell lines. The carcinoma cell lines are resistant to the growth inhibitory effects of TGF-β1. The CIN cell lines are significantly more sensitive than the carcinoma cell lines ( P < 0.001), but significantly less sensitive than normal cervical cells ( P < 0.05). A CIN cell line which contains HPV 31b DNA is more sensitive to TGF-β1 at early passage than at late passage ( P < 0.05). There are no differences in the sensitivity to the growth inhibitory effects of TGF-β1 between subclones of this cell line that have different episomal HPV DNA content, population-doubling time, or differentiation characteristics. Both normal and abnormal cervical epithelial cells were able to secrete latent TGF-β1 or TGF-β2. We conclude that resistance to growth inhibition by TGF-β1 is likely to be a late event in the development of cervical carcinoma; it is not the mere consequence of immortalization by HPV genes acquired following transfection in vitro or infection in vivo.