title: Characterization of aldehyde dehydrogenase 1 high ovarian cancer cells: Towards targeted stem cell therapy.
abstract: The cancer stem cell (CSC) paradigm hypothesizes that successful clinical eradication of CSCs may lead to durable remission for patients with ovarian cancer. Despite mounting evidence in support of ovarian CSCs, their phenotype and clinical relevance remain unclear. We and others have found high aldehyde dehydrogenase 1 (ALDH(high)) expression in a variety of normal and malignant stem cells, and sought to better characterize ALDH(high) cells in ovarian cancer.
  
  
  
  We compared ALDH(high) to ALDH(low) cells in two ovarian cancer models representing distinct subtypes: FNAR-C1 cells, derived from a spontaneous rat endometrioid carcinoma, and the human SKOV3 cell line (described as both serous and clear cell subtypes). We assessed these populations for stem cell features then analyzed expression by microarray and qPCR.
  
  
  
  ALDH(high) cells displayed CSC properties, including: smaller size, quiescence, regenerating the phenotypic diversity of the cell lines in vitro, lack of contact inhibition, nonadherent growth, multi-drug resistance, and in vivo tumorigenicity. Microarray and qPCR analysis of the expression of markers reported by others to enrich for ovarian CSCs revealed that ALDH(high) cells of both models showed downregulation of CD24, but inconsistent expression of CD44, KIT and CD133. However, the following druggable targets were consistently expressed in the ALDH(high) cells from both models: mTOR signaling, her-2/neu, CD47 and FGF18/FGFR3.
  
  
  
  Based on functional characterization, ALDH(high) ovarian cancer cells represent an ovarian CSC population. Differential gene expression identified druggable targets that have the potential for therapeutic efficacy against ovarian CSCs from multiple subtypes.
authors.affiliation: Department of Pathology, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD, USA. Electronic address: acsharrow@gmail.com.
authors.forename: Allison C
authors.initials: AC
authors.lastname: Sharrow
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD, USA. Electronic address: bperkin6@jhmi.edu.
authors.forename: Brandy
authors.initials: B
authors.lastname: Perkins
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD, USA.
authors.forename: Michael I
authors.initials: MI
authors.lastname: Collector
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD, USA. Electronic address: Wyu8@jhmi.edu.
authors.forename: Wayne
authors.initials: W
authors.lastname: Yu
authors.affiliation: Departments of Pathology and Molecular & Comparative Pathobiology, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD, USA. Electronic address: bsimons3@jhmi.edu.
authors.forename: Brian W
authors.initials: BW
authors.lastname: Simons
authors.affiliation: Sidney Kimmel Comprehensive Cancer Center, Johns Hopkins University School of Medicine, 1650 Orleans St., Baltimore, MD, USA. Electronic address: rjjones@jhmi.edu.
authors.forename: Richard J
authors.initials: RJ
authors.lastname: Jones
mesh_terms: D000080924:Aldehyde Dehydrogenase 1 Family; D000445:Aldehyde Oxidoreductases / Q000096:biosynthesis* / Q000235:genetics; D000818:Animals; D048708:Cell Growth Processes / Q000502:physiology; D005260:Female; D006801:Humans; D058990:Molecular Targeted Therapy; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000201:enzymology* / Q000473:pathology*; D010051:Ovarian Neoplasms / Q000188:drug therapy / Q000201:enzymology* / Q000235:genetics / Q000473:pathology*; D051381:Rats; D011917:Rats, Inbred Lew; D050697:Retinal Dehydrogenase / Q000096:biosynthesis* / Q000235:genetics
chemical_list: D000445:Aldehyde Oxidoreductases; D000080924:Aldehyde Dehydrogenase 1 Family; C523119:Aldh1a1 protein, rat; D050697:Retinal Dehydrogenase; C038828:long-chain-aldehyde dehydrogenase
keywords: Aldehyde dehydrogenase 1; Cancer stem cells; Ovarian cancer; Stem cell-targeted therapy