Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth

Hannah van Malenstein; Jeroen Dekervel; Chris Verslype; Eric Van Cutsem; Petra Windmolders; Frederik Nevens; Jos van Pelt

doi:10.1016/j.canlet.2012.10.021

Long-term exposure to sorafenib of liver cancer cells induces resistance with epithelial-to-mesenchymal transition, increased invasion and risk of rebound growth

Cancer Lett. 2013 Feb 1;329(1):74-83. doi: 10.1016/j.canlet.2012.10.021. Epub 2012 Oct 27.

Authors

Hannah van Malenstein¹, Jeroen Dekervel, Chris Verslype, Eric Van Cutsem, Petra Windmolders, Frederik Nevens, Jos van Pelt

Affiliation

¹ Liver Research Facility / Labo Hepatology, Faculty of Medicine, University Hospitals Leuven, KU Leuven, Belgium.

PMID: 23111106
DOI: 10.1016/j.canlet.2012.10.021

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Anilides / pharmacology
Antineoplastic Agents / pharmacology*
Cadherins / metabolism
Carcinoma, Hepatocellular / drug therapy*
Carcinoma, Hepatocellular / genetics
Carcinoma, Hepatocellular / metabolism
Carcinoma, Hepatocellular / pathology
Cell Line, Tumor
Chromones / pharmacology
Drug Resistance, Neoplasm*
Epithelial-Mesenchymal Transition / drug effects*
Gene Expression Regulation, Neoplastic / drug effects
Humans
Keratin-19 / metabolism
Liver Neoplasms / drug therapy*
Liver Neoplasms / genetics
Liver Neoplasms / metabolism
Liver Neoplasms / pathology*
Morpholines / pharmacology
Niacinamide / analogs & derivatives*
Niacinamide / pharmacology
Phenylurea Compounds / pharmacology*
Proto-Oncogene Proteins c-akt / antagonists & inhibitors
Proto-Oncogene Proteins c-akt / metabolism
Pyridines / pharmacology
Sorafenib
Vimentin / metabolism

Substances

Anilides
Antineoplastic Agents
Cadherins
Chromones
HhAntag691
Keratin-19
Morpholines
Phenylurea Compounds
Pyridines
Vimentin
Niacinamide
2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one
Sorafenib
Proto-Oncogene Proteins c-akt