Journal Article

Label-retaining liver cancer cells are relatively resistant to sorafenib

Thorgeirsson, Snorri S, Xin, Hong-Wu, Koizumi, Tomotake, Ambe, Chenwi M, Burka, Douglas, Rudloff, Udo, Avital, Itzhak, Hari, Danielle M, Ray, Satyajit, Miller, Tyler C, Herrmann, Michelle A, Goldsmith, Paul K, Chen, Jin-Qiu, Wiegand, Gordon W, Anderson, Andrew J, Langan, Russell C, Stojadinovic, Alexander, Mullinax, John E

2013

Overview

Objective The standard therapy for advanced hepatocellular carcinoma (HCC) is sorafenib, with most patients experiencing disease progression within 6 months. Label-retaining cancer cells (LRCC) represent a novel subpopulation of cancer stem cells (CSC). The objective was to test whether LRCC are resistant to sorafenib. Methods We tested human HCC derived LRCC and non-LRCC before and after treatment with sorafenib. Results LRCC derived from human HCC are relatively resistant to sorafenib. The proportion of LRCC in HCC cell lines is increased after sorafenib while the general population of cancer cells undergoes growth suppression. We show that LRCC demonstrate improved viability and toxicity profiles, and reduced apoptosis, over non-LRCC. We show that after treatment with sorafenib, LRCC upregulate the CSC marker aldehyde dehydrogenase 1 family, wingless-type MMTV-integration-site family, cell survival and proliferation genes, and downregulate apoptosis, cell cycle arrest, cell adhesion and stem cells differentiation genes. This phenomenon was accompanied by non-uniform activation of specific isoforms of the sorafenib target proteins extracellular-signal-regulated kinases and v-akt-murine-thymoma-viral-oncogene homologue (AKT) in LRCC but not in non-LRCC. A molecular pathway map for sorafenib treated LRCC is proposed. Conclusions Our results suggest that HCC derived LRCC are relatively resistant to sorafenib. Since LRCC can generate tumours with as few as 10 cells, our data suggest a potential role for these cells in disease recurrence. Further investigation of this phenomenon might provide novel insights into cancer biology, cancer recurrence and drug resistance with important implications for the development of novel cancer therapies based on targeting LRCC.

• Publisher: BMJ Publishing Group Ltd and British Society of Gastroenterology,BMJ Publishing Group LTD
• Subject: Antineoplastic Agents - therapeutic use / Apoptosis / Apoptosis - drug effects / Autophagy / Cancer / Cancer therapies / Carcinoma, Hepatocellular - drug therapy / Cell adhesion & migration / Cell cycle / Cell division / Cell Line, Tumor - cytology / Cell Line, Tumor - drug effects / Cell Proliferation / Cyclin-dependent kinases / Cytochrome / Cytoplasm / Drug Resistance / Drug Resistance, Neoplasm / Extracellular Signal-Regulated MAP Kinases - metabolism / Gene expression / Gene Expression Profiling / Hepatocellular Carcinoma / Humans / Hypotheses / Hypoxia / Kinases / Liver cancer / Liver Neoplasms - drug therapy / Metabolism / Metastasis / Niacinamide - analogs & derivatives / Niacinamide - therapeutic use / Oncogene Protein v-akt - metabolism / Phenylurea Compounds - therapeutic use / Polypeptides / Proteins / Real-Time Polymerase Chain Reaction / Sorafenib / Stem Cells / Stem Cells - drug effects / Stress response