RESISTANCE TO GROWTH-INHIBITION BY TRANSFORMING-GROWTH-FACTOR-BETA INMALIGNANT GLIOMA-CELLS WITH FUNCTIONAL RECEPTORS

Object. The aim of this study was to investigate the mechanism by whic h malignant glioma cells escape from growth inhibition mediated by tra nsforming growth factor-beta (TGF-beta), a ubiquitous cytokine that in hibits cell proliferation by causing growth arrest in the G(1) phase o f the cell cycle. Methods. The authors measured the response of eight malignant glioma cell lines to the growth-inhibiting activity of TGF-b eta in vitro and the expression of TGF-beta Types I and II receptors i n malignant glioma cells. The effect of TGF-beta on the expression of a p27(Kip1) cyclin-dependent kinase inhibitor was also investigated to assess the downstream signal transmission from TGF-beta receptors. Al l malignant glioma cell lines were insensitive to growth inhibition by TGF-beta 1 and TGF-beta 2. Analyses of TGF-beta receptors by means of affinity labeling in which I-125-TGF-beta 1 was used showed that six glioma lines had both TGF-beta Types I and II receptors on their cell surfaces, whereas two lines had very small amounts of TGF-beta Type I and/or Type II receptors. Northern blot analysis showed that all tumor lines expressed variable levels of messenger RNAs for both TGF-beta T ypes I and II receptors. Flow cytometric analyses revealed that treatm ent of malignant glioma cells with TGF-beta 1 significantly downregula ted the expression of p27(Kip1) protein in all malignant glioma cell l ines except one. Conclusions. The authors suggest that most malignant glioma cells express TGF-beta Types I and II receptors, which can tran smit some signals downstream and that the loss of response to TGF-beta growth inhibition may not be caused by an abnormality of the TGF-beta receptors.