title: Inhibition of endogenous SPARC enhances pancreatic cancer cell growth: modulation by FGFR1-III isoform expression.
abstract: BACKGROUND
  Secreted protein acidic and rich in cysteine (SPARC) is a multi-faceted protein-modulating cell-cell and cell-matrix interactions. In cancer, SPARC can be not only associated with a highly aggressive phenotype, but also acts as a tumour suppressor. The aim of this study was to characterise the function of SPARC and its modulation by fibroblast growth factor receptor (FGFR) 1 isoforms in pancreatic ductal adenocarcinoma (PDAC).
  
  
  RESULTS
  Exogenous SPARC inhibited growth, movement, and migration. ShRNA inhibition of endogenous SPARC in ASPC-1 and PANC-1 cells resulted in increased anchorage-dependent and -independent growth, transwell migration, and xenograft growth as well as increased mitogenic efficacy of fibroblast growth factor (FGF) 1 and FGF2. Endogenous SPARC expression in PANC-1 cells was increased in FGFR1-IIIb over-expressing cells, but decreased in FGFR1-IIIc over-expressing cells. The up-regulation of endogenous SPARC was abrogated by the p38-mitogen-activated protein kinase inhibitor SB203580. SPARC was detectable in conditioned medium of pancreatic stellate cells (PSCs), but not PDAC cells. Conditioned medium of PDAC cells reduced endogenous SPARC expression of PSCs.
  
  
  CONCLUSIONS
  Endogenous SPARC inhibits the malignant phenotype of PDAC cells and may, therefore, act as a tumour suppressor in PDAC. Endogenous SPARC expression can be modulated by FGFR1-III isoform expression. In addition, PDAC cells may inhibit endogenous SPARC expression in surrounding PSCs by paracrine actions.
authors.affiliation: Clinic of General, Visceral, and Transplantation Surgery, University of Ulm, Steinhoevelstrasse 9, Ulm 89075, Germany.
authors.forename: G
authors.initials: G
authors.lastname: Chen
authors.forename: X
authors.initials: X
authors.lastname: Tian
authors.forename: Z
authors.initials: Z
authors.lastname: Liu
authors.forename: S
authors.initials: S
authors.lastname: Zhou
authors.forename: B
authors.initials: B
authors.lastname: Schmidt
authors.forename: D
authors.initials: D
authors.lastname: Henne-Bruns
authors.forename: M
authors.initials: M
authors.lastname: Bachem
authors.forename: M
authors.initials: M
authors.lastname: Kornmann
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D002455:Cell Division / Q000502:physiology; D045744:Cell Line, Tumor / Q000187:drug effects / Q000378:metabolism; D002465:Cell Movement / Q000502:physiology; D017077:Culture Media, Conditioned / Q000494:pharmacology; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects / Q000502:physiology*; D006801:Humans; D007093:Imidazoles / Q000494:pharmacology; D009363:Neoplasm Proteins / Q000037:antagonists & inhibitors / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D015676:Osteonectin / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D010190:Pancreatic Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D019899:Paracrine Communication; D010641:Phenotype; D020033:Protein Isoforms / Q000235:genetics / Q000502:physiology; D011725:Pyridines / Q000494:pharmacology; D051496:Receptor, Fibroblast Growth Factor, Type 1 / Q000235:genetics / Q000502:physiology*; D011993:Recombinant Fusion Proteins / Q000502:physiology; D048051:p38 Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors / Q000502:physiology
chemical_list: D017077:Culture Media, Conditioned; D007093:Imidazoles; D009363:Neoplasm Proteins; D015676:Osteonectin; D020033:Protein Isoforms; D011725:Pyridines; D011993:Recombinant Fusion Proteins; C496348:FGFR1 protein, human; D051496:Receptor, Fibroblast Growth Factor, Type 1; D048051:p38 Mitogen-Activated Protein Kinases; C093642:SB 203580