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 of epithelial cell proliferation. It has been proposed that loss of sensitivity to growth inhibition by TGF-beta 1 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-beta 1 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-beta 1 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-beta 1. 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-beta 1 at early passage than at late passage (P < 0.05). There are no differences in the sensitivity to the growth inhibitory effects of TGF-beta 1 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-beta 1 or TGF-beta 2. We conclude that resistance to growth inhibition by TGF-beta 1 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.
Department of Obstetrics and Gynecology, Rush Medical College, Chicago, Illinois 60612.
K
K
De Geest
C A
CA
Bergman
M E
ME
Turyk
B S
BS
Frank
G D
GD
Wilbanks
D000818:Animals; D002294:Carcinoma, Squamous Cell / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002461:Cell Line, Transformed; D002478:Cells, Cultured; D002584:Cervix Uteri / Q000166:cytology / Q000821:virology; D004279:DNA, Viral / Q000235:genetics; D005260:Female; D006801:Humans; D051379:Mice; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D027383:Papillomaviridae / Q000235:genetics; D051381:Rats; D017207:Rats, Sprague-Dawley; D014162:Transfection; D016212:Transforming Growth Factor beta / Q000096:biosynthesis / Q000494:pharmacology*; D014407:Tumor Cells, Cultured / Q000378:metabolism / Q000473:pathology / Q000821:virology; D002583:Uterine Cervical Neoplasms / Q000378:metabolism / Q000473:pathology* / Q000821:virology; D002578:Uterine Cervical Dysplasia / Q000378:metabolism / Q000473:pathology* / Q000821:virology
D004279:DNA, Viral; D016212:Transforming Growth Factor beta