Activated hepatic stellate cells induce tumor progression of neoplastic hepatocytes in a TGF-beta dependent fashion.
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)-beta 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 beta-catenin. Genetic interference with TGF-beta 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 beta-catenin accumulation, indicating a crosstalk between TGF-beta and beta-catenin signaling. Together, these data demonstrate that activated HSCs and myofibroblasts directly govern hepatocarcinogenesis in a TGF-beta dependent fashion by inducing autocrine TGF-beta signaling and nuclear beta-catenin accumulation in neoplastic hepatocytes. These results indicate that intervention with TGF-beta signaling is highly promising in liver cancer therapy.
Mikula
M
M
Department of Medicine I, Division: Institute of Cancer Research, Medical University of Vienna, Vienna, Austria.
Proell
V
V
Fischer
A N M
AN
Mikulits
W
W
D000818:Animals; D002448:Cell Adhesion / Q000187:drug effects; D002467:Cell Nucleus / Q000378:metabolism; D017690:Cell Transplantation; D018450:Disease Progression; D005347:Fibroblasts / Q000187:drug effects; D005355:Fibrosis; D022781:Hepatocytes / Q000187:drug effects* / Q000473:pathology*; D006801:Humans; D008113:Liver Neoplasms / Q000473:pathology*; D051379:Mice; D008954:Models, Biological; D019899:Paracrine Communication / Q000187:drug effects; D051381:Rats; D015398:Signal Transduction / Q000187:drug effects; D051899:Smad2 Protein / Q000378:metabolism; D051900:Smad3 Protein / Q000378:metabolism; D051906:Smad7 Protein / Q000378:metabolism; D016212:Transforming Growth Factor beta / Q000494:pharmacology*; D051176:beta Catenin / Q000378:metabolism
D051899:Smad2 Protein; D051900:Smad3 Protein; D051906:Smad7 Protein; D016212:Transforming Growth Factor beta; D051176:beta Catenin