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Label-retaining liver cancer cells are relatively resistant to sorafenib
  1. Hong-Wu Xin1,
  2. Chenwi M Ambe1,
  3. Danielle M Hari1,
  4. Gordon W Wiegand1,
  5. Tyler C Miller1,
  6. Jin-Qiu Chen2,
  7. Andrew J Anderson1,
  8. Satyajit Ray1,
  9. John E Mullinax1,
  10. Tomotake Koizumi1,
  11. Russell C Langan1,
  12. Douglas Burka1,
  13. Michelle A Herrmann2,
  14. Paul K Goldsmith2,
  15. Alexander Stojadinovic3,4,
  16. Udo Rudloff1,
  17. Snorri S Thorgeirsson5,
  18. Itzhak Avital1,4,6
  1. 1Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  2. 2Collaborative Protein Technology Resource, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  3. 3Department of Surgery, Division of Surgical Oncology, Walter Reed National Military Medical Center, Bethesda, Maryland, USA
  4. 4Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, Maryland, USA
  5. 5Laboratory for Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, Maryland, USA
  6. 6Bon Secours Cancer Institute, Richmond, Virginia, USA
  1. Correspondence to Dr Snorri S Thorgeirsson, Center of Excellence in Integrative Cancer Biology and Genomics, Laboratory of Experimental Carcinogenesis, Center for Cancer Research, National Cancer Institute, NIH, 37 Convent Drive MSC 4262, Building 37, Room 4146A, Bethesda, MD 20892-4262, USA; snorri_thorgeirsson{at}nih.gov; Dr Itzhak Avital, Bon Secours Cancer Institute, 6605 West Broad Street, Richmond, VA 23230, USA; itzhak.avital{at}gmail.com

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.

  • Cancer
  • Cell Proliferation
  • Drug Resistance
  • Hepatocellular Carcinoma
  • Stem Cells

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