Insufficient TGF-beta 1 production inactivates the autocrine growth suppressive circuit in human ovarian cancer cell lines.

Abstract TGF-beta 1 is a secreted polypeptide that elicits an antiproliferanve response in many cell types. However, many epithelial cancer cell lines are resistant to TGF-beta 1 growth inhibition. We investigated the in vitro growth suppressive effect of TGF-beta 1 on five ovarian cancer cell lines. Two of these (OVCAR-3 and AZ364) were growth inhibited by TGF-beta 1. The other three cell lines (SKOV-3, AZ224 and AZ547), were resistant to the antiproliferative action of the cytokine. All five cell lines produce TGF-beta 1 mRNA at very different levels and also secrete the TGF-beta 1 polypeptide, but mainly in a biologically latent form as tested by ELISA; this probably explains the fact that the TGF-beta 1 autocrine growth inhibition circuit is not active, even in sensitive cell lines. Even complete activation of the in vitro secreted latent form would be insufficient to induce growth arrest when compared to the levels of exogenous TGF-beta 1 needed to induce growth arrest in sensitive cell lines. The TGF-beta 1 receptor type I mRNA is expressed by all five ovarian cancer cell lines, but two of them (AZ224 and AZ547) lack detectable TGF-beta 1 receptor type II mRNA expression. Since TGF-beta 1 signaling requires both receptor types, the lack of receptor type II in two cell lines may explain their resistance to growth inhibition. Further experiments should be carried out on receptors and downstream components to pinpoint the cause of resistance in the SKOV cell line.