Transforming growth factor-β-mediated autocrine growth regulation of gliomas as detected with phosphorothioate antisense oligonucleotides

Transforming growth factors-β1 and -β2 (TGF-β1 and -β2) are important growth-regulatory proteins for astroglial neoplasms. We analyzed their role in tumor-cell proliferation in 12 glioma cell lines, employing phosphorothioate antisense oligodeoxynucleotides (S-ODNs, 14 mer), specifically targeted against the coding sequences of TGF-β1-mRNA and TGF-β2-mRNA. TGF-β1-S-ODNs inhibited cell proliferation in 5 of 12 gliomas, whereas TGF-β2-S-ODNs reduced the cell proliferation in all glioma cell lines, compared to nonsense-S-ODN-treated and S-ODN-untreated cells as controls. The efficacy and specificity of antisense effects was validated by Northern-blot analysis and determination of protein concentrations in culture supernatants (ELISA). Exogenous hrTGF-β1 either stimulated or inhibited the cell lines, whereas pnTGF-β2 stimulated the proliferation of most glioma cells. Blocking the extracellular pathway of TGF-β by neutralizing antibodies only slightly inhibited those cell lines, which were markedly stimulated by TGF-βs. As the effects of TGF-β2-S-ODNs were much stronger than those of TGF-β neutralizing antibodies, we postulate that the endogenously produced TGF-β2 control glioma-cell proliferation, in part by an intracellular loop. © 1996 Wiley-Liss, Inc.