Restoration of an impaired TGF-beta1 autocrine growth-inhibitory circuit results in growth inhibition of ovarian epithelial cancer cells and complete inhibition of their tumorigenicity

The disruption of the transforming growth factor beta1 (TGF-beta1) autocrine growth-suppressive circuit is a major and possibly early event mediating the malignant transformation of normal epithelia. TGF-beta1 is secreted as a latent homodimer-peptide that, upon activation, binds a receptor complex. This in turn activates a signal transduction cascade that results in proliferation inhibition of epithelial cells. The growth-inhibitory pathway can be interrupted at several levels: insufficient secretion and activation of TGF-beta1 ligand, mutational inactivation of the receptors or signal transduction intermediates or at the level of the nuclear effector molecules. We have investigated the effect of restoring the growth-inhibitory autocrine circuit in epithelial cancer cells that have retained sensitivity to growth inhibition by TGF-beta1 but which produce and secrete insufficient amounts of endogenous peptide. These cancer cells were transduced with a recombinant adenovirus containing a TGF-beta1 cDNA driven by a CMV promoter and coding for a constitutively bioactive TGF-beta1 peptide. Restituting the TGF-beta1 autocrine growth-suppressive circuit in these cancer cells had a potent growth-inhibitory effect in vitro. Moreover, in vitro transduced cells lost their tumorigenicity in nude mice. As disruption of TGF-beta's autocrine growth circuit is thought to be an early event in the malignant transformation of several epithelial cancers, early correction of this defect might in the future lead to cancer preventive strategies.