title: A human model of epithelial to mesenchymal transition to monitor drug efficacy in hepatocellular carcinoma progression.
abstract: The epithelial to mesenchymal transition (EMT) of malignant hepatocytes is a crucial event in hepatocellular carcinoma (HCC) progression and recurrence. We aimed to establish a human model of EMT to examine drug efficacy and specificity in HCC progression. Human HCC cell populations were characterized by immunofluorescence analysis, migration and invasion assays, array comparative genomic hybridization, whole-genome expression profiling, and promoter methylation. Therapeutic agents clinically used against HCC were examined for efficacy by determination of IC(50) values. We show that liver cancer cell lines exhibited either an epithelial or mesenchymal phenotype of which the latter showed strong migratory and invasive abilities in vitro. The common cellular origin of both cell types indicated that mesenchymal HCC cells have been derived from epithelial hepatocytes through EMT in the HCC patient. Drug exposure of mesenchymal HCC cells showed higher resistance to the targeted therapeutic agents sorafenib and erlotinib as compared to epithelial HCC cells, which were slightly more resistant to cytostatic drugs. Most remarkably, combined treatment with doxorubicin and sorafenib caused increased susceptibility of both HCC cell types resulting in enhanced drug efficacy. Taken together, this EMT model of human HCC allows the identification of molecular mechanisms and the assessment of therapeutic drug efficacy during liver cancer progression in preclinical studies.
authors.affiliation: Department of Medicine I, Division: Institute of Cancer Research, Comprehensive Cancer Center, Medical University of Vienna, Borschkegasse 8a, 1090 Vienna, Austria.
authors.forename: Franziska
authors.initials: F
authors.lastname: van Zijl
authors.forename: Sabine
authors.initials: S
authors.lastname: Mall
authors.forename: Georg
authors.initials: G
authors.lastname: Machat
authors.forename: Christine
authors.initials: C
authors.lastname: Pirker
authors.forename: Robert
authors.initials: R
authors.lastname: Zeillinger
authors.forename: Andreas
authors.initials: A
authors.lastname: Weinhaeusel
authors.forename: Martin
authors.initials: M
authors.lastname: Bilban
authors.forename: Walter
authors.initials: W
authors.lastname: Berger
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Mikulits
mesh_terms: D000970:Antineoplastic Agents / Q000494:pharmacology*; D006528:Carcinoma, Hepatocellular / Q000503:physiopathology*; D045744:Cell Line, Tumor; D002465:Cell Movement; D002471:Cell Transformation, Neoplastic / Q000187:drug effects* / Q000378:metabolism; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics; D018450:Disease Progression; D004354:Drug Screening Assays, Antitumor / Q000379:methods*; D004847:Epithelial Cells / Q000187:drug effects / Q000473:pathology*; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000503:physiopathology*; D008297:Male; D008648:Mesoderm / Q000187:drug effects / Q000473:pathology*; D018895:Microsatellite Repeats / Q000235:genetics; D008875:Middle Aged; D015676:Osteonectin / Q000235:genetics / Q000378:metabolism; D010641:Phenotype
chemical_list: D000970:Antineoplastic Agents; D015676:Osteonectin