RESISTANCE OF HUMAN SQUAMOUS CARCINOMA-CELLS TO TRANSFORMING GROWTH-FACTOR-BETA-1 IS A RECESSIVE TRAIT

Because most human squamous carcinoma cell lines of the aerodigestive and genital tracts are refractory to the antiproliferative action of transforming growth factor beta1 (TGFbeta1) in vitro, we have begun to identify the causes for resistance of squamous carcinoma cell lines to TGFbeta1 by using somatic cell genetics. Two stable hybrid cell lines (FaDu-HKc.1 and FaDu-HKc.2) were obtained by fusing a TGFbeta1-resistant human squamous carcinoma cell line, FaDu-Hyg(R), with a human papilloma virus 16-immortalized, TGFbeta1-sensitive, human foreskin keratinocyte cell line, HKc-neo(R). Whereas TGFbeta1 did not inhibit DNA synthesis in parental FaDu-Hyg(R) cells, it reduced DNA synthetic activity of HKc-neo(R), FaDu-HKc.1, and FaDu-HKc.2 cells by 75-85% (IC50, 2-5 pM). Although squamous carcinoma cells express lower than normal levels of TGFbeta1 type II receptors on their cell surface, TGFbeta1 type II receptor mRNA was detected in all four cell lines. Recessive genes involved in TGFbeta1 signaling may be localized to the distal portion of chromosome 18q, as this was the sole chromosomal region of homozygous deletion in parental FaDu-Hyg(R) cells. Furthermore, our previous observation that mutant p53 decreases sensitivity of keratinocytes to TGFbeta1 was supported by the finding that the level of the mutant p53 protein expressed by the hybrid cell lines was greatly reduced. In summary, TGFbeta1 resistance of FaDu cells appears to be recessive and is presumably due to the loss of one or more post-receptor elements of the signaling pathway.