Mario Mikula and Verena Proell contributed equally to this work.
Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-β dependent fashion†
Article first published online: 1 AUG 2006
Copyright © 2006 Wiley-Liss, Inc.
Journal of Cellular Physiology
Volume 209, Issue 2, pages 560–567, November 2006
How to Cite
Mikula, M., Proell, V., Fischer, A.N.M. and Mikulits, W. (2006), Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-β dependent fashion. J. Cell. Physiol., 209: 560–567. doi: 10.1002/jcp.20772
- Issue published online: 29 AUG 2006
- Article first published online: 1 AUG 2006
- Manuscript Accepted: 26 JUN 2006
- Manuscript Received: 8 MAR 2006
- Austrian Science Fund (FWF). Grant Number: SFB F28
- Jubiläumsfonds der Oesterreichischen Nationalbank. Grant Number: OENB 10171
- Herzfelder'sche Familienstiftung
The development of hepatocellular carcinomas from malignant hepatocytes is frequently associated with intra- and peritumoral accumulation of connective tissue arising from activated hepatic stellate cells. For both tumorigenesis and hepatic fibrogenesis, transforming growth factor (TGF)-β signaling executes key roles and therefore is considered as a hallmark of these pathological events. By employing cellular transplantation we show that the interaction of neoplastic MIM-R hepatocytes with the tumor microenvironment, containing either activated hepatic stellate cells (M1-4HSCs) or myofibroblasts derived thereof (M-HTs), induces progression in malignancy. Cotransplantation of MIM-R hepatocytes with M-HTs yielded strongest MIM-R generated tumor formation accompanied by nuclear localization of Smad2/3 as well as of β-catenin. Genetic interference with TGF-β signaling by gain of antagonistic Smad7 in MIM-R hepatocytes diminished epithelial dedifferentiation and tumor progression upon interaction with M1-4HSCs or M-HTs. Further analysis showed that tumors harboring disrupted Smad signaling are devoid of nuclear β-catenin accumulation, indicating a crosstalk between TGF-β and β-catenin signaling. Together, these data demonstrate that activated HSCs and myofibroblasts directly govern hepatocarcinogenesis in a TGF-β dependent fashion by inducing autocrine TGF-β signaling and nuclear β-catenin accumulation in neoplastic hepatocytes. These results indicate that intervention with TGF-β signaling is highly promising in liver cancer therapy. J. Cell. Physiol. 209: 560–567, 2006. © 2006 Wiley-Liss, Inc.