title: Label-retaining liver cancer cells are relatively resistant to sorafenib.
abstract: 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.
authors: Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, , Bethesda, Maryland, USA.
authors: Hong-Wu
authors: HW
authors: Xin
authors: Chenwi M
authors: CM
authors: Ambe
authors: Danielle M
authors: DM
authors: Hari
authors: Gordon W
authors: GW
authors: Wiegand
authors: Tyler C
authors: TC
authors: Miller
authors: Jin-Qiu
authors: JQ
authors: Chen
authors: Andrew J
authors: AJ
authors: Anderson
authors: Satyajit
authors: S
authors: Ray
authors: John E
authors: JE
authors: Mullinax
authors: Tomotake
authors: T
authors: Koizumi
authors: Russell C
authors: RC
authors: Langan
authors: Douglas
authors: D
authors: Burka
authors: Michelle A
authors: MA
authors: Herrmann
authors: Paul K
authors: PK
authors: Goldsmith
authors: Alexander
authors: A
authors: Stojadinovic
authors: Udo
authors: U
authors: Rudloff
authors: Snorri S
authors: SS
authors: Thorgeirsson
authors: Itzhak
authors: I
authors: Avital
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use*; D017209:Apoptosis / Q000187:drug effects; D006528:Carcinoma, Hepatocellular / Q000188:drug therapy*; D045744:Cell Line, Tumor / Q000166:cytology / Q000187:drug effects; D019008:Drug Resistance, Neoplasm; D048049:Extracellular Signal-Regulated MAP Kinases / Q000378:metabolism; D020869:Gene Expression Profiling; D006801:Humans; D008113:Liver Neoplasms / Q000188:drug therapy*; D009536:Niacinamide / Q000031:analogs & derivatives* / Q000627:therapeutic use; D051058:Oncogene Protein v-akt / Q000378:metabolism; D010671:Phenylurea Compounds / Q000627:therapeutic use*; D060888:Real-Time Polymerase Chain Reaction; D000077157:Sorafenib; D013234:Stem Cells / Q000187:drug effects
chemical_list: D000970:Antineoplastic Agents; D010671:Phenylurea Compounds; D009536:Niacinamide; D000077157:Sorafenib; D051058:Oncogene Protein v-akt; D048049:Extracellular Signal-Regulated MAP Kinases
keywords: Cancer; Cell Proliferation; Drug Resistance; Hepatocellular Carcinoma; Stem Cells