 Restoration of an impaired TGF-beta1 autocrine growth-inhibitory circuit using a gene transfer approach results in growth inhibition of some epithelial cancer cell lines.
Z. Zeinoun, E. Teugels, J. Vermeij, B. Neyns, Jacques De Greve.
AZ-VUB, Brussels, Brabant, Belgium
The disruption of the TGF-beta1 autocrine growth-inhibitory circuit is a major and possibly early event mediating the malignant transformation of normal epithelia. TGF-beta1 is a secreted latent homodimer-peptide that, upon activation, binds a receptors-complex, and relays a transduction signal across the cytoplasm of the cell that normally results in proliferation-inhibition and apoptosis. This pathway can be disturbed at several levels: insufficient secretion and activation of TGF-beta1 ligand, mutational inactivation of the receptors or molecules in the signal transduction cascade or at the level of the nuclear effector molecules. We aimed at transducing a TGF-beta1 cDNA driven by a CMV promoter and coding for a biologically activated TGF-beta1 peptide using a replication-defective adenovirus vector as the gene transfer vehicle in an attempt to restore the autocrine growth-suppressive circuit. The infection of epithelial cancer cells with rAd/TGF-beta1 virus resulted in the production and secretion of bioactive TGF-beta1, detected and gauged by immunocytochemistry and immunosorbant assays, in high amounts. The responsive cancer cell lines infected by rAd/TGF-beta1 were growth inhibited in vitro and lost their tumorgenicity in nude mice. Conclusion: Restituting the TGF-beta1 autocrine growth-suppressive circuit by means of infections with a rAd/TGF-beta1 virus in TGF-beta1 sensitive cancer cells, but which have insufficient endogenous TGF-beta1, has a potent preclinical growth inhibitory effect. As disruption of autocrine growth circuits are thought to be early events in the malignant transformation, early correction of these defects using such gene transfer approaches might in the future lead to cancer preventive strategies.
KEY WORDS:
TGF-beta,
adenovirus,
gene therapy,
epithelial cancer cells.
For more information, contact zzeinoun@minf.vub.ac.be
Paper presented at the International Symposium on Predictive Oncology and Intervention Strategies; Paris, France; February 9 - 12, 2002; in the section on Gene Therapy, Part 1.
This presentation received an honorable mention in our poster contest and was recognized with the Symposium Presidents' Award for Scientific Excellence.
http://www.cancerprev.org/Journal/Issues/26/101/994/4664
|
