title: High ALDH activity identifies chemotherapy-resistant Ewing's sarcoma stem cells that retain sensitivity to EWS-FLI1 inhibition.
abstract: BACKGROUND
  Cancer stem cells are a chemotherapy-resistant population capable of self-renewal and of regenerating the bulk tumor, thereby causing relapse and patient death. Ewing's sarcoma, the second most common form of bone tumor in adolescents and young adults, follows a clinical pattern consistent with the Cancer Stem Cell model - remission is easily achieved, even for patients with metastatic disease, but relapse remains frequent and is usually fatal.
  
  
  RESULTS
  We have isolated a subpopulation of Ewing's sarcoma cells, from both human cell lines and human xenografts grown in immune deficient mice, which express high aldehyde dehydrogenase (ALDH(high)) activity and are enriched for clonogenicity, sphere-formation, and tumor initiation. The ALDH(high) cells are resistant to chemotherapy in vitro, but this can be overcome by the ATP binding cassette transport protein inhibitor, verapamil. Importantly, these cells are not resistant to YK-4-279, a small molecule inhibitor of EWS-FLI1 that is selectively toxic to Ewing's sarcoma cells both in vitro and in vivo.
  
  
  CONCLUSIONS
  Ewing's sarcoma contains an ALDH(high) stem-like population of chemotherapy-resistant cells that retain sensitivity to EWS-FLI1 inhibition. Inhibiting the EWS-FLI1 oncoprotein may prove to be an effective means of improving patient outcomes by targeting Ewing's sarcoma stem cells that survive standard chemotherapy.
authors.affiliation: Division of Pediatric Oncology, Department of Oncology, Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University, Baltimore, Maryland, United States of America.
authors.forename: Ola
authors.initials: O
authors.lastname: Awad
authors.forename: Jason T
authors.initials: JT
authors.lastname: Yustein
authors.forename: Preeti
authors.initials: P
authors.lastname: Shah
authors.forename: Naheed
authors.initials: N
authors.lastname: Gul
authors.forename: Varalakshmi
authors.initials: V
authors.lastname: Katuri
authors.forename: Alison
authors.initials: A
authors.lastname: O'Neill
authors.forename: Yali
authors.initials: Y
authors.lastname: Kong
authors.forename: Milton L
authors.initials: ML
authors.lastname: Brown
authors.forename: Jeffrey A
authors.initials: JA
authors.lastname: Toretsky
authors.forename: David M
authors.initials: DM
authors.lastname: Loeb
mesh_terms: D000444:Aldehyde Dehydrogenase / Q000378:metabolism*; D000818:Animals; D000970:Antineoplastic Agents / Q000494:pharmacology; D002121:Calcium Channel Blockers / Q000494:pharmacology; D045744:Cell Line, Tumor; D049109:Cell Proliferation / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D004317:Doxorubicin / Q000494:pharmacology; D019008:Drug Resistance, Neoplasm / Q000187:drug effects; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D053631:Interleukin Receptor Common gamma Subunit / Q000235:genetics / Q000378:metabolism; D051379:Mice; D016688:Mice, Inbred NOD; D018345:Mice, Knockout; D016513:Mice, SCID; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism / Q000473:pathology*; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism*; D051789:Proto-Oncogene Protein c-fli-1 / Q000235:genetics / Q000378:metabolism*; D034802:RNA-Binding Protein EWS; D020133:Reverse Transcriptase Polymerase Chain Reaction; D012512:Sarcoma, Ewing / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology*; D012513:Sarcoma, Experimental / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D018874:Spheroids, Cellular / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D014183:Transplantation, Heterologous; D014700:Verapamil / Q000494:pharmacology
chemical_list: D000970:Antineoplastic Agents; D002121:Calcium Channel Blockers; C106031:EWS-FLI fusion protein; D053631:Interleukin Receptor Common gamma Subunit; D015514:Oncogene Proteins, Fusion; D051789:Proto-Oncogene Protein c-fli-1; D034802:RNA-Binding Protein EWS; D004317:Doxorubicin; D014700:Verapamil; D000444:Aldehyde Dehydrogenase