title: Epithelial to Stromal Re-Distribution of Primary Cilia during Pancreatic Carcinogenesis.
abstract: BACKGROUND
  The Hedgehog (HH) pathway is a mediator in pancreatic ductal adenocarcinoma (PDAC). Surprisingly, previous studies suggested that primary cilia (PC), the essential organelles for HH signal transduction, were lost in PDAC. The aim of this study was to determine the presence of PC in human normal pancreas, chronic pancreatitis, and during carcinogenesis to PDAC with focus on both epithelia and stroma.
  
  
  METHODS
  PC were analyzed in paraffin sections from normal pancreas, chronic pancreatitis, intraductal papillary-mucinous neoplasia, and PDAC, as well as in primary human pancreatic stellate cells (PSC) and pancreatic cancer cell lines by double immunofluorescence staining for acetylated α-tubuline and γ-tubuline. Co-staining for the HH receptors PTCH1, PTCH2 and SMO was also performed.
  
  
  RESULTS
  PC are gradually lost during pancreatic carcinogenesis in the epithelium: the fraction of cells with PC gradually and significantly decreased from 32% in ducts of normal pancreas, to 21% in ducts of chronic pancreatitis, to 18% in PanIN1a, 6% in PanIN2, 3% in PanIN3 and to 1.2% in invasive PDAC. However, this loss of PC in the neoplastic epithelium is accompanied by a gain of PC in the surrounding stroma. The fraction of stromal cells with PC significantly increased from 13% around normal ducts to about 30% around PanIN and PDAC. HH-receptors were detected in tumor stroma but not in epithelial cells. PC are also present in PSC and pancreatic cancer cell lines.
  
  
  CONCLUSIONS
  PC are not lost during pancreatic carcinogenesis but re-distributed from the epithelium to the stroma. This redistribution may explain the re-direction of HH signaling towards the stroma during pancreatic carcinogenesis.
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors: Simon
authors: S
authors: Schimmack
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors: Sarah
authors: S
authors: Kneller
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors: Nigora
authors: N
authors: Dadabaeva
authors: Institute of Pathology Heidelberg, Im Neuenheimer Feld 224, 69120 Heidelberg, Germany.
authors: Frank
authors: F
authors: Bergmann
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors: Andrew
authors: A
authors: Taylor
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors: Thilo
authors: T
authors: Hackert
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.|University Hospital of General, Visceral, Transplantation, Vascular and Thoracic Surgery of Munich, Campus Großhadern, Marchioninistraße 15, 81377 Munich, Germany.
authors: Jens
authors: J
authors: Werner
authors: Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, Im Neuenheimer Feld 110, 69120 Heidelberg, Germany.
authors: Oliver
authors: O
authors: Strobel
mesh_terms: D021441:Carcinoma, Pancreatic Ductal / Q000378:metabolism / Q000473:pathology*; D002478:Cells, Cultured; D002923:Cilia / Q000378:metabolism*; D018450:Disease Progression; D004847:Epithelial Cells / Q000166:cytology / Q000378:metabolism*; D053823:Hedgehog Proteins / Q000378:metabolism; D006801:Humans; D008856:Microscopy, Fluorescence; D060787:Neoplasm Grading; D010179:Pancreas / Q000378:metabolism / Q000473:pathology; D058954:Pancreatic Stellate Cells / Q000166:cytology / Q000378:metabolism; D050500:Pancreatitis, Chronic / Q000378:metabolism / Q000473:pathology; D000072081:Patched-1 Receptor / Q000378:metabolism; D015398:Signal Transduction; D000072086:Smoothened Receptor / Q000378:metabolism; D017154:Stromal Cells / Q000166:cytology / Q000378:metabolism*
chemical_list: D053823:Hedgehog Proteins; C000606236:PTCH1 protein, human; D000072081:Patched-1 Receptor; D000072086:Smoothened Receptor