title: Enhanced regulation of cell cycle and suppression of osteoblast differentiation molecular signatures by prostate cancer stem-like holoclones.
abstract: OBJECTIVE
  Targeting the stem cell properties of tumor-initiating cells is an avenue through which cancer treatment may be improved. Before this can be achieved, so-called 'cancer stem cell' (CSC) models must be developed and characterized in specific malignancies.
  
  
  METHODS
  In this study, holoclone formation assays were used to characterise stem-like molecular signatures in prostate cancer (PCa) cells.
  
  
  RESULTS
  LNCaP and PC3 parent cells were capable of responding to stem cell differentiation morphogen retinoic acid (RA), suggesting the presence of inherent stem-like properties. LNCaP cells, which represent early, androgen-responsive disease, formed holoclones after twenty six days. PC3 cells, which represent advanced, metastatic, castration-resistant disease, formed holoclones after only six days. Holoclones displayed decreased expression of RA-genes, suggesting a more immature, less differentiated phenotype. Gene and microRNA arrays demonstrated that holoclones downregulated a number of stem cell differentiation regulators while displaying enhanced regulation of G2 to M transition and the mitotic spindle checkpoint components of the cell cycle. PC3 holoclones displayed pronounced downregulation of known regulators of osteoblast differentiation from mesenchymal stem cells and Epithelial Mesenchymal Transition.
  
  
  CONCLUSIONS
  Our results suggest that some PCa cells retain the ability to transition to a more immature state in which differentiation and metastatic mechanisms are suppressed. The highlighting of osteoblast differentiation regulators in this mechanism is particularly notable, considering the propensity of PCa to metastasise to bone.
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: Michael F
authors.initials: MF
authors.lastname: Gallagher
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: Yvonne
authors.initials: Y
authors.lastname: Salley
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: Cathy D
authors.initials: CD
authors.lastname: Spillane
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: Brendan
authors.initials: B
authors.lastname: Ffrench
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: Salah
authors.initials: S
authors.lastname: El Baruni
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland.
authors.forename: Gordon
authors.initials: G
authors.lastname: Blacksheilds
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland.
authors.forename: Paul
authors.initials: P
authors.lastname: Smyth
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: Cara
authors.initials: C
authors.lastname: Martin
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland.
authors.forename: Orla
authors.initials: O
authors.lastname: Sheils
authors.affiliation: School of Medicine and Medical Science, Conway Institute, University College Dublin, Dublin 4, Ireland.
authors.forename: William
authors.initials: W
authors.lastname: Watson
authors.affiliation: Department of Histopathology, Central Pathology Laboratory, University of Dublin, Trinity College, St James Hospital, Dublin 8, Ireland Pathology Department, Coombe Women's and Infants University Hospital, Dublin 8, Ireland.
authors.forename: John J
authors.initials: JJ
authors.lastname: O'Leary
mesh_terms: D002453:Cell Cycle / Q000502:physiology; D002454:Cell Differentiation / Q000502:physiology*; D045744:Cell Line, Tumor; D006801:Humans; D008297:Male; D014411:Neoplastic Stem Cells / Q000378:metabolism / Q000473:pathology*; D020411:Oligonucleotide Array Sequence Analysis; D010006:Osteoblasts / Q000166:cytology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D059467:Transcriptome
keywords: CANCER STEM CELLS; METASTASIS; PROSTATE