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

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• 作者：Hannah van Malenstein^a ; Jeroen Dekervel^a ; Chris Verslype^a ; ^b ; Eric Van Cutsem^b ; Petra Windmolders^a ; Frederik Nevens^a ; Jos van Pelt^a ; ^{jos.vanpelt@med.kuleuven.be}
• 关键词：¦¤log ; (2log fold change) ; ACTB ; ¦Â-actin ; ATCC ; American type culture collection ; BCLC ; Barcelona Clinic Liver Cancer ; BrdU ; bromodeoxyuridine ; CDH1 ; E-cadherin ; DAVID ; database for Annotation ; Visualization and Integrated Discovery ; EMT ; epithelial-to-m
• 刊名：Cancer Letters
• 出版年：2013
• 出版时间：1 February, 2013
• 年：2013
• 卷：329
• 期：1
• 页码：74-83
• 全文大小：1134 K

文摘

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.