title: Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth.
abstract: Sorafenib leads to a survival benefit in patients with advanced hepatocellular carcinoma but its use is hampered by the occurrence of drug resistance. To investigate the molecular mechanisms involved we developed five resistant human liver cell lines in which we studied morphology, gene expression and invasive potential. The cells changed their appearance, lost E-cadherin and KRT19 and showed high expression of vimentin, indicating epithelial-to-mesenchymal transition. Resistant cells showed reduced adherent growth, became more invasive and lost liver-specific gene expression. Furthermore, following withdrawal of sorafenib, the resistant cells showed rebound growth, a phenomenon also found in patients. This cell model was further used to investigate strategies for restoration of sensitivity to sorafenib.
authors.affiliation: Liver Research Facility / Labo Hepatology, Faculty of Medicine, University Hospitals Leuven, KU Leuven, Belgium.
authors.forename: Hannah
authors.initials: H
authors.lastname: van Malenstein
authors.forename: Jeroen
authors.initials: J
authors.lastname: Dekervel
authors.forename: Chris
authors.initials: C
authors.lastname: Verslype
authors.forename: Eric
authors.initials: E
authors.lastname: Van Cutsem
authors.forename: Petra
authors.initials: P
authors.lastname: Windmolders
authors.forename: Frederik
authors.initials: F
authors.lastname: Nevens
authors.forename: Jos
authors.initials: J
authors.lastname: van Pelt
mesh_terms: D000813:Anilides / Q000494:pharmacology; D000970:Antineoplastic Agents / Q000494:pharmacology*; D015820:Cadherins / Q000378:metabolism; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology; D045744:Cell Line, Tumor; D002867:Chromones / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm; D058750:Epithelial-Mesenchymal Transition / Q000187:drug effects*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D053539:Keratin-19 / Q000378:metabolism; D008113:Liver Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D009025:Morpholines / Q000494:pharmacology; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000494:pharmacology; D010671:Phenylurea Compounds / Q000494:pharmacology*; D051057:Proto-Oncogene Proteins c-akt / Q000037:antagonists & inhibitors / Q000378:metabolism; D011725:Pyridines / Q000494:pharmacology; D000077157:Sorafenib; D014746:Vimentin / Q000378:metabolism
chemical_list: D000813:Anilides; D000970:Antineoplastic Agents; D015820:Cadherins; D002867:Chromones; C538724:HhAntag691; D053539:Keratin-19; D009025:Morpholines; D010671:Phenylurea Compounds; D011725:Pyridines; D014746:Vimentin; D009536:Niacinamide; C085911:2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one; D000077157:Sorafenib; D051057:Proto-Oncogene Proteins c-akt