DIFFERENTIAL RESPONSE OF CERVICAL INTRAEPITHELIAL AND CERVICAL-CARCINOMA CELL-LINES TO TRANSFORMING GROWTH-FACTOR-BETA-1

Transforming growth factor-beta 1 (TGF-beta 1) is a potent inhibitor o f epithelial cell proliferation. It has been proposed that loss of sen sitivity to growth inhibition by TGF-beta 1 may be an important step i n the development of cervical carcinoma, but it remains unclear whethe r this represents an early or a late event. We compared the sensitivit y to TGF-beta 1 of nontumorigenic human papillomavirus deoxyribonuclei c acid (HPV DNA)-positive cell lines derived from cervical intraepithe lial neoplasia (CIN), of newly established cervical carcinoma cell lin es, of nontumorigenic HPV DNA-transfected cervical cell lines, and of normal ectocervical cells. There is a dose-dependent inhibition of DNA synthesis by TGF-beta 1 in the CIN cell lines and the HPV DNA-transfe cted cell lines. The carcinoma cell lines are resistant to the growth inhibitory effects of TGF-beta 1. The CIN cell lines are significantly more sensitive than the carcinoma cell lines (P < 0.001), but signifi cantly less sensitive than normal cervical cells (P < 0.05). A CIN cel l line which contains HPV 31b DNA is more sensitive to TGF-beta 1 at e arly passage than at late passage (P < 0.05). There are no differences in the sensitivity to the growth inhibitory effects of TGF-beta 1 bet ween 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 secre te latent TGF-beta 1 or TGF-beta 2. We conclude that resistance to gro wth inhibition by TGF-beta 1 is likely to be a late event in the devel opment of cervical carcinoma; it is not the mere consequence of immort alization by HPV genes acquired following transfection in vitro or inf ection in vivo. (C) 1994 Academic Press, Inc.