Abstracts Poster Abstracts - Dr Falk

92Activated hepatic stellate cells and myofibroblasts accelerateTGF-beta dependent tumor progression of hepatocytes in a dualtransplantation modelVerena Pröll, Mario Mikula and Wolfgang MikulitsDepartment of Medicine I, Division: Institute of Cancer Research, Medical University ofVienna, Borschke-Gasse 8a, A-1090 Vienna, AustriaIntroduction: The progression of hepatocellular carcinomas (HCCs) derived fromparenchymal hepatocytes is almost exclusively accompanied by the intra- andperitumoral accumulation of connective tissue known as fibrosis. For both hepatictumorigenesis and fibrogenesis, transforming growth factor (TGF)-beta executes a keyrole and thus represent a hallmark in these pathophysiological events.Methods: Making use of a dual transplantation model we investigated that theinteraction of the fibrotic tumor microenvironment, containing either non-tumorigenicactivated hepatic stellate cells (HSCs) or HSC-derived myofibroblasts (MFBs), togetherwith neoplastic MIM-R hepatocytes.Results: Co-transplantation of HSCs or MFBs with MIM-R hepatocytes drasticallyaccelerates their progression in malignancy. Contrary to carcinomas derived fromco-inoculated HSCs and MIM-R cells, co-transplantation of MFBs with aberrant MIM-Rhepatocytes yielded strongest tumor formation along with undifferentiated canceroustissue displaying constitutive TGF-beta signaling and nuclear localization of $-cateninin hepatocytes. Genetic interference of TGF-beta signaling through expression ofinhibitory Smad7 in MIM-R hepatocytes revealed that dual transplantation of these cellswith TGF-beta1 secreting MFBs fails to enforce tumor progression. Functional analysisof experimental tumors further showed that their reduced malignancy due to disruptedSmad signaling was devoid of nuclear beta-catenin accumulation.Discussion/Conclusion: Together these data provide direct evidence that HSC, andto a larger extant, MFBs are capable to govern late stage carcinogenesis of hepatocytesin a paracrine fashion which might ultimately lead to the fatal autocrine regulation ofTGF-beta signaling observed in HCCs.