title: Cathepsin D acts as an essential mediator to promote malignancy of benign prostatic epithelium.
abstract: BACKGROUND
  Stromal-epithelial interactions are important in both development and prostate cancer. Stromal changes have been shown to be powerful prognostic indicators of prostate cancer progression and of patient death helping to define lethal versus indolent phenotypes. The specific molecular underpinnings of these interactions are incompletely understood. We investigated whether stromal cathepsin D (CathD) overexpression affects prostate tumorigenesis through a paracrine mechanism.
  
  
  METHODS
  Normal prostate fibroblasts (NPF) were retrovirally transduced to overexpress cyclin D1 (CD1) and were designated NPF(CD1) . Cathepsin D expression was knocked down using shRNA in cancer associated fibroblasts (CAF) and NPF(CD1) . We analyzed these stromal cell lines using immunohistochemistry, Western blot, and tissue recombination.
  
  
  RESULTS
  An examination of human prostate tissue revealed significantly increased stromal staining of CathD in malignant prostate tissue. Overexpression of CD1 in normal prostate fibroblasts (NPF(CD1) ) produced a phenotype similar to, but more moderate than, CAF in a tissue recombination model. Knockdown studies revealed that CathD is required for NPF(CD1) motility and invasive growth in vitro. BPH-1 cell proliferation was found to be induced when cultured with NPF(CD1) conditioned medium, this effect was inhibited when CathD was knocked down in NPF(CD1) cells. Overexpression of CathD in prostate stromal cells induced malignancy in adjacent epithelium, and this transformation was inhibited when stromal CathD expression was knocked down in CAF.
  
  
  CONCLUSIONS
  The study presented here demonstrates increased CathD expression is seen in human CAF. The upregulation of CD1 results in concomitant increases in CathD expression. Elevated CathD expression in the stroma contributes to tumor promotion.
authors.affiliation: Department of Cancer Biology, Vanderbilt University Medical Center, Nashville, Tennessee 37232-2765, USA.
authors.forename: Freddie L
authors.initials: FL
authors.lastname: Pruitt
authors.forename: Yue
authors.initials: Y
authors.lastname: He
authors.forename: Omar E
authors.initials: OE
authors.lastname: Franco
authors.forename: Ming
authors.initials: M
authors.lastname: Jiang
authors.forename: Justin M
authors.initials: JM
authors.lastname: Cates
authors.forename: Simon W
authors.initials: SW
authors.lastname: Hayward
mesh_terms: D018949:Antigens, CD1 / Q000235:genetics / Q000378:metabolism; D002402:Cathepsin D / Q000235:genetics* / Q000378:metabolism; D002460:Cell Line; D002465:Cell Movement / Q000502:physiology; D002471:Cell Transformation, Neoplastic / Q000235:genetics / Q000378:metabolism*; D004847:Epithelial Cells / Q000166:cytology / Q000502:physiology; D005347:Fibroblasts / Q000166:cytology / Q000502:physiology; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D006801:Humans; D008297:Male; D019899:Paracrine Communication / Q000502:physiology; D011467:Prostate / Q000166:cytology / Q000502:physiology*; D011470:Prostatic Hyperplasia / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D011471:Prostatic Neoplasms / Q000235:genetics / Q000473:pathology / Q000503:physiopathology*; D034741:RNA, Small Interfering / Q000235:genetics; D017154:Stromal Cells / Q000166:cytology / Q000502:physiology; D015854:Up-Regulation / Q000502:physiology
chemical_list: D018949:Antigens, CD1; D034741:RNA, Small Interfering; C533922:CTSD protein, human; D002402:Cathepsin D