title: Stem cell pathways contribute to clinical chemoresistance in ovarian cancer.
abstract: OBJECTIVE
  Within heterogeneous tumors, subpopulations often labeled cancer stem cells (CSC) have been identified that have enhanced tumorigenicity and chemoresistance in ex vivo models. However, whether these populations are more capable of surviving chemotherapy in de novo tumors is unknown.
  
  
  METHODS
  We examined 45 matched primary/recurrent tumor pairs of high-grade ovarian adenocarcinomas for expression of CSC markers ALDH1A1, CD44, and CD133 using immunohistochemistry. Tumors collected immediately after completion of primary therapy were then laser capture microdissected and subjected to a quantitative PCR array examining stem cell biology pathways (Hedgehog, Notch, TGF-β, and Wnt). Select genes of interest were validated as important targets using siRNA-mediated downregulation.
  
  
  RESULTS
  Primary samples were composed of low densities of ALDH1A1, CD44, and CD133. Tumors collected immediately after primary therapy were more densely composed of each marker, whereas samples collected at first recurrence, before initiating secondary therapy, were composed of similar percentages of each marker as their primary tumor. In tumors collected from recurrent platinum-resistant patients, only CD133 was significantly increased. Of stem cell pathway members examined, 14% were significantly overexpressed in recurrent compared with matched primary tumors. Knockdown of genes of interest, including endoglin/CD105 and the hedgehog mediators Gli1 and Gli2, led to decreased ovarian cancer cell viability, with Gli2 showing a novel contribution to cisplatin resistance.
  
  
  CONCLUSIONS
  These data indicate that ovarian tumors are enriched with CSCs and stem cell pathway mediators, especially at the completion of primary therapy. This suggests that stem cell subpopulations contribute to tumor chemoresistance and ultimately recurrent disease.
authors.affiliation: Department of Obstetrics, University of Alabama at Birmingham, Birmingham, Alabama 35294, USA.
authors.forename: Adam D
authors.initials: AD
authors.lastname: Steg
authors.forename: Kerri S
authors.initials: KS
authors.lastname: Bevis
authors.forename: Ashwini A
authors.initials: AA
authors.lastname: Katre
authors.forename: Angela
authors.initials: A
authors.lastname: Ziebarth
authors.forename: Zachary C
authors.initials: ZC
authors.lastname: Dobbin
authors.forename: Ronald D
authors.initials: RD
authors.lastname: Alvarez
authors.forename: Kui
authors.initials: K
authors.lastname: Zhang
authors.forename: Michael
authors.initials: M
authors.lastname: Conner
authors.forename: Charles N
authors.initials: CN
authors.lastname: Landen
mesh_terms: D000071916:AC133 Antigen; D000230:Adenocarcinoma / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D000444:Aldehyde Dehydrogenase / Q000032:analysis / Q000096:biosynthesis; D000080924:Aldehyde Dehydrogenase 1 Family; D015703:Antigens, CD / Q000032:analysis / Q000096:biosynthesis / Q000235:genetics; D000970:Antineoplastic Agents / Q000627:therapeutic use; D015153:Blotting, Western; D019008:Drug Resistance, Neoplasm / Q000502:physiology*; D000071063:Endoglin; D005260:Female; D020869:Gene Expression Profiling; D006023:Glycoproteins / Q000032:analysis / Q000096:biosynthesis; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis / Q000096:biosynthesis; D007150:Immunohistochemistry; D051741:Kruppel-Like Transcription Factors / Q000096:biosynthesis / Q000235:genetics; D061346:Laser Capture Microdissection; D009364:Neoplasm Recurrence, Local / Q000378:metabolism; D014411:Neoplastic Stem Cells / Q000378:metabolism* / Q000473:pathology; D009687:Nuclear Proteins / Q000096:biosynthesis / Q000235:genetics; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D010455:Peptides / Q000032:analysis; D011956:Receptors, Cell Surface / Q000096:biosynthesis / Q000235:genetics; D050697:Retinal Dehydrogenase; D020133:Reverse Transcriptase Polymerase Chain Reaction; D015398:Signal Transduction / Q000502:physiology*; D000075746:Zinc Finger Protein Gli2
chemical_list: D000071916:AC133 Antigen; D015703:Antigens, CD; D000970:Antineoplastic Agents; C064206:ENG protein, human; D000071063:Endoglin; C082593:GLI2 protein, human; D006023:Glycoproteins; D018960:Hyaluronan Receptors; D051741:Kruppel-Like Transcription Factors; D009687:Nuclear Proteins; C000606023:PROM1 protein, human; D010455:Peptides; D011956:Receptors, Cell Surface; D000075746:Zinc Finger Protein Gli2; D000080924:Aldehyde Dehydrogenase 1 Family; D000444:Aldehyde Dehydrogenase; C510223:ALDH1A1 protein, human; D050697:Retinal Dehydrogenase