| [ Summary ] |
Resistance to the growth inhibitory effects of transforming growth factor (TGF-β) is a frequent consequence of malignant transformation. On the other hand, serum concentrations of TGF-β and vascular endothelial growth factor (VEGF) are elevated as tumors progress. TGF-β signaling involves TGF-β type I receptor-mediated phosphorylation of Smad 2 and Smad 3. We investigated the involvement of autocrine TGF-β signals in cell growth and VEGF production of human hepatocellular carcinoma(HCC). HCC cells showed resistance to the growth inhibitory effects of TGF-β. In addition, tumor-derived TGF-β induced ligand-dependent signaling through the activated Smad 3 and Smad 4 complex, and the transcriptional activity of VEGF gene, suggesting that autocrine TGF-β signals in human HCC accelerate their malignant potential by enhancing VEGF production. From the view point of TGF-β signaling, a key therapeutic challenge in HCC would be restoration of the lost tumor suppressor function observed in normal hepatocytes at the expense of oncogenic effects that would lead to more aggressive HCC. Specific inhibitors of the TGF-β-mediated Smad pathway might prove useful in this respect. Investigation concerning the distribution of phosphorylated Smad 2 / 3 in a given specimen would be needed to predict potential responses to molecularly targeted therapies for human HCC. |